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1. Determination of the frequency and distribution of APC, PIK3CA, and SMAD4 gene mutations in Ugandan patients with colorectal cancer

Author: Richard Wismayer, Rosie Matthews, Celina Whalley, Julius Kiwanuka, Fredrick Elishama Kakembo, Steve Thorn, Henry Wabinga, Michael Odida, and Ian Tomlinson
Subjects: APC, PIK3CA, SMAD4, Variants, Mutation, Colorectal cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Uganda is a developing low-income country with a low incidence of colorectal cancer, which is steadily increasing. Ugandan colorectal cancer (CRC) patients are young and present with advanced-stage disease. In our population, there is a scarcity of genetic oncological studies, therefore, we investigated the mutational status of CRC tissues, focusing in particular on the adenomatous polyposis coli (APC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and SMAD4 genes. Our objective was to determine whether there were any differences between other populations and Ugandan patients. We performed next-generation sequencing on the extracted DNA from formalin-fixed paraffin-embedded adenocarcinoma samples from 127 patients (mean (SD) age: 54.9 (16.0) years; male:female sex ratio: 1.2:1). Most tumours were located in the rectum 56 (44.1%), 14 (11%) tumours were high grade, and 96 (75.6%) were moderate grade CRC. Stage III + IV CRC tumours were found in 109 (85.8%) patients. We identified 48 variants of APC, including 9 novel APC mutations that were all pathogenic or deleterious. For PIK3CA, we found 19 variants, of which 9 were deleterious or pathogenic. Four PIK3CA novel pathogenic or deleterious variants were included (c.1397C > G, c.2399_2400insA, c.2621G > C, c.2632C > G). Three SMAD4 variants were reported, including two pathogenic or deleterious variants (c.1268G > T, c.556dupC) and one tolerant (c.563A > C) variant. One novel SMAD4 deleterious mutation (c.1268G > T) was reported. In conclusion, we provide clinicopathological information and new genetic variation data pertinent to CRC in Uganda.
Published: 2024
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2. Single-cell AI-based detection and prognostic and predictive value of DNA mismatch repair deficiency in colorectal cancer

Author: Marta Nowak, Faiz Jabbar, Ann-Katrin Rodewald, Luciana Gneo, Tijana Tomasevic, Andrea Harkin, Tim Iveson, Mark Saunders, Rachel Kerr, Karin Oein, Noori Maka, Jennifer Hay, Joanne Edwards, Ian Tomlinson, Owen Sansom, Caroline Kelly, Francesco Pezzella, David Kerr, Alistair Easton, Enric Domingo, Viktor H. Koelzer, David N. Church, Bengt Glimelius, Ismail Gogenur, Emma Jaeger, Hannah Morgan, Clare Orange, Claire Palles, and Campbell Roxburgh
Subjects: colorectal cancer, mismatch repair deficiency, microsatellite instability, AI, digital pathology, Medicine (General), R5-920
Abstract: Summary: Testing for DNA mismatch repair deficiency (MMRd) is recommended for all colorectal cancers (CRCs). Automating this would enable precision medicine, particularly if providing information on etiology not captured by deep learning (DL) methods. We present AIMMeR, an AI-based method for determination of mismatch repair (MMR) protein expression at a single-cell level in routine pathology samples. AIMMeR shows an area under the receiver-operator curve (AUROC) of 0.98, and specificity of ≥75% at 98% sensitivity against pathologist ground truth in stage II/III in two trial cohorts, with positive predictive value of ≥98% for the commonest pattern of somatic MMRd. Lower agreement with microsatellite instability (MSI) testing (AUROC 0.86) reflects discordance between MMR and MSI PCR rather than AIMMeR misclassification. Analysis of the SCOT trial confirms MMRd prognostic value in oxaliplatin-treated patients; while MMRd does not predict differential benefit of chemotherapy duration, it correlates with difference in relapse by regimen (PInteraction = 0.04). AIMMeR may help reduce pathologist workload and streamline diagnostics in CRC.
Published: 2024
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3. Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Author: Zhishan Chen, Xingyi Guo, Ran Tao, Jeroen R. Huyghe, Philip J. Law, Ceres Fernandez-Rozadilla, Jie Ping, Guochong Jia, Jirong Long, Chao Li, Quanhu Shen, Yuhan Xie, Maria N. Timofeeva, Minta Thomas, Stephanie L. Schmit, Virginia Díez-Obrero, Matthew Devall, Ferran Moratalla-Navarro, Juan Fernandez-Tajes, Claire Palles, Kitty Sherwood, Sarah E. W. Briggs, Victoria Svinti, Kevin Donnelly, Susan M. Farrington, James Blackmur, Peter G. Vaughan-Shaw, Xiao-Ou Shu, Yingchang Lu, Peter Broderick, James Studd, Tabitha A. Harrison, David V. Conti, Fredrick R. Schumacher, Marilena Melas, Gad Rennert, Mireia Obón-Santacana, Vicente Martín-Sánchez, Jae Hwan Oh, Jeongseon Kim, Sun Ha Jee, Keum Ji Jung, Sun-Seog Kweon, Min-Ho Shin, Aesun Shin, Yoon-Ok Ahn, Dong-Hyun Kim, Isao Oze, Wanqing Wen, Keitaro Matsuo, Koichi Matsuda, Chizu Tanikawa, Zefang Ren, Yu-Tang Gao, Wei-Hua Jia, John L. Hopper, Mark A. Jenkins, Aung Ko Win, Rish K. Pai, Jane C. Figueiredo, Robert W. Haile, Steven Gallinger, Michael O. Woods, Polly A. Newcomb, David Duggan, Jeremy P. Cheadle, Richard Kaplan, Rachel Kerr, David Kerr, Iva Kirac, Jan Böhm, Jukka-Pekka Mecklin, Pekka Jousilahti, Paul Knekt, Lauri A. Aaltonen, Harri Rissanen, Eero Pukkala, Johan G. Eriksson, Tatiana Cajuso, Ulrika Hänninen, Johanna Kondelin, Kimmo Palin, Tomas Tanskanen, Laura Renkonen-Sinisalo, Satu Männistö, Demetrius Albanes, Stephanie J. Weinstein, Edward Ruiz-Narvaez, Julie R. Palmer, Daniel D. Buchanan, Elizabeth A. Platz, Kala Visvanathan, Cornelia M. Ulrich, Erin Siegel, Stefanie Brezina, Andrea Gsur, Peter T. Campbell, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Martha L. Slattery, John D. Potter, Kostas K. Tsilidis, Matthias B. Schulze, Marc J. Gunter, Neil Murphy, Antoni Castells, Sergi Castellví-Bel, Leticia Moreira, Volker Arndt, Anna Shcherbina, D. Timothy Bishop, Graham G. Giles, Melissa C. Southey, Gregory E. Idos, Kevin J. McDonnell, Zomoroda Abu-Ful, Joel K. Greenson, Katerina Shulman, Flavio Lejbkowicz, Kenneth Offit, Yu-Ru Su, Robert Steinfelder, Temitope O. Keku, Bethany van Guelpen, Thomas J. Hudson, Heather Hampel, Rachel Pearlman, Sonja I. Berndt, Richard B. Hayes, Marie Elena Martinez, Sushma S. Thomas, Paul D. P. Pharoah, Susanna C. Larsson, Yun Yen, Heinz-Josef Lenz, Emily White, Li Li, Kimberly F. Doheny, Elizabeth Pugh, Tameka Shelford, Andrew T. Chan, Marcia Cruz-Correa, Annika Lindblom, David J. Hunter, Amit D. Joshi, Clemens Schafmayer, Peter C. Scacheri, Anshul Kundaje, Robert E. Schoen, Jochen Hampe, Zsofia K. Stadler, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Christopher K. Edlund, W. James Gauderman, David Shibata, Amanda Toland, Sanford Markowitz, Andre Kim, Stephen J. Chanock, Franzel van Duijnhoven, Edith J. M. Feskens, Lori C. Sakoda, Manuela Gago-Dominguez, Alicja Wolk, Barbara Pardini, Liesel M. FitzGerald, Soo Chin Lee, Shuji Ogino, Stephanie A. Bien, Charles Kooperberg, Christopher I. Li, Yi Lin, Ross Prentice, Conghui Qu, Stéphane Bézieau, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Loic Le Marchand, Anna H. Wu, Chenxu Qu, Caroline E. McNeil, Gerhard Coetzee, Caroline Hayward, Ian J. Deary, Sarah E. Harris, Evropi Theodoratou, Stuart Reid, Marion Walker, Li Yin Ooi, Ken S. Lau, Hongyu Zhao, Li Hsu, Qiuyin Cai, Malcolm G. Dunlop, Stephen B. Gruber, Richard S. Houlston, Victor Moreno, Graham Casey, Ulrike Peters, Ian Tomlinson, and Wei Zheng
Subjects: Science
Abstract: Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
Published: 2024
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4. JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors

Author: Kathryn A. F. Pennel, Phimmada Hatthakarnkul, Colin S. Wood, Guang-Yu Lian, Sara S. F. Al-Badran, Jean A. Quinn, Assya Legrini, Jitwadee Inthagard, Peter G. Alexander, Hester van Wyk, Ahmad Kurniawan, Umar Hashmi, Michael A. Gillespie, Megan Mills, Aula Ammar, Jennifer Hay, Ditte Andersen, Colin Nixon, Selma Rebus, David K. Chang, Caroline Kelly, Andrea Harkin, Janet Graham, David Church, Ian Tomlinson, Mark Saunders, Tim Iveson, Tamsin R. M. Lannagan, Rene Jackstadt, Noori Maka, Paul G. Horgan, Campbell S. D. Roxburgh, Owen J. Sansom, Donald C. McMillan, Colin W. Steele, Nigel B. Jamieson, James H. Park, Antonia K. Roseweir, and Joanne Edwards
Subjects: Colorectal cancer, Cellular signaling, JAK/STAT3 signal transduction, Tumor microenvironment, Prognosis, Spatial biology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSPhigh) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSPhigh group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression.
Published: 2024
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5. Identification and validation of a machine learning model of complete response to radiation in rectal cancer reveals immune infiltrate and TGFβ as key predictorsResearch in context

Author: Enric Domingo, Sanjay Rathee, Andrew Blake, Leslie Samuel, Graeme Murray, David Sebag-Montefiore, Simon Gollins, Nicholas West, Rubina Begum, Susan Richman, Phil Quirke, Keara Redmond, Aikaterini Chatzipli, Alessandro Barberis, Sylvana Hassanieh, Umair Mahmood, Michael Youdell, Ultan McDermott, Viktor Koelzer, Simon Leedham, Ian Tomlinson, Philip Dunne, Francesca M. Buffa, Timothy S. Maughan, Francesca Buffa, Geoffrey Higgins, Christopher Holmes, Timothy Maughan, Gillies McKenna, James Robineau, Philip Quirke, Matthew Seymour, Richard Kennedy, Mark Lawler, Manuel Salto-Tellez, Peter Campbell, Claire Hardy, Simon Bach, Andrew Beggs, Jean-Baptiste Cazier, Gary Middleton, Dion Morton, Celina Whalley, Louise Brown, Richard Kaplan, Richard Wilson, Richard Adams, Richard Sullivan, Paul Harkin, Steven Walker, Jim Hill, Chieh-Hsi Wu, and Dennis Horgan
Subjects: Rectal neoplasms, Radiotherapy, Precision medicine, Prediction, TGFβ, Immune response, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: It is uncertain which biological features underpin the response of rectal cancer (RC) to radiotherapy. No biomarker is currently in clinical use to select patients for treatment modifications. Methods: We identified two cohorts of patients (total N = 249) with RC treated with neoadjuvant radiotherapy (45Gy/25) plus fluoropyrimidine. This discovery set included 57 cases with pathological complete response (pCR) to chemoradiotherapy (23%). Pre-treatment cancer biopsies were assessed using transcriptome-wide mRNA expression and targeted DNA sequencing for copy number and driver mutations. Biological candidate and machine learning (ML) approaches were used to identify predictors of pCR to radiotherapy independent of tumour stage. Findings were assessed in 107 cases from an independent validation set (GSE87211). Findings: Three gene expression sets showed significant independent associations with pCR: Fibroblast-TGFβ Response Signature (F-TBRS) with radioresistance; and cytotoxic lymphocyte (CL) expression signature and consensus molecular subtype CMS1 with radiosensitivity. These associations were replicated in the validation cohort. In parallel, a gradient boosting machine model comprising the expression of 33 genes generated in the discovery cohort showed high performance in GSE87211 with 90% sensitivity, 86% specificity. Biological and ML signatures indicated similar mechanisms underlying radiation response, and showed better AUC and p-values than published transcriptomic signatures of radiation response in RC. Interpretation: RCs responding completely to chemoradiotherapy (CRT) have biological characteristics of immune response and absence of immune inhibitory TGFβ signalling. These tumours may be identified with a potential biomarker based on a 33 gene expression signature. This could help select patients likely to respond to treatment with a primary radiotherapy approach as for anal cancer. Conversely, those with predicted radioresistance may be candidates for clinical trials evaluating addition of immune-oncology agents and stromal TGFβ signalling inhibition. Funding: The Stratification in Colorectal Cancer Consortium (S:CORT) was funded by the Medical Research Council and Cancer Research UK (MR/M016587/1).
Published: 2024
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6. Intra-prostatic tumour evolution, steps in metastatic spread and histogenomic associations revealed by integration of multi-region whole-genome sequencing with histopathological features

Author: Srinivasa Rao, Clare Verrill, Lucia Cerundolo, Nasullah Khalid Alham, Zeynep Kaya, Miriam O’Hanlon, Alicia Hayes, Adam Lambert, Martha James, Iain D. C. Tullis, Jane Niederer, Shelagh Lovell, Altan Omer, Francisco Lopez, Tom Leslie, Francesca Buffa, Richard J. Bryant, Alastair D. Lamb, Boris Vojnovic, David C. Wedge, Ian G. Mills, Dan J. Woodcock, Ian Tomlinson, and Freddie C. Hamdy
Subjects: Prostate cancer, Cancer evolution, Histopathology, Prostate cancer metastasis, Intra-tumour heterogeneity, Spatial genomic analysis, Medicine, Genetics, QH426-470
Abstract: Abstract Background Extension of prostate cancer beyond the primary site by local invasion or nodal metastasis is associated with poor prognosis. Despite significant research on tumour evolution in prostate cancer metastasis, the emergence and evolution of cancer clones at this early stage of expansion and spread are poorly understood. We aimed to delineate the routes of evolution and cancer spread within the prostate and to seminal vesicles and lymph nodes, linking these to histological features that are used in diagnostic risk stratification. Methods We performed whole-genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and lymph nodes of five treatment-naive patients with locally advanced disease. We spatially mapped the clonal composition of cancer across the prostate and the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes in each individual by analysing a total of > 19,000 copy number corrected single nucleotide variants. Results In each patient, we identified sample locations corresponding to the earliest part of the malignancy. In patient 10, we mapped the spread of cancer from the apex of the prostate to the seminal vesicles and identified specific genomic changes associated with the transformation of adenocarcinoma to amphicrine morphology during this spread. Furthermore, we show that the lymph node metastases in this patient arose from specific cancer clones found at the base of the prostate and the seminal vesicles. In patient 15, we observed increased mutational burden, altered mutational signatures and histological changes associated with whole genome duplication. In all patients in whom histological heterogeneity was observed (4/5), we found that the distinct morphologies were located on separate branches of their respective evolutionary trees. Conclusions Our results link histological transformation with specific genomic alterations and phylogenetic branching. These findings have implications for diagnosis and risk stratification, in addition to providing a rationale for further studies to characterise the genetic changes causally linked to morphological transformation. Our study demonstrates the value of integrating multi-region sequencing with histopathological data to understand tumour evolution and identify mechanisms of prostate cancer spread.
Published: 2024
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7. Adult stem cell activity in naked mole rats for long-term tissue maintenance

Author: Shamir Montazid, Sheila Bandyopadhyay, Daniel W. Hart, Nan Gao, Brian Johnson, Sri G. Thrumurthy, Dustin J. Penn, Bettina Wernisch, Mukesh Bansal, Philipp M. Altrock, Fabian Rost, Patrycja Gazinska, Piotr Ziolkowski, Bu’Hussain Hayee, Yue Liu, Jiangmeng Han, Annamaria Tessitore, Jana Koth, Walter F. Bodmer, James E. East, Nigel C. Bennett, Ian Tomlinson, and Shazia Irshad
Subjects: Science
Abstract: Abstract The naked mole rat (NMR), Heterocephalus glaber, the longest-living rodent, provides a unique opportunity to explore how evolution has shaped adult stem cell (ASC) activity and tissue function with increasing lifespan. Using cumulative BrdU labelling and a quantitative imaging approach to track intestinal ASCs (Lgr5 + ) in their native in vivo state, we find an expanded pool of Lgr5 + cells in NMRs, and these cells specifically at the crypt base (Lgr5 +CBC ) exhibit slower division rates compared to those in short-lived mice but have a similar turnover as human LGR5 +CBC cells. Instead of entering quiescence (G0), NMR Lgr5 +CBC cells reduce their division rates by prolonging arrest in the G1 and/or G2 phases of the cell cycle. Moreover, we also observe a higher proportion of differentiated cells in NMRs that confer enhanced protection and function to the intestinal mucosa which is able to detect any chemical imbalance in the luminal environment efficiently, triggering a robust pro-apoptotic, anti-proliferative response within the stem/progenitor cell zone.
Published: 2023
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8. Accounting for intensity variation in image analysis of large‐scale multiplexed clinical trial datasets

Author: Anja L Frei, Anthony McGuigan, Ritik RAK Sinha, Mark A Glaire, Faiz Jabbar, Luciana Gneo, Tijana Tomasevic, Andrea Harkin, Tim J Iveson, Mark Saunders, Karin Oein, Noori Maka, Francesco Pezella, Leticia Campo, Jennifer Hay, Joanne Edwards, Owen J Sansom, Caroline Kelly, Ian Tomlinson, Wanja Kildal, Rachel S Kerr, David J Kerr, Håvard E Danielsen, Enric Domingo, TransSCOT Consortium, David N Church, and Viktor H Koelzer
Subjects: digital pathology, fluorescence microscopy, image analysis, Pathology, RB1-214
Abstract: Abstract Multiplex immunofluorescence (mIF) imaging can provide comprehensive quantitative and spatial information for multiple immune markers for tumour immunoprofiling. However, application at scale to clinical trial samples sourced from multiple institutions is challenging due to pre‐analytical heterogeneity. This study reports an analytical approach to the largest multi‐parameter immunoprofiling study of clinical trial samples to date. We analysed 12,592 tissue microarray (TMA) spots from 3,545 colorectal cancers sourced from more than 240 institutions in two clinical trials (QUASAR 2 and SCOT) stained for CD4, CD8, CD20, CD68, FoxP3, pan‐cytokeratin, and DAPI by mIF. TMA slides were multi‐spectrally imaged and analysed by cell‐based and pixel‐based marker analysis. We developed an adaptive thresholding method to account for inter‐ and intra‐slide intensity variation in TMA analysis. Applying this method effectively ameliorated inter‐ and intra‐slide intensity variation improving the image analysis results compared with methods using a single global threshold. Correlation of CD8 data derived by our mIF analysis approach with single‐plex chromogenic immunohistochemistry CD8 data derived from subsequent sections indicates the validity of our method (Spearman's rank correlation coefficients ρ between 0.63 and 0.66, p ≪ 0.01) as compared with the current gold standard analysis approach. Evaluation of correlation between cell‐based and pixel‐based analysis results confirms equivalency (ρ > 0.8, p ≪ 0.01, except for CD20 in the epithelial region) of both analytical approaches. These data suggest that our adaptive thresholding approach can enable analysis of mIF‐stained clinical trial TMA datasets by digital pathology at scale for precision immunoprofiling.
Published: 2023
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9. Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer‐specific survival

Author: Anna Morra, Maartje A. C. Schreurs, Irene L. Andrulis, Hoda Anton‐Culver, Annelie Augustinsson, Matthias W. Beckmann, Sabine Behrens, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Annegien Broeks, Saundra S. Buys, Nicola J. Camp, Jose E. Castelao, Melissa H. Cessna, Jenny Chang‐Claude, Wendy K. Chung, NBCS Collaborators, Sarah V. Colonna, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Peter Devilee, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Douglas F. Easton, Diana M. Eccles, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Tanja N. Fehm, Jonine D. Figueroa, Henrik Flyger, Marike Gabrielson, Manuela Gago‐Dominguez, Montserrat García‐Closas, José A. García‐Sáenz, Jeanine Genkinger, Felix Grassmann, Melanie Gündert, Eric Hahnen, Christopher A. Haiman, Ute Hamann, Patricia A. Harrington, Jaana M. Hartikainen, Reiner Hoppe, John L. Hopper, Richard S. Houlston, Anthony Howell, ABCTB Investigators, kConFab Investigators, Anna Jakubowska, Wolfgang Janni, Helena Jernström, Esther M. John, Nichola Johnson, Michael E. Jones, Vessela N. Kristensen, Allison W. Kurian, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Jan Lubiński, Michael P. Lux, Arto Mannermaa, Dimitrios Mavroudis, Anna Marie Mulligan, Taru A. Muranen, Heli Nevanlinna, Ines Nevelsteen, Patrick Neven, William G. Newman, Nadia Obi, Kenneth Offit, Andrew F. Olshan, Tjoung‐Won Park‐Simon, Alpa V. Patel, Paolo Peterlongo, Kelly‐Anne Phillips, Dijana Plaseska‐Karanfilska, Eric C. Polley, Nadege Presneau, Katri Pylkäs, Brigitte Rack, Paolo Radice, Muhammad U. Rashid, Valerie Rhenius, Mark Robson, Atocha Romero, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Sabine Schuetze, Christopher Scott, Mitul Shah, Snezhana Smichkoska, Melissa C. Southey, William J. Tapper, Lauren R. Teras, Rob A. E. M. Tollenaar, Katarzyna Tomczyk, Ian Tomlinson, Melissa A. Troester, Celine M. Vachon, Elke M. vanVeen, Qin Wang, Camilla Wendt, Hans Wildiers, Robert Winqvist, Argyrios Ziogas, Per Hall, Paul D. P. Pharoah, Muriel A. Adank, Antoinette Hollestelle, Marjanka K. Schmidt, and Maartje J. Hooning
Subjects: CHEK2 c.1100delC germline genetic variant, contralateral breast cancer risk, radiotherapy, survival, systemic treatment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.
Published: 2023
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10. Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair

Author: Kitty Sherwood, Joseph C. Ward, Ignacio Soriano, Lynn Martin, Archie Campbell, Raheleh Rahbari, Ioannis Kafetzopoulos, Duncan Sproul, Andrew Green, Julian R. Sampson, Alan Donaldson, Kai-Ren Ong, Karl Heinimann, Maartje Nielsen, Huw Thomas, Andrew Latchford, Claire Palles, and Ian Tomlinson
Subjects: Science
Abstract: Abstract DNA repair defects underlie many cancer syndromes. We tested whether de novo germline mutations (DNMs) are increased in families with germline defects in polymerase proofreading or base excision repair. A parent with a single germline POLE or POLD1 mutation, or biallelic MUTYH mutations, had 3-4 fold increased DNMs over sex-matched controls. POLE had the largest effect. The DNMs carried mutational signatures of the appropriate DNA repair deficiency. No DNM increase occurred in offspring of MUTYH heterozygous parents. Parental DNA repair defects caused about 20–150 DNMs per child, additional to the ~60 found in controls, but almost all extra DNMs occurred in non-coding regions. No increase in post-zygotic mutations was detected, excepting a child with bi-allelic MUTYH mutations who was excluded from the main analysis; she had received chemotherapy and may have undergone oligoclonal haematopoiesis. Inherited DNA repair defects associated with base pair-level mutations increase DNMs, but phenotypic consequences appear unlikely.
Published: 2023
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11. Functional analysis reveals driver cooperativity and novel mechanisms in endometrial carcinogenesis

Author: Matthew Brown, Alicia Leon, Katarzyna Kedzierska, Charlotte Moore, Hayley L Belnoue‐Davis, Susanne Flach, John P Lydon, Francesco J DeMayo, Annabelle Lewis, Tjalling Bosse, Ian Tomlinson, and David N Church
Subjects: Driver genes, Endometrial cancer, Fbxw7, Functional models, GEMM, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract High‐risk endometrial cancer has poor prognosis and is increasing in incidence. However, understanding of the molecular mechanisms which drive this disease is limited. We used genetically engineered mouse models (GEMM) to determine the functional consequences of missense and loss of function mutations in Fbxw7, Pten and Tp53, which collectively occur in nearly 90% of high‐risk endometrial cancers. We show that Trp53 deletion and missense mutation cause different phenotypes, with the latter a substantially stronger driver of endometrial carcinogenesis. We also show that Fbxw7 missense mutation does not cause endometrial neoplasia on its own, but potently accelerates carcinogenesis caused by Pten loss or Trp53 missense mutation. By transcriptomic analysis, we identify LEF1 signalling as upregulated in Fbxw7/FBXW7‐mutant mouse and human endometrial cancers, and in human isogenic cell lines carrying FBXW7 mutation, and validate LEF1 and the additional Wnt pathway effector TCF7L2 as novel FBXW7 substrates. Our study provides new insights into the biology of high‐risk endometrial cancer and suggests that targeting LEF1 may be worthy of investigation in this treatment‐resistant cancer subgroup.
Published: 2023
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12. Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels

Author: Xuemin Wang, Pik Fang Kho, Dhanya Ramachandran, Cemsel Bafligil, Frederic Amant, Ellen L. Goode, Rodney J. Scott, Ian Tomlinson, D. Gareth Evans, Emma J. Crosbie, Thilo Dörk, Amanda B. Spurdle, Dylan M. Glubb, and Tracy A. O'Mara
Subjects: Bioinformatics, Systems biology, Cancer, Genomics, Science
Abstract: Summary: To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression of CYP3A7, a gene involved in testosterone metabolism. Thus, our findings suggest opportunities for hormone therapy to prevent or treat endometrial cancer.
Published: 2023
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13. Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Author: Leila Dorling, Sara Carvalho, Jamie Allen, Michael T. Parsons, Cristina Fortuno, Anna González-Neira, Stephan M. Heijl, Muriel A. Adank, Thomas U. Ahearn, Irene L. Andrulis, Päivi Auvinen, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Marina Bermisheva, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Michael Bremer, Ignacio Briceno, Nicola J. Camp, Archie Campbell, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, NBCS Collaborators, J. Margriet Collée, Kamila Czene, Joe Dennis, Thilo Dörk, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, Marike Gabrielson, Manuela Gago-Dominguez, Montserrat García-Closas, Graham G. Giles, Gord Glendon, Pascal Guénel, Melanie Gündert, Andreas Hadjisavvas, Eric Hahnen, Per Hall, Ute Hamann, Elaine F. Harkness, Mikael Hartman, Frans B. L. Hogervorst, Antoinette Hollestelle, Reiner Hoppe, Anthony Howell, kConFab Investigators, SGBCC Investigators, Anna Jakubowska, Audrey Jung, Elza Khusnutdinova, Sung-Won Kim, Yon-Dschun Ko, Vessela N. Kristensen, Inge M. M. Lakeman, Jingmei Li, Annika Lindblom, Maria A. Loizidou, Artitaya Lophatananon, Jan Lubiński, Craig Luccarini, Michael J. Madsen, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Dimitrios Mavroudis, Roger L. Milne, Nur Aishah Mohd Taib, Kenneth Muir, Heli Nevanlinna, William G. Newman, Jan C. Oosterwijk, Sue K. Park, Paolo Peterlongo, Paolo Radice, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Mitul Shah, Xueling Sim, Melissa C. Southey, Harald Surowy, Maija Suvanto, Ian Tomlinson, Diana Torres, Thérèse Truong, Christi J. van Asperen, Regina Waltes, Qin Wang, Xiaohong R. Yang, Paul D. P. Pharoah, Marjanka K. Schmidt, Javier Benitez, Bas Vroling, Alison M. Dunning, Soo Hwang Teo, Anders Kvist, Miguel de la Hoya, Peter Devilee, Amanda B. Spurdle, Maaike P. G. Vreeswijk, and Douglas F. Easton
Subjects: Breast cancer, Genetic epidemiology, Risk prediction, Missense variants, Medicine, Genetics, QH426-470
Abstract: Abstract Background Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47–2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
Published: 2022
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14. Rare germline copy number variants (CNVs) and breast cancer risk

Author: Joe Dennis, Jonathan P. Tyrer, Logan C. Walker, Kyriaki Michailidou, Leila Dorling, Manjeet K. Bolla, Qin Wang, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Laura E. Beane Freeman, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Natalia V. Bogdanova, Stig E. Bojesen, Hermann Brenner, Jose E. Castelao, Jenny Chang-Claude, Georgia Chenevix-Trench, Christine L. Clarke, NBCS Collaborators, J. Margriet Collée, CTS Consortium, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Peter Devilee, Thilo Dörk, Laure Dossus, A. Heather Eliassen, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Olivia Fletcher, Henrik Flyger, Lin Fritschi, Marike Gabrielson, Manuela Gago-Dominguez, Montserrat García-Closas, Graham G. Giles, Anna González-Neira, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Per Hall, Antoinette Hollestelle, Reiner Hoppe, John L. Hopper, Anthony Howell, ABCTB Investigators, kConFab/AOCS Investigators, Agnes Jager, Anna Jakubowska, Esther M. John, Nichola Johnson, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Renske Keeman, Elza Khusnutdinova, Cari M. Kitahara, Yon-Dschun Ko, Veli-Matti Kosma, Stella Koutros, Peter Kraft, Vessela N. Kristensen, Katerina Kubelka-Sabit, Allison W. Kurian, James V. Lacey, Diether Lambrechts, Nicole L. Larson, Martha Linet, Alicja Ogrodniczak, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, Dimitrios Mavroudis, Roger L. Milne, Taru A. Muranen, Rachel A. Murphy, Heli Nevanlinna, Janet E. Olson, Håkan Olsson, Tjoung-Won Park-Simon, Charles M. Perou, Paolo Peterlongo, Dijana Plaseska-Karanfilska, Katri Pylkäs, Gad Rennert, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Rana Shibli, Ann Smeets, Penny Soucy, Melissa C. Southey, Anthony J. Swerdlow, Rulla M. Tamimi, Jack A. Taylor, Lauren R. Teras, Mary Beth Terry, Ian Tomlinson, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Camilla Wendt, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Wei Zheng, Argyrios Ziogas, Jacques Simard, Alison M. Dunning, Paul D. P. Pharoah, and Douglas F. Easton
Subjects: Biology (General), QH301-705.5
Abstract: Dennis et al. investigate potential breast cancer associations with rare germline copy number variants (CNVs) by conducting a genome-wide analysis in a large breast cancer case-control dataset. The authors detected associations with exonic deletions in established breast cancer susceptibility genes and suggestive associations for a number of non-coding CNVs.
Published: 2022
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15. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author: Maria Escala-Garcia, Sander Canisius, Renske Keeman, Jonathan Beesley, Hoda Anton-Culver, Volker Arndt, Annelie Augustinsson, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Marina Bermisheva, Stig E. Bojesen, Manjeet K. Bolla, Hermann Brenner, Federico Canzian, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Fergus J. Couch, Kamila Czene, Mary B. Daly, Joe Dennis, Peter Devilee, Thilo Dörk, Alison M. Dunning, Douglas F. Easton, Arif B. Ekici, A. Heather Eliassen, Peter A. Fasching, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, José A. García-Sáenz, Jürgen Geisler, Graham G. Giles, Mervi Grip, Melanie Gündert, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Jaana M. Hartikainen, Bernadette A. M. Heemskerk-Gerritsen, Antoinette Hollestelle, Reiner Hoppe, John L. Hopper, David J. Hunter, William Jacot, Anna Jakubowska, Esther M. John, Audrey Y. Jung, Rudolf Kaaks, Elza Khusnutdinova, Linetta B. Koppert, Peter Kraft, Vessela N. Kristensen, Allison W. Kurian, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Robert N. Luben, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Dimitrios Mavroudis, Taru A. Muranen, Heli Nevanlinna, Andrew F. Olshan, Håkan Olsson, Tjoung-Won Park-Simon, Alpa V. Patel, Paolo Peterlongo, Paul D. P. Pharoah, Kevin Punie, Paolo Radice, Gad Rennert, Hedy S. Rennert, Atocha Romero, Rebecca Roylance, Thomas Rüdiger, Matthias Ruebner, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Minouk J. Schoemaker, Christopher Scott, Melissa C. Southey, Harald Surowy, Anthony J. Swerdlow, Rulla M. Tamimi, Lauren R. Teras, Emilie Thomas, Ian Tomlinson, Melissa A. Troester, Celine M. Vachon, Qin Wang, Robert Winqvist, Alicja Wolk, Argyrios Ziogas, kConFab/AOCS Investigators, Kyriaki Michailidou, Georgia Chenevix-Trench, Thomas Bachelot, and Marjanka K. Schmidt
Subjects: Medicine, Science
Abstract: Abstract Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.
Published: 2021
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16. Author Correction: Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair

Author: Kitty Sherwood, Joseph C. Ward, Ignacio Soriano, Lynn Martin, Archie Campbell, Raheleh Rahbari, Ioannis Kafetzopoulos, Duncan Sproul, Andrew Green, Julian R. Sampson, Alan Donaldson, Kai-Ren Ong, Karl Heinimann, Maartje Nielsen, Huw Thomas, Andrew Latchford, Claire Palles, and Ian Tomlinson
Subjects: Science
Published: 2023
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17. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author: Anna Morra, Maria Escala-Garcia, Jonathan Beesley, Renske Keeman, Sander Canisius, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Paul L. Auer, Annelie Augustinsson, Laura E. Beane Freeman, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Stig E. Bojesen, Manjeet K. Bolla, Hermann Brenner, Thomas Brüning, Saundra S. Buys, Bette Caan, Daniele Campa, Federico Canzian, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Ting-Yuan David Cheng, Christine L. Clarke, NBCS Collaborators, Sarah V. Colonna, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Thilo Dörk, Laure Dossus, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Lin Fritschi, Manuela Gago-Dominguez, José A. García-Sáenz, Graham G. Giles, Mervi Grip, Pascal Guénel, Melanie Gündert, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Steven N. Hart, Jaana M. Hartikainen, Arndt Hartmann, Wei He, Maartje J. Hooning, Reiner Hoppe, John L. Hopper, Anthony Howell, David J. Hunter, ABCTB Investigators, kConFab Investigators, Agnes Jager, Anna Jakubowska, Wolfgang Janni, Esther M. John, Audrey Y. Jung, Rudolf Kaaks, Machteld Keupers, Cari M. Kitahara, Stella Koutros, Peter Kraft, Vessela N. Kristensen, Allison W. Kurian, James V. Lacey, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Martha Linet, Robert N. Luben, Jan Lubiński, Michael Lush, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, John W. M. Martens, Maria Elena Martinez, Dimitrios Mavroudis, Kyriaki Michailidou, Roger L. Milne, Anna Marie Mulligan, Taru A. Muranen, Heli Nevanlinna, William G. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Andrew F. Olshan, Håkan Olsson, Nick Orr, Tjoung-Won Park-Simon, Alpa V. Patel, Bernard Peissel, Paolo Peterlongo, Dijana Plaseska-Karanfilska, Karolina Prajzendanc, Ross Prentice, Nadege Presneau, Brigitte Rack, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Rebecca Roylance, Matthias Ruebner, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Andreas Schneeweiss, Christopher Scott, Mitul Shah, Snezhana Smichkoska, Melissa C. Southey, Jennifer Stone, Harald Surowy, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Lauren R. Teras, Mary Beth Terry, Rob A. E. M. Tollenaar, Ian Tomlinson, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Qin Wang, Amber N. Hurson, Robert Winqvist, Alicja Wolk, Argyrios Ziogas, Hiltrud Brauch, Montserrat García-Closas, Paul D. P. Pharoah, Douglas F. Easton, Georgia Chenevix-Trench, and Marjanka K. Schmidt
Subjects: Common germline genetic variants, Breast cancer-specific survival, Patient subgroups, Tumor biology, Systemic treatment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP
Published: 2021
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18. Genetic mapping of novel modifiers for Apc Min induced intestinal polyps’ development using the genetic architecture power of the collaborative cross mice

Author: Alexandra Dorman, Ilona Binenbaum, Hanifa J. Abu-Toamih Atamni, Aristotelis Chatziioannou, Ian Tomlinson, Richard Mott, and Fuad A. Iraqi
Subjects: Apc Min, Colorectal cancer, Collaborative cross, Familial adenomatous polyposis, Genetic modifier, Moms, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract: Abstract Background Familial adenomatous polyposis is an inherited genetic disease, characterized by colorectal polyps. It is caused by inactivating mutations in the Adenomatous polyposis coli (Apc) gene. Mice carrying a nonsense mutation in the Apc gene at R850, which is designated Apc Min/+ (Multiple intestinal neoplasia), develop intestinal adenomas. Several genetic modifier loci of Min (Mom) were previously mapped, but so far, most of the underlying genes have not been identified. To identify novel modifier loci associated with Apc Min/+ , we performed quantitative trait loci (QTL) analysis for polyp development using 49 F1 crosses between different Collaborative Cross (CC) lines and C57BL/6 J-Apc Min/+ mice. The CC population is a genetic reference panel of recombinant inbred lines, each line independently descended from eight genetically diverse founder strains. C57BL/6 J-Apc Min/+ males were mated with females from 49 CC lines. F1 offspring were terminated at 23 weeks and polyp counts from three sub-regions (SB1–3) of small intestinal and colon were recorded. Results The number of polyps in all these sub-regions and colon varied significantly between the different CC lines. At 95% genome-wide significance, we mapped nine novel QTL for variation in polyp number, with distinct QTL associated with each intestinal sub-region. QTL confidence intervals varied in width between 2.63–17.79 Mb. We extracted all genes in the mapped QTL at 90 and 95% CI levels using the BioInfoMiner online platform to extract, significantly enriched pathways and key linker genes, that act as regulatory and orchestrators of the phenotypic landscape associated with the Apc Min/+ mutation. Conclusions Genomic structure of the CC lines has allowed us to identify novel modifiers and confirmed some of the previously mapped modifiers. Key genes involved mainly in metabolic and immunological processes were identified. Future steps in this analysis will be to identify regulatory elements – and possible epistatic effects – located in the mapped QTL.
Published: 2021
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19. Histological phenotypic subtypes predict recurrence risk and response to adjuvant chemotherapy in patients with stage III colorectal cancer

Author: Antonia K Roseweir, James H Park, Sanne ten Hoorn, Arfon GMT Powell, Susan Aherne, Campbell SD Roxburgh, Donald C McMillan, Paul G Horgan, Elizabeth Ryan, Kieran Sheahan, Louis Vermeulen, James Paul, Andrea Harkin, Janet Graham, Owen Sansom, David N Church, Ian Tomlinson, Mark Saunders, Tim J Iveson, and Joanne Edwards
Subjects: colorectal cancer, subtyping, histopathology, adjuvant treatment, recurrence, precision medicine, Pathology, RB1-214
Abstract: Abstract Histological ‘phenotypic subtypes’ that classify patients into four groups (immune, canonical, latent and stromal) have previously been demonstrated to stratify survival in a stage I–III colorectal cancer (CRC) pilot cohort. However, clinical utility has not yet been validated. Therefore, this study assessed prognostic value of these subtypes in additional patient cohorts along with associations with risk of recurrence and response to chemotherapy. Two independent stage I–III CRC patient cohorts (internal and external cohort) were utilised to investigate phenotypic subtypes. The primary endpoint was disease‐free survival (DFS) and the secondary endpoint was recurrence risk (RR). Stage II–III patients, from the SCOT adjuvant chemotherapy trial, were utilised to further validate prognostic value and for exploratory analysis assessing associations with adjuvant chemotherapy. In an 893‐patient internal cohort, phenotypic subtype independently associated with DFS (p = 0.025) and this was attenuated in stage III patients (p = 0.020). Phenotypic subtype also independently associated with RR (p
Published: 2020
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20. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author: Yan Dora Zhang, Amber N. Hurson, Haoyu Zhang, Parichoy Pal Choudhury, Douglas F. Easton, Roger L. Milne, Jacques Simard, Per Hall, Kyriaki Michailidou, Joe Dennis, Marjanka K. Schmidt, Jenny Chang-Claude, Puya Gharahkhani, David Whiteman, Peter T. Campbell, Michael Hoffmeister, Mark Jenkins, Ulrike Peters, Li Hsu, Stephen B. Gruber, Graham Casey, Stephanie L. Schmit, Tracy A. O’Mara, Amanda B. Spurdle, Deborah J. Thompson, Ian Tomlinson, Immaculata De Vivo, Maria Teresa Landi, Matthew H. Law, Mark M. Iles, Florence Demenais, Rajiv Kumar, Stuart MacGregor, D. Timothy Bishop, Sarah V. Ward, Melissa L. Bondy, Richard Houlston, John K. Wiencke, Beatrice Melin, Jill Barnholtz-Sloan, Ben Kinnersley, Margaret R. Wrensch, Christopher I. Amos, Rayjean J. Hung, Paul Brennan, James McKay, Neil E. Caporaso, Sonja I. Berndt, Brenda M. Birmann, Nicola J. Camp, Peter Kraft, Nathaniel Rothman, Susan L. Slager, Andrew Berchuck, Paul D. P. Pharoah, Thomas A. Sellers, Simon A. Gayther, Celeste L. Pearce, Ellen L. Goode, Joellen M. Schildkraut, Kirsten B. Moysich, Laufey T. Amundadottir, Eric J. Jacobs, Alison P. Klein, Gloria M. Petersen, Harvey A. Risch, Rachel Z. Stolzenberg-Solomon, Brian M. Wolpin, Donghui Li, Rosalind A. Eeles, Christopher A. Haiman, Zsofia Kote-Jarai, Fredrick R. Schumacher, Ali Amin Al Olama, Mark P. Purdue, Ghislaine Scelo, Marlene D. Dalgaard, Mark H. Greene, Tom Grotmol, Peter A. Kanetsky, Katherine A. McGlynn, Katherine L. Nathanson, Clare Turnbull, Fredrik Wiklund, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), Renal Cancer GWAS, Testicular Cancer Consortium (TECAC), Stephen J. Chanock, Nilanjan Chatterjee, and Montserrat Garcia-Closas
Subjects: Science
Abstract: In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.
Published: 2020
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21. A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

Author: Maria Escala-Garcia, Jean Abraham, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Alan Ashworth, Paul L. Auer, Päivi Auvinen, Matthias W. Beckmann, Jonathan Beesley, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, William Blot, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Anne-Lise Børresen-Dale, Hiltrud Brauch, Hermann Brenner, Sara Y. Brucker, Barbara Burwinkel, Carlos Caldas, Federico Canzian, Jenny Chang-Claude, Stephen J. Chanock, Suet-Feung Chin, Christine L. Clarke, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Peter Devilee, Janet A. Dunn, Alison M. Dunning, Miriam Dwek, Helena M. Earl, Diana M. Eccles, A. Heather Eliassen, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Susan M. Gapstur, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Angela George, Graham G. Giles, David E. Goldgar, Anna González-Neira, Mervi Grip, Pascal Guénel, Qi Guo, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Patricia A. Harrington, Louise Hiller, Maartje J. Hooning, John L. Hopper, Anthony Howell, Chiun-Sheng Huang, Guanmengqian Huang, David J. Hunter, Anna Jakubowska, Esther M. John, Rudolf Kaaks, Pooja Middha Kapoor, Renske Keeman, Cari M. Kitahara, Linetta B. Koppert, Peter Kraft, Vessela N. Kristensen, Diether Lambrechts, Loic Le Marchand, Flavio Lejbkowicz, Annika Lindblom, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Tabea Maurer, Dimitrios Mavroudis, Alfons Meindl, Roger L. Milne, Anna Marie Mulligan, Susan L. Neuhausen, Heli Nevanlinna, William G. Newman, Andrew F. Olshan, Janet E. Olson, Håkan Olsson, Nick Orr, Paolo Peterlongo, Christos Petridis, Ross L. Prentice, Nadege Presneau, Kevin Punie, Dhanya Ramachandran, Gad Rennert, Atocha Romero, Mythily Sachchithananthan, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Lukas Schwentner, Christopher Scott, Jacques Simard, Christof Sohn, Melissa C. Southey, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Manuel R. Teixeira, Mary Beth Terry, Heather Thorne, Rob A. E. M. Tollenaar, Ian Tomlinson, Melissa A. Troester, Thérèse Truong, Clare Turnbull, Celine M. Vachon, Lizet E. van der Kolk, Qin Wang, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Argyrios Ziogas, Paul D. P. Pharoah, Per Hall, Lodewyk F. A. Wessels, Georgia Chenevix-Trench, Gary D. Bader, Thilo Dörk, Douglas F. Easton, Sander Canisius, and Marjanka K. Schmidt
Subjects: Science
Abstract: In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.
Published: 2020
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22. Expression of the cancer-associated DNA polymerase ε P286R in fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication.

Author: Ignacio Soriano, Enrique Vazquez, Nagore De Leon, Sibyl Bertrand, Ellen Heitzer, Sophia Toumazou, Zhihan Bo, Claire Palles, Chen-Chun Pai, Timothy C Humphrey, Ian Tomlinson, Sue Cotterill, and Stephen E Kearsey
Subjects: Genetics, QH426-470
Abstract: Somatic and germline mutations in the proofreading domain of the replicative DNA polymerase ε (POLE-exonuclease domain mutations, POLE-EDMs) are frequently found in colorectal and endometrial cancers and, occasionally, in other tumours. POLE-associated cancers typically display hypermutation, and a unique mutational signature, with a predominance of C > A transversions in the context TCT and C > T transitions in the context TCG. To understand better the contribution of hypermutagenesis to tumour development, we have modelled the most recurrent POLE-EDM (POLE-P286R) in Schizosaccharomyces pombe. Whole-genome sequencing analysis revealed that the corresponding pol2-P287R allele also has a strong mutator effect in vivo, with a high frequency of base substitutions and relatively few indel mutations. The mutations are equally distributed across different genomic regions, but in the immediate vicinity there is an asymmetry in AT frequency. The most abundant base-pair changes are TCT > TAT transversions and, in contrast to human mutations, TCG > TTG transitions are not elevated, likely due to the absence of cytosine methylation in fission yeast. The pol2-P287R variant has an increased sensitivity to elevated dNTP levels and DNA damaging agents, and shows reduced viability on depletion of the Pfh1 helicase. In addition, S phase is aberrant and RPA foci are elevated, suggestive of ssDNA or DNA damage, and the pol2-P287R mutation is synthetically lethal with rad3 inactivation, indicative of checkpoint activation. Significantly, deletion of genes encoding some translesion synthesis polymerases, most notably Pol κ, partially suppresses pol2-P287R hypermutation, indicating that polymerase switching contributes to this phenotype.
Published: 2021
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23. Frequency of pathogenic germline variants in BRCA1, BRCA2, PALB2, CHEK2 and TP53 in ductal carcinoma in situ diagnosed in women under the age of 50 years

Author: Christos Petridis, Iteeka Arora, Vandna Shah, Anargyros Megalios, Charlotte Moss, Anca Mera, Angela Clifford, Cheryl Gillett, Sarah E. Pinder, Ian Tomlinson, Rebecca Roylance, Michael A. Simpson, and Elinor J. Sawyer
Subjects: Germline variants, BRCA2, CHEK2, PALB2, BRCA1, TP53, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Introduction Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal breast cancer, and approximately 20% of screen-detected tumours are pure DCIS. Most risk factors for breast cancer have similar associations with DCIS and IDC; however, there is limited data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in DCIS and which women with DCIS should be referred for genetic screening. The aim of this study was to assess the frequency of germline variants in BRCA2, BRCA1, CHEK2, PALB2 and TP53 in DCIS in women aged less than 50 years of age. Methods After DNA extraction from the peripheral blood, Access Array technology (Fluidigm) was used to amplify all exons of these five known breast cancer predisposition genes using a custom made targeted sequencing panel in 655 cases of pure DCIS presenting in women under the age of 50 years together with 1611 controls. Results Case-control analysis revealed an excess of pathogenic variants in BRCA2 (OR = 27.96, 95%CI 6.56–119.26, P = 2.0 × 10−10) and CHEK2 (OR = 8.04, 95%CI 2.93–22.05, P = 9.0 × 10−6), with weaker associations with PALB2 (P = 0.003), BRCA1 (P = 0.007) and TP53 (P = 0.02). For oestrogen receptor (ER)-positive DCIS the frequency of pathogenic variants was 9% under the age of 50 (14% with a family history of breast cancer) and 29% under the age of 40 (42% with a family history of breast cancer). For ER-negative DCIS, the frequency was 9% (16% with a family history of breast cancer) and 8% (11% with a family history of breast cancer) under the ages of 50 and 40, respectively. Conclusions This study has shown that breast tumourigenesis in women with pathogenic variants in BRCA2, CHEK2, PALB2, BRCA1 and TP53 can involve a DCIS precursor stage and that the focus of genetic testing in DCIS should be on women under the age of 40 with ER-positive DCIS.
Published: 2019
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24. Association analyses identify 31 new risk loci for colorectal cancer susceptibility

Author: Philip J. Law, Maria Timofeeva, Ceres Fernandez-Rozadilla, Peter Broderick, James Studd, Juan Fernandez-Tajes, Susan Farrington, Victoria Svinti, Claire Palles, Giulia Orlando, Amit Sud, Amy Holroyd, Steven Penegar, Evropi Theodoratou, Peter Vaughan-Shaw, Harry Campbell, Lina Zgaga, Caroline Hayward, Archie Campbell, Sarah Harris, Ian J. Deary, John Starr, Laura Gatcombe, Maria Pinna, Sarah Briggs, Lynn Martin, Emma Jaeger, Archana Sharma-Oates, James East, Simon Leedham, Roland Arnold, Elaine Johnstone, Haitao Wang, David Kerr, Rachel Kerr, Tim Maughan, Richard Kaplan, Nada Al-Tassan, Kimmo Palin, Ulrika A. Hänninen, Tatiana Cajuso, Tomas Tanskanen, Johanna Kondelin, Eevi Kaasinen, Antti-Pekka Sarin, Johan G. Eriksson, Harri Rissanen, Paul Knekt, Eero Pukkala, Pekka Jousilahti, Veikko Salomaa, Samuli Ripatti, Aarno Palotie, Laura Renkonen-Sinisalo, Anna Lepistö, Jan Böhm, Jukka-Pekka Mecklin, Daniel D. Buchanan, Aung-Ko Win, John Hopper, Mark E. Jenkins, Noralane M. Lindor, Polly A. Newcomb, Steven Gallinger, David Duggan, Graham Casey, Per Hoffmann, Markus M. Nöthen, Karl-Heinz Jöckel, Douglas F. Easton, Paul D. P. Pharoah, Julian Peto, Federico Canzian, Anthony Swerdlow, Rosalind A. Eeles, Zsofia Kote-Jarai, Kenneth Muir, Nora Pashayan, The PRACTICAL consortium, Andrea Harkin, Karen Allan, John McQueen, James Paul, Timothy Iveson, Mark Saunders, Katja Butterbach, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Iva Kirac, Petar Matošević, Philipp Hofer, Stefanie Brezina, Andrea Gsur, Jeremy P. Cheadle, Lauri A. Aaltonen, Ian Tomlinson, Richard S. Houlston, and Malcolm G. Dunlop
Subjects: Science
Abstract: In colorectal cancer (CRC), finding loci associated with risk may give insight into disease aetiology. Here, the authors report a genome-wide association analysis in Europeans of 34,627 CRC cases and 71,379 controls, and find 31 new risk loci and 17 new risk SNPs at previously reported loci.
Published: 2019
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25. Representative Sequencing: Unbiased Sampling of Solid Tumor Tissue

Author: Kevin Litchfield, Stacey Stanislaw, Lavinia Spain, Lisa L. Gallegos, Andrew Rowan, Desiree Schnidrig, Heidi Rosenbaum, Alexandre Harle, Lewis Au, Samantha M. Hill, Zayd Tippu, Jennifer Thomas, Lisa Thompson, Hang Xu, Stuart Horswell, Aoune Barhoumi, Carol Jones, Katherine F. Leith, Daniel L. Burgess, Thomas B.K. Watkins, Emilia Lim, Nicolai J. Birkbak, Philippe Lamy, Iver Nordentoft, Lars Dyrskjøt, Lisa Pickering, Stephen Hazell, Mariam Jamal-Hanjani, James Larkin, Charles Swanton, Nelson R. Alexander, Samra Turajlic, Chris Abbosh, Kai-Keen Shiu, John Bridgewater, Daniel Hochhauser, Martin Forster, Siow-Ming Lee, Tanya Ahmad, Dionysis Papadatos-Pastos, Sam Janes, Peter Van Loo, Katey Enfield, Nicholas McGranahan, Ariana Huebner, Sergio Quezada, Stephan Beck, Peter Parker, Henning Walczak, Tariq Enver, Rob Hynds, Mary Falzon, Ian Proctor, Ron Sinclair, Chi-wah Lok, Zoe Rhodes, David Moore, Teresa Marafioti, Elaine Borg, Miriam Mitchison, Reena Khiroya, Giorgia Trevisan, Peter Ellery, Mark Linch, Sebastian Brandner, Crispin Hiley, Selvaraju Veeriah, Maryam Razaq, Heather Shaw, Gert Attard, Mita Afroza Akther, Cristina Naceur-Lombardelli, Lizi Manzano, Maise Al-Bakir, Simranpreet Summan, Nnenna Kanu, Sophie Ward, Uzma Asghar, Faye Gishen, Adrian Tookman, Paddy Stone, Caroline Stirling, Andrew Furness, Kim Edmonds, Nikki Hunter, Sarah Sarker, Sarah Vaughan, Mary Mangwende, Karla Pearce, Scott Shepherd, Haixi Yan, Ben Shum, Eleanor Carlyle, Steve Hazell, Annika Fendler, Fiona Byrne, Nadia Yousaf, Sanjay Popat, Olivia Curtis, Gordon Stamp, Antonia Toncheva, Emma Nye, Aida Murra, Justine Korteweg, Nahid Sheikh, Debra Josephs, Ashish Chandra, James Spicer, Ula Mahadeva, Anna Green, Ruby Stewart, Lara-Rose Iredale, Tina Mackay, Ben Deakin, Debra Enting, Sarah Rudman, Sharmistha Ghosh, Lena Karapagniotou, Elias Pintus, Andrew Tutt, Sarah Howlett, Vasiliki Michalarea, James Brenton, Carlos Caldas, Rebecca Fitzgerald, Merche Jimenez-Linan, Elena Provenzano, Alison Cluroe, Grant Stewart, Colin Watts, Richard Gilbertson, Ultan McDermott, Simon Tavare, Emma Beddowes, Patricia Roxburgh, Andrew Biankin, Anthony Chalmers, Sioban Fraser, Karin Oien, Andrew Kidd, Kevin Blyth, Matt Krebs, Fiona Blackhall, Yvonne Summers, Caroline Dive, Richard Marais, Fabio Gomes, Mat Carter, Jo Dransfield, John Le Quesne, Dean Fennell, Jacqui Shaw, Babu Naidu, Shobhit Baijal, Bruce Tanchel, Gerald Langman, Andrew Robinson, Martin Collard, Peter Cockcroft, Charlotte Ferris, Hollie Bancroft, Amy Kerr, Gary Middleton, Joanne Webb, Salma Kadiri, Peter Colloby, Bernard Olisemeke, Rodelaine Wilson, Ian Tomlinson, Sanjay Jogai, Christian Ottensmeier, David Harrison, Massimo Loda, Adrienne Flanagan, Mairead McKenzie, Allan Hackshaw, Jonathan Ledermann, Abby Sharp, Laura Farrelly, and Hayley Bridger
Subjects: tumor sampling, tumor sequencing, representative sampling, molecular profiling, tumor hetereogeneity, biomarkers, Biology (General), QH301-705.5
Abstract: Summary: Although thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias is inherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g., 6 mm biopsy), which becomes grossly under-powered as tumor volume scales. Here, we demonstrate representative sequencing (Rep-Seq) as a new method to achieve unbiased tumor tissue sampling. Rep-Seq uses fixed residual tumor material, which is homogenized and subjected to next-generation sequencing. Analysis of intratumor tumor mutation burden (TMB) variability shows a high level of misclassification using current single-biopsy methods, with 20% of lung and 52% of bladder tumors having at least one biopsy with high TMB but low clonal TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure.
Published: 2020
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26. Identification of nine new susceptibility loci for endometrial cancer

Author: Tracy A. O’Mara, Dylan M. Glubb, Frederic Amant, Daniela Annibali, Katie Ashton, John Attia, Paul L. Auer, Matthias W. Beckmann, Amanda Black, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, Louise Brinton, Daniel D. Buchanan, Barbara Burwinkel, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, Maxine M. Chen, Timothy H. T. Cheng, Christine L. Clarke, Mark Clendenning, Linda S. Cook, Fergus J. Couch, Angela Cox, Marta Crous-Bous, Kamila Czene, Felix Day, Joe Dennis, Jeroen Depreeuw, Jennifer Anne Doherty, Thilo Dörk, Sean C. Dowdy, Matthias Dürst, Arif B. Ekici, Peter A. Fasching, Brooke L. Fridley, Christine M. Friedenreich, Lin Fritschi, Jenny Fung, Montserrat García-Closas, Mia M. Gaudet, Graham G. Giles, Ellen L. Goode, Maggie Gorman, Christopher A. Haiman, Per Hall, Susan E. Hankison, Catherine S. Healey, Alexander Hein, Peter Hillemanns, Shirley Hodgson, Erling A. Hoivik, Elizabeth G. Holliday, John L. Hopper, David J. Hunter, Angela Jones, Camilla Krakstad, Vessela N. Kristensen, Diether Lambrechts, Loic Le Marchand, Xiaolin Liang, Annika Lindblom, Jolanta Lissowska, Jirong Long, Lingeng Lu, Anthony M. Magliocco, Lynn Martin, Mark McEvoy, Alfons Meindl, Kyriaki Michailidou, Roger L. Milne, Miriam Mints, Grant W. Montgomery, Rami Nassir, Håkan Olsson, Irene Orlow, Geoffrey Otton, Claire Palles, John R. B. Perry, Julian Peto, Loreall Pooler, Jennifer Prescott, Tony Proietto, Timothy R. Rebbeck, Harvey A. Risch, Peter A. W. Rogers, Matthias Rübner, Ingo Runnebaum, Carlotta Sacerdote, Gloria E. Sarto, Fredrick Schumacher, Rodney J. Scott, V. Wendy Setiawan, Mitul Shah, Xin Sheng, Xiao-Ou Shu, Melissa C. Southey, Anthony J. Swerdlow, Emma Tham, Jone Trovik, Constance Turman, Jonathan P. Tyrer, Celine Vachon, David VanDen Berg, Adriaan Vanderstichele, Zhaoming Wang, Penelope M. Webb, Nicolas Wentzensen, Henrica M. J. Werner, Stacey J. Winham, Alicja Wolk, Lucy Xia, Yong-Bing Xiang, Hannah P. Yang, Herbert Yu, Wei Zheng, Paul D. P. Pharoah, Alison M. Dunning, Peter Kraft, Immaculata De Vivo, Ian Tomlinson, Douglas F. Easton, Amanda B. Spurdle, and Deborah J. Thompson
Subjects: Science
Abstract: Endometrial cancer is the most common invasive gynaecological cancer in developed countries. Here a meta-analysis identifies an additional nine novel endometrial cancer risk loci and eQTL analysis reveals risk variants associate with reduced expression of negative regulators of oncogenic signal transduction proteins.
Published: 2018
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27. Genetic overlap between endometriosis and endometrial cancer: evidence from cross‐disease genetic correlation and GWAS meta‐analyses

Author: Jodie N. Painter, Tracy A. O'Mara, Andrew P. Morris, Timothy H. T. Cheng, Maggie Gorman, Lynn Martin, Shirley Hodson, Angela Jones, Nicholas G. Martin, Scott Gordon, Anjali K. Henders, John Attia, Mark McEvoy, Elizabeth G. Holliday, Rodney J. Scott, Penelope M. Webb, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Matthias Rübner, Per Hall, Kamila Czene, Thilo Dörk, Matthias Dürst, Peter Hillemanns, Ingo Runnebaum, Diether Lambrechts, Frederic Amant, Daniela Annibali, Jeroen Depreeuw, Adriaan Vanderstichele, Ellen L. Goode, Julie M. Cunningham, Sean C. Dowdy, Stacey J. Winham, Jone Trovik, Erling Hoivik, Henrica M. J. Werner, Camilla Krakstad, Katie Ashton, Geoffrey Otton, Tony Proietto, Emma Tham, Miriam Mints, Shahana Ahmed, Catherine S. Healey, Mitul Shah, Paul D. P. Pharoah, Alison M. Dunning, Joe Dennis, Manjeet K. Bolla, Kyriaki Michailidou, Qin Wang, Jonathan P. Tyrer, John L. Hopper, Julian Peto, Anthony J. Swerdlow, Barbara Burwinkel, Hermann Brenner, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Jenny Chang‐Claude, Fergus J. Couch, Graham G. Giles, Vessela N. Kristensen, Angela Cox, Krina T. Zondervan, Dale R. Nyholt, Stuart MacGregor, Grant W. Montgomery, Ian Tomlinson, Douglas F. Easton, Deborah J. Thompson, and Amanda B. Spurdle
Subjects: Cross‐disease analysis, endometrial cancer, endometriosis, genome‐wide association study, genetic correlation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg = 0.23, P = 9.3 × 10−3), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10−3) and concordance in effect direction (P = 2.0 × 10−3) between the two diseases. Cross‐disease GWAS meta‐analysis highlighted 13 distinct loci associated at P ≤ 10−5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10−8, OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross‐disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.
Published: 2018
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28. Robust RNA-based in situ mutation detection delineates colorectal cancer subclonal evolution

Author: Ann-Marie Baker, Weini Huang, Xiao-Ming Mindy Wang, Marnix Jansen, Xiao-Jun Ma, Jeffrey Kim, Courtney M. Anderson, Xingyong Wu, Liuliu Pan, Nan Su, Yuling Luo, Enric Domingo, Timon Heide, Andrea Sottoriva, Annabelle Lewis, Andrew D. Beggs, Nicholas A. Wright, Manuel Rodriguez-Justo, Emily Park, Ian Tomlinson, and Trevor A. Graham
Subjects: Science
Abstract: Methods that analyze intra-tumor genetic heterogeneity often do not preserve the spatial context of tumor subclones. Here, the authors present BaseScope, a mutation-specific RNA in situ hybridization assay and spatially map colorectal cancer and adenoma KRAS, BRAF and PIK3CA driver gene mutant subclones.
Published: 2017
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29. Multilevel genomics of colorectal cancers with microsatellite instability—clinical impact of JAK1 mutations and consensus molecular subtype 1

Author: Anita Sveen, Bjarne Johannessen, Torstein Tengs, Stine A. Danielsen, Ina A. Eilertsen, Guro E. Lind, Kaja C. G. Berg, Edward Leithe, Leonardo A. Meza-Zepeda, Enric Domingo, Ola Myklebost, David Kerr, Ian Tomlinson, Arild Nesbakken, Rolf I. Skotheim, and Ragnhild A. Lothe
Subjects: Colorectal cancer, Consensus molecular subtypes, Immunogenicity, Immunotherapy resistance, JAK1, Microsatellite instability, Medicine, Genetics, QH426-470
Abstract: Abstract Background Approximately 15% of primary colorectal cancers have DNA mismatch repair deficiency, causing a complex genome with thousands of small mutations—the microsatellite instability (MSI) phenotype. We investigated molecular heterogeneity and tumor immunogenicity in relation to clinical endpoints within this distinct subtype of colorectal cancers. Methods A total of 333 primary MSI+ colorectal tumors from multiple cohorts were analyzed by multilevel genomics and computational modeling—including mutation profiling, clonality modeling, and neoantigen prediction in a subset of the tumors, as well as gene expression profiling for consensus molecular subtypes (CMS) and immune cell infiltration. Results Novel, frequent frameshift mutations in four cancer-critical genes were identified by deep exome sequencing, including in CRTC1, BCL9, JAK1, and PTCH1. JAK1 loss-of-function mutations were validated with an overall frequency of 20% in Norwegian and British patients, and mutated tumors had up-regulation of transcriptional signatures associated with resistance to anti-PD-1 treatment. Clonality analyses revealed a high level of intra-tumor heterogeneity; however, this was not associated with disease progression. Among the MSI+ tumors, the total mutation load correlated with the number of predicted neoantigens (P = 4 × 10−5), but not with immune cell infiltration—this was dependent on the CMS class; MSI+ tumors in CMS1 were highly immunogenic compared to MSI+ tumors in CMS2-4. Both JAK1 mutations and CMS1 were favorable prognostic factors (hazard ratios 0.2 [0.05–0.9] and 0.4 [0.2–0.9], respectively, P = 0.03 and 0.02). Conclusions Multilevel genomic analyses of MSI+ colorectal cancer revealed molecular heterogeneity with clinical relevance, including tumor immunogenicity and a favorable patient outcome associated with JAK1 mutations and the transcriptomic subgroup CMS1, emphasizing the potential for prognostic stratification of this clinically important subtype. See related research highlight by Samstein and Chan 10.1186/s13073-017-0438-9
Published: 2017
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30. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus

Author: Kate Lawrenson, Siddhartha Kar, Karen McCue, Karoline Kuchenbaeker, Kyriaki Michailidou, Jonathan Tyrer, Jonathan Beesley, Susan J. Ramus, Qiyuan Li, Melissa K. Delgado, Janet M. Lee, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Banu K. Arun, Brita Arver, Elisa V. Bandera, Monica Barile, Rosa B. Barkardottir, Daniel Barrowdale, Matthias W. Beckmann, Javier Benitez, Andrew Berchuck, Maria Bisogna, Line Bjorge, Carl Blomqvist, William Blot, Natalia Bogdanova, Anders Bojesen, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Fiona Bruinsma, Joan Brunet, Shaik Ahmad Buhari, Barbara Burwinkel, Ralf Butzow, Saundra S. Buys, Qiuyin Cai, Trinidad Caldes, Ian Campbell, Rikki Canniotto, Jenny Chang-Claude, Jocelyne Chiquette, Ji-Yeob Choi, Kathleen B. M. Claes, GEMO Study Collaborators, Linda S. Cook, Angela Cox, Daniel W. Cramer, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Francesca Damiola, Agnieszka Dansonka-Mieszkowska, Hatef Darabi, Joe Dennis, Peter Devilee, Orland Diez, Jennifer A. Doherty, Susan M. Domchek, Cecilia M. Dorfling, Thilo Dörk, Martine Dumont, Hans Ehrencrona, Bent Ejlertsen, Steve Ellis, EMBRACE, Christoph Engel, Eunjung Lee, D. Gareth Evans, Peter A. Fasching, Lidia Feliubadalo, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Lenka Foretova, Florentia Fostira, William D. Foulkes, Brooke L. Fridley, Eitan Friedman, Debra Frost, Gaetana Gambino, Patricia A. Ganz, Judy Garber, Montserrat García-Closas, Aleksandra Gentry-Maharaj, Maya Ghoussaini, Graham G. Giles, Rosalind Glasspool, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Ellen L. Goode, Marc T. Goodman, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Emily Hallberg, Ute Hamann, Thomas V. O. Hansen, Patricia A. Harrington, Mikael Hartman, Norhashimah Hassan, Sue Healey, The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Florian Heitz, Josef Herzog, Estrid Høgdall, Claus K. Høgdall, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Peter J. Hulick, Tomasz Huzarski, Evgeny N. Imyanitov, KConFab Investigators, Australian Ovarian Cancer Study Group, Claudine Isaacs, Hidemi Ito, Anna Jakubowska, Ramunas Janavicius, Allan Jensen, Esther M. John, Nichola Johnson, Maria Kabisch, Daehee Kang, Miroslav Kapuscinski, Beth Y. Karlan, Sofia Khan, Lambertus A. Kiemeney, Susanne Kruger Kjaer, Julia A. Knight, Irene Konstantopoulou, Veli-Matti Kosma, Vessela Kristensen, Jolanta Kupryjanczyk, Ava Kwong, Miguel de la Hoya, Yael Laitman, Diether Lambrechts, Nhu Le, Kim De Leeneer, Jenny Lester, Douglas A. Levine, Jingmei Li, Annika Lindblom, Jirong Long, Artitaya Lophatananon, Jennifer T. Loud, Karen Lu, Jan Lubinski, Arto Mannermaa, Siranoush Manoukian, Loic Le Marchand, Sara Margolin, Frederik Marme, Leon F. A. G. Massuger, Keitaro Matsuo, Sylvie Mazoyer, Lesley McGuffog, Catriona McLean, Iain McNeish, Alfons Meindl, Usha Menon, Arjen R. Mensenkamp, Roger L. Milne, Marco Montagna, Kirsten B. Moysich, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, Roberta B. Ness, Susan L. Neuhausen, Heli Nevanlinna, Silje Nord, Robert L. Nussbaum, Kunle Odunsi, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Janet E. Olson, Curtis Olswold, David O’Malley, Irene Orlow, Nick Orr, Ana Osorio, Sue Kyung Park, Celeste L. Pearce, Tanja Pejovic, Paolo Peterlongo, Georg Pfeiler, Catherine M. Phelan, Elizabeth M. Poole, Katri Pylkäs, Paolo Radice, Johanna Rantala, Muhammad Usman Rashid, Gad Rennert, Valerie Rhenius, Kerstin Rhiem, Harvey A. Risch, Gus Rodriguez, Mary Anne Rossing, Anja Rudolph, Helga B. Salvesen, Suleeporn Sangrajrang, Elinor J. Sawyer, Joellen M. Schildkraut, Marjanka K. Schmidt, Rita K. Schmutzler, Thomas A. Sellers, Caroline Seynaeve, Mitul Shah, Chen-Yang Shen, Xiao-Ou Shu, Weiva Sieh, Christian F. Singer, Olga M. Sinilnikova, Susan Slager, Honglin Song, Penny Soucy, Melissa C. Southey, Marie Stenmark-Askmalm, Dominique Stoppa-Lyonnet, Christian Sutter, Anthony Swerdlow, Sandrine Tchatchou, Manuel R. Teixeira, Soo H. Teo, Kathryn L. Terry, Mary Beth Terry, Mads Thomassen, Maria Grazia Tibiletti, Laima Tihomirova, Silvia Tognazzo, Amanda Ewart Toland, Ian Tomlinson, Diana Torres, Thérèse Truong, Chiu-chen Tseng, Nadine Tung, Shelley S. Tworoger, Celine Vachon, Ans M. W. van den Ouweland, Helena C. van Doorn, Elizabeth J. van Rensburg, Laura J. Van't Veer, Adriaan Vanderstichele, Ignace Vergote, Joseph Vijai, Qin Wang, Shan Wang-Gohrke, Jeffrey N. Weitzel, Nicolas Wentzensen, Alice S. Whittemore, Hans Wildiers, Robert Winqvist, Anna H. Wu, Drakoulis Yannoukakos, Sook-Yee Yoon, Jyh-Cherng Yu, Wei Zheng, Ying Zheng, Kum Kum Khanna, Jacques Simard, Alvaro N. Monteiro, Juliet D. French, Fergus J. Couch, Matthew L. Freedman, Douglas F. Easton, Alison M. Dunning, Paul D. Pharoah, Stacey L. Edwards, Georgia Chenevix-Trench, Antonis C. Antoniou, and Simon A. Gayther
Subjects: Science
Abstract: A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.
Published: 2016
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31. Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies

Author: Karin Hellner, Fabrizio Miranda, Donatien Fotso Chedom, Sandra Herrero-Gonzalez, Daniel M. Hayden, Rick Tearle, Mara Artibani, Mohammad KaramiNejadRanjbar, Ruth Williams, Kezia Gaitskell, Samar Elorbany, Ruoyan Xu, Alex Laios, Petronela Buiga, Karim Ahmed, Sunanda Dhar, Rebecca Yu Zhang, Leticia Campo, Kevin A. Myers, María Lozano, María Ruiz-Miró, Sónia Gatius, Alba Mota, Gema Moreno-Bueno, Xavier Matias-Guiu, Javier Benítez, Lorna Witty, Gil McVean, Simon Leedham, Ian Tomlinson, Radoje Drmanac, Jean-Baptiste Cazier, Robert Klein, Kevin Dunne, Robert C. Bast Jr, Stephen H. Kennedy, Bassim Hassan, Stefano Lise, María José Garcia, Brock A. Peters, Christopher Yau, Tatjana Sauka-Spengler, and Ahmed Ashour Ahmed
Subjects: Ovarian cancer, Fallopian tube, BRCA mutations, SOX2, Screening, Precancer, Medicine, Medicine (General), R5-920
Abstract: Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE) cells. We identified frequent mutations involving a 40 kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p
Published: 2016
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32. Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer

Author: Daniel Chubb, Peter Broderick, Sara E. Dobbins, Matthew Frampton, Ben Kinnersley, Steven Penegar, Amy Price, Yussanne P. Ma, Amy L. Sherborne, Claire Palles, Maria N. Timofeeva, D. Timothy Bishop, Malcolm G. Dunlop, Ian Tomlinson, and Richard S. Houlston
Subjects: Science
Abstract: The genetic factors that predispose individuals to familial colorectal cancer are poorly understood. In this study, the authors use whole exome sequencing of 1,006 patients and 1,609 healthy controls and show it is unlikely that further major high-penetrance susceptibility genes exist.
Published: 2016
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33. Differential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy

Author: John M. Findlay, Francesc Castro-Giner, Seiko Makino, Emily Rayner, Christiana Kartsonaki, William Cross, Michal Kovac, Danny Ulahannan, Claire Palles, Richard S. Gillies, Thomas P. MacGregor, David Church, Nicholas D. Maynard, Francesca Buffa, Jean-Baptiste Cazier, Trevor A. Graham, Lai-Mun Wang, Ricky A. Sharma, Mark Middleton, and Ian Tomlinson
Subjects: Science
Abstract: Oesophageal adenocarcinoma is often treated with chemotherapy before surgery. Here, the authors sequence cancer samples before and after chemotherapy and examine how the genome changes, focusing on changes in driver gene mutations and differential clonal evolution between good and poor responders.
Published: 2016
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34. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Fergus J. Couch, Karoline B. Kuchenbaecker, Kyriaki Michailidou, Gustavo A. Mendoza-Fandino, Silje Nord, Janna Lilyquist, Curtis Olswold, Emily Hallberg, Simona Agata, Habibul Ahsan, Kristiina Aittomäki, Christine Ambrosone, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Banu K. Arun, Brita Arver, Monica Barile, Rosa B. Barkardottir, Daniel Barrowdale, Lars Beckmann, Matthias W. Beckmann, Javier Benitez, Stephanie V. Blank, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldes, Maria A. Caligo, Federico Canzian, Jane Carpenter, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Angela Cox, Simon S. Cross, Julie M. Cunningham, Kamila Czene, Mary B. Daly, Francesca Damiola, Hatef Darabi, Miguel de la Hoya, Peter Devilee, Orland Diez, Yuan C. Ding, Riccardo Dolcetti, Susan M. Domchek, Cecilia M. Dorfling, Isabel dos-Santos-Silva, Martine Dumont, Alison M. Dunning, Diana M. Eccles, Hans Ehrencrona, Arif B. Ekici, Heather Eliassen, Steve Ellis, Peter A. Fasching, Jonine Figueroa, Dieter Flesch-Janys, Asta Försti, Florentia Fostira, William D. Foulkes, Tara Friebel, Eitan Friedman, Debra Frost, Marike Gabrielson, Marilie D. Gammon, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, Mia M. Gaudet, Simon A. Gayther, Anne-Marie Gerdes, Maya Ghoussaini, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Marc Gunter, Lothar Haeberle, Christopher A. Haiman, Ute Hamann, Thomas V. O. Hansen, Steven Hart, Sue Healey, Tuomas Heikkinen, Brian E. Henderson, Josef Herzog, Frans B. L. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Keith Humphreys, David J. Hunter, Tomasz Huzarski, Evgeny N. Imyanitov, Claudine Isaacs, Anna Jakubowska, Paul James, Ramunas Janavicius, Uffe Birk Jensen, Esther M. John, Michael Jones, Maria Kabisch, Siddhartha Kar, Beth Y. Karlan, Sofia Khan, Kay-Tee Khaw, Muhammad G. Kibriya, Julia A. Knight, Yon-Dschun Ko, Irene Konstantopoulou, Veli-Matti Kosma, Vessela Kristensen, Ava Kwong, Yael Laitman, Diether Lambrechts, Conxi Lazaro, Eunjung Lee, Loic Le Marchand, Jenny Lester, Annika Lindblom, Noralane Lindor, Sara Lindstrom, Jianjun Liu, Jirong Long, Jan Lubinski, Phuong L. Mai, Enes Makalic, Kathleen E. Malone, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, Frederik Marme, John W. M. Martens, Lesley McGuffog, Alfons Meindl, Austin Miller, Roger L. Milne, Penelope Miron, Marco Montagna, Sylvie Mazoyer, Anna M. Mulligan, Taru A. Muranen, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Janet E. Olson, Ana Osorio, Sue K. Park, Petra H. Peeters, Bernard Peissel, Paolo Peterlongo, Julian Peto, Catherine M. Phelan, Robert Pilarski, Bruce Poppe, Katri Pylkäs, Paolo Radice, Nazneen Rahman, Johanna Rantala, Christine Rappaport, Gad Rennert, Andrea Richardson, Mark Robson, Isabelle Romieu, Anja Rudolph, Emiel J. Rutgers, Maria-Jose Sanchez, Regina M. Santella, Elinor J. Sawyer, Daniel F. Schmidt, Marjanka K. Schmidt, Rita K. Schmutzler, Fredrick Schumacher, Rodney Scott, Leigha Senter, Priyanka Sharma, Jacques Simard, Christian F. Singer, Olga M. Sinilnikova, Penny Soucy, Melissa Southey, Doris Steinemann, Marie Stenmark-Askmalm, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Csilla I. Szabo, Rulla Tamimi, William Tapper, Manuel R. Teixeira, Soo-Hwang Teo, Mary B. Terry, Mads Thomassen, Deborah Thompson, Laima Tihomirova, Amanda E. Toland, Robert A. E. M. Tollenaar, Ian Tomlinson, Thérèse Truong, Helen Tsimiklis, Alex Teulé, Rosario Tumino, Nadine Tung, Clare Turnbull, Giski Ursin, Carolien H. M. van Deurzen, Elizabeth J. van Rensburg, Raymonda Varon-Mateeva, Zhaoming Wang, Shan Wang-Gohrke, Elisabete Weiderpass, Jeffrey N. Weitzel, Alice Whittemore, Hans Wildiers, Robert Winqvist, Xiaohong R. Yang, Drakoulis Yannoukakos, Song Yao, M Pilar Zamora, Wei Zheng, Per Hall, Peter Kraft, Celine Vachon, Susan Slager, Georgia Chenevix-Trench, Paul D. P. Pharoah, Alvaro A. N. Monteiro, Montserrat García-Closas, Douglas F. Easton, and Antonis C. Antoniou
Subjects: Science
Abstract: Oestrogen negative breast cancer is associated with a poor prognosis. In this study, the authors perform a meta-analysis of 11 breast cancer genome-wide association studies and identify four new loci associated with oestrogen negative breast cancer risk. These findings may aid in stratifying patients in the clinic.
Published: 2016
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35. Correspondence: SEMA4A variation and risk of colorectal cancer

Author: Ben Kinnersley, Daniel Chubb, Sara E. Dobbins, Matthew Frampton, Stephan Buch, Maria N. Timofeeva, Sergi Castellví-Bel, Susan M. Farrington, Asta Forsti, Jochen Hampe, Kari Hemminki, Robert M. W. Hofstra, Emma Northwood, Claire Palles, Manuela Pinheiro, Clara Ruiz-Ponte, Clemens Schafmayer, Manuel R. Teixeira, Helga Westers, Tom van Wezel, D. Timothy Bishop, Ian Tomlinson, Malcolm G. Dunlop, and Richard S. Houlston
Subjects: Science
Published: 2016
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36. Clinical applicability and cost of a 46-gene panel for genomic analysis of solid tumours: Retrospective validation and prospective audit in the UK National Health Service.

Author: Angela Hamblin, Sarah Wordsworth, Jilles M Fermont, Suzanne Page, Kulvinder Kaur, Carme Camps, Pamela Kaisaki, Avinash Gupta, Denis Talbot, Mark Middleton, Shirley Henderson, Anthony Cutts, Dimitrios V Vavoulis, Nick Housby, Ian Tomlinson, Jenny C Taylor, and Anna Schuh
Subjects: Medicine
Abstract: BackgroundSingle gene tests to predict whether cancers respond to specific targeted therapies are performed increasingly often. Advances in sequencing technology, collectively referred to as next generation sequencing (NGS), mean the entire cancer genome or parts of it can now be sequenced at speed with increased depth and sensitivity. However, translation of NGS into routine cancer care has been slow. Healthcare stakeholders are unclear about the clinical utility of NGS and are concerned it could be an expensive addition to cancer diagnostics, rather than an affordable alternative to single gene testing.Methods and findingsWe validated a 46-gene hotspot cancer panel assay allowing multiple gene testing from small diagnostic biopsies. From 1 January 2013 to 31 December 2013, solid tumour samples (including non-small-cell lung carcinoma [NSCLC], colorectal carcinoma, and melanoma) were sequenced in the context of the UK National Health Service from 351 consecutively submitted prospective cases for which treating clinicians thought the patient had potential to benefit from more extensive genetic analysis. Following histological assessment, tumour-rich regions of formalin-fixed paraffin-embedded (FFPE) sections underwent macrodissection, DNA extraction, NGS, and analysis using a pipeline centred on Torrent Suite software. With a median turnaround time of seven working days, an integrated clinical report was produced indicating the variants detected, including those with potential diagnostic, prognostic, therapeutic, or clinical trial entry implications. Accompanying phenotypic data were collected, and a detailed cost analysis of the panel compared with single gene testing was undertaken to assess affordability for routine patient care. Panel sequencing was successful for 97% (342/351) of tumour samples in the prospective cohort and showed 100% concordance with known mutations (detected using cobas assays). At least one mutation was identified in 87% (296/342) of tumours. A locally actionable mutation (i.e., available targeted treatment or clinical trial) was identified in 122/351 patients (35%). Forty patients received targeted treatment, in 22/40 (55%) cases solely due to use of the panel. Examination of published data on the potential efficacy of targeted therapies showed theoretically actionable mutations (i.e., mutations for which targeted treatment was potentially appropriate) in 66% (71/107) and 39% (41/105) of melanoma and NSCLC patients, respectively. At a cost of £339 (US$449) per patient, the panel was less expensive locally than performing more than two or three single gene tests. Study limitations include the use of FFPE samples, which do not always provide high-quality DNA, and the use of "real world" data: submission of cases for sequencing did not always follow clinical guidelines, meaning that when mutations were detected, patients were not always eligible for targeted treatments on clinical grounds.ConclusionsThis study demonstrates that more extensive tumour sequencing can identify mutations that could improve clinical decision-making in routine cancer care, potentially improving patient outcomes, at an affordable level for healthcare providers.
Published: 2017
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37. A Polymorphic Enhancer near GREM1 Influences Bowel Cancer Risk through Differential CDX2 and TCF7L2 Binding

Author: Annabelle Lewis, Luke Freeman-Mills, Elisa de la Calle-Mustienes, Rosa María Giráldez-Pérez, Hayley Davis, Emma Jaeger, Martin Becker, Nina C. Hubner, Luan N. Nguyen, Jorge Zeron-Medina, Gareth Bond, Hendrik G. Stunnenberg, Jaime J. Carvajal, Jose Luis Gomez-Skarmeta, Simon Leedham, and Ian Tomlinson
Subjects: Biology (General), QH301-705.5
Abstract: A rare germline duplication upstream of the bone morphogenetic protein antagonist GREM1 causes a Mendelian-dominant predisposition to colorectal cancer (CRC). The underlying disease mechanism is strong, ectopic GREM1 overexpression in the intestinal epithelium. Here, we confirm that a common GREM1 polymorphism, rs16969681, is also associated with CRC susceptibility, conferring ∼20% differential risk in the general population. We hypothesized the underlying cause to be moderate differences in GREM1 expression. We showed that rs16969681 lies in a region of active chromatin with allele- and tissue-specific enhancer activity. The CRC high-risk allele was associated with stronger gene expression, and higher Grem1 mRNA levels increased the intestinal tumor burden in ApcMin mice. The intestine-specific transcription factor CDX2 and Wnt effector TCF7L2 bound near rs16969681, with significantly higher affinity for the risk allele, and CDX2 overexpression in CDX2/GREM1-negative cells caused re-expression of GREM1. rs16969681 influences CRC risk through effects on Wnt-driven GREM1 expression in colorectal tumors.
Published: 2014
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38. Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.

Author: Yan Guo, Shaneda Warren Andersen, Xiao-Ou Shu, Kyriaki Michailidou, Manjeet K Bolla, Qin Wang, Montserrat Garcia-Closas, Roger L Milne, Marjanka K Schmidt, Jenny Chang-Claude, Allison Dunning, Stig E Bojesen, Habibul Ahsan, Kristiina Aittomäki, Irene L Andrulis, Hoda Anton-Culver, Volker Arndt, Matthias W Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, Natalia V Bogdanova, Bernardo Bonanni, Anne-Lise Børresen-Dale, Judith Brand, Hiltrud Brauch, Hermann Brenner, Thomas Brüning, Barbara Burwinkel, Graham Casey, Georgia Chenevix-Trench, Fergus J Couch, Angela Cox, Simon S Cross, Kamila Czene, Peter Devilee, Thilo Dörk, Martine Dumont, Peter A Fasching, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Florentia Fostira, Marilie Gammon, Graham G Giles, Pascal Guénel, Christopher A Haiman, Ute Hamann, Maartje J Hooning, John L Hopper, Anna Jakubowska, Farzana Jasmine, Mark Jenkins, Esther M John, Nichola Johnson, Michael E Jones, Maria Kabisch, Muhammad Kibriya, Julia A Knight, Linetta B Koppert, Veli-Matti Kosma, Vessela Kristensen, Loic Le Marchand, Eunjung Lee, Jingmei Li, Annika Lindblom, Robert Luben, Jan Lubinski, Kathi E Malone, Arto Mannermaa, Sara Margolin, Frederik Marme, Catriona McLean, Hanne Meijers-Heijboer, Alfons Meindl, Susan L Neuhausen, Heli Nevanlinna, Patrick Neven, Janet E Olson, Jose I A Perez, Barbara Perkins, Paolo Peterlongo, Kelly-Anne Phillips, Katri Pylkäs, Anja Rudolph, Regina Santella, Elinor J Sawyer, Rita K Schmutzler, Caroline Seynaeve, Mitul Shah, Martha J Shrubsole, Melissa C Southey, Anthony J Swerdlow, Amanda E Toland, Ian Tomlinson, Diana Torres, Thérèse Truong, Giske Ursin, Rob B Van Der Luijt, Senno Verhoef, Alice S Whittemore, Robert Winqvist, Hui Zhao, Shilin Zhao, Per Hall, Jacques Simard, Peter Kraft, Paul Pharoah, David Hunter, Douglas F Easton, and Wei Zheng
Subjects: Medicine
Abstract: BackgroundObservational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.MethodsWe applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.ResultsIn the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31-0.62, p = 9.91 × 10-8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46-0.71, p = 1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60-0.84, p = 1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p ConclusionsBMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.
Published: 2016
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39. RAD51B in Familial Breast Cancer.

Author: Liisa M Pelttari, Sofia Khan, Mikko Vuorela, Johanna I Kiiski, Sara Vilske, Viivi Nevanlinna, Salla Ranta, Johanna Schleutker, Robert Winqvist, Anne Kallioniemi, Thilo Dörk, Natalia V Bogdanova, Jonine Figueroa, Paul D P Pharoah, Marjanka K Schmidt, Alison M Dunning, Montserrat García-Closas, Manjeet K Bolla, Joe Dennis, Kyriaki Michailidou, Qin Wang, John L Hopper, Melissa C Southey, Efraim H Rosenberg, Peter A Fasching, Matthias W Beckmann, Julian Peto, Isabel Dos-Santos-Silva, Elinor J Sawyer, Ian Tomlinson, Barbara Burwinkel, Harald Surowy, Pascal Guénel, Thérèse Truong, Stig E Bojesen, Børge G Nordestgaard, Javier Benitez, Anna González-Neira, Susan L Neuhausen, Hoda Anton-Culver, Hermann Brenner, Volker Arndt, Alfons Meindl, Rita K Schmutzler, Hiltrud Brauch, Thomas Brüning, Annika Lindblom, Sara Margolin, Arto Mannermaa, Jaana M Hartikainen, Georgia Chenevix-Trench, kConFab/AOCS Investigators, Laurien Van Dyck, Hilde Janssen, Jenny Chang-Claude, Anja Rudolph, Paolo Radice, Paolo Peterlongo, Emily Hallberg, Janet E Olson, Graham G Giles, Roger L Milne, Christopher A Haiman, Fredrick Schumacher, Jacques Simard, Martine Dumont, Vessela Kristensen, Anne-Lise Borresen-Dale, Wei Zheng, Alicia Beeghly-Fadiel, Mervi Grip, Irene L Andrulis, Gord Glendon, Peter Devilee, Caroline Seynaeve, Maartje J Hooning, Margriet Collée, Angela Cox, Simon S Cross, Mitul Shah, Robert N Luben, Ute Hamann, Diana Torres, Anna Jakubowska, Jan Lubinski, Fergus J Couch, Drakoulis Yannoukakos, Nick Orr, Anthony Swerdlow, Hatef Darabi, Jingmei Li, Kamila Czene, Per Hall, Douglas F Easton, Johanna Mattson, Carl Blomqvist, Kristiina Aittomäki, and Heli Nevanlinna
Subjects: Medicine, Science
Abstract: Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
Published: 2016
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40. Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.

Author: Hisani N Horne, Charles C Chung, Han Zhang, Kai Yu, Ludmila Prokunina-Olsson, Kyriaki Michailidou, Manjeet K Bolla, Qin Wang, Joe Dennis, John L Hopper, Melissa C Southey, Marjanka K Schmidt, Annegien Broeks, Kenneth Muir, Artitaya Lophatananon, Peter A Fasching, Matthias W Beckmann, Olivia Fletcher, Nichola Johnson, Elinor J Sawyer, Ian Tomlinson, Barbara Burwinkel, Frederik Marme, Pascal Guénel, Thérèse Truong, Stig E Bojesen, Henrik Flyger, Javier Benitez, Anna González-Neira, Hoda Anton-Culver, Susan L Neuhausen, Hermann Brenner, Volker Arndt, Alfons Meindl, Rita K Schmutzler, Hiltrud Brauch, Ute Hamann, Heli Nevanlinna, Sofia Khan, Keitaro Matsuo, Hiroji Iwata, Thilo Dörk, Natalia V Bogdanova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Veli-Matti Kosma, Georgia Chenevix-Trench, kConFab/AOCS Investigators, Anna H Wu, David Ven den Berg, Ann Smeets, Hui Zhao, Jenny Chang-Claude, Anja Rudolph, Paolo Radice, Monica Barile, Fergus J Couch, Celine Vachon, Graham G Giles, Roger L Milne, Christopher A Haiman, Loic Le Marchand, Mark S Goldberg, Soo H Teo, Nur A M Taib, Vessela Kristensen, Anne-Lise Borresen-Dale, Wei Zheng, Martha Shrubsole, Robert Winqvist, Arja Jukkola-Vuorinen, Irene L Andrulis, Julia A Knight, Peter Devilee, Caroline Seynaeve, Montserrat García-Closas, Kamila Czene, Hatef Darabi, Antoinette Hollestelle, John W M Martens, Jingmei Li, Wei Lu, Xiao-Ou Shu, Angela Cox, Simon S Cross, William Blot, Qiuyin Cai, Mitul Shah, Craig Luccarini, Caroline Baynes, Patricia Harrington, Daehee Kang, Ji-Yeob Choi, Mikael Hartman, Kee Seng Chia, Maria Kabisch, Diana Torres, Anna Jakubowska, Jan Lubinski, Suleeporn Sangrajrang, Paul Brennan, Susan Slager, Drakoulis Yannoukakos, Chen-Yang Shen, Ming-Feng Hou, Anthony Swerdlow, Nick Orr, Jacques Simard, Per Hall, Paul D P Pharoah, Douglas F Easton, Stephen J Chanock, Alison M Dunning, and Jonine D Figueroa
Subjects: Medicine, Science
Abstract: The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.
Published: 2016
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41. Erythrocytosis associated with a novel missense mutation in the BPGM gene

Author: Nayia Petousi, Richard R. Copley, Terence R.J. Lappin, Sally E. Haggan, Celeste M. Bento, Holger Cario, Melanie J. Percy, The WGS Consortium, Peter J. Ratcliffe, Peter A. Robbins, Mary Frances McMullin, Peter Donnelly, John Bell, David Bentley, Gil McVean, Peter Ratcliffe, Jenny Taylor, Andrew Wilkie, Peter Donelly, John Broxholme, David Buck, Jean-Baptiste Cazier, Richard Cornall, Lorna Gregory, Julian Knight, Gerton Lunter, Ian Tomlinson, Christopher Allan, Moustafa Attar, Angie Green, Sean Humphray, Zoya Kingsbury, Sarah Lamble, Lorne Lonie, Alistair Pagnamenta, Paolo Piazza, Guadelupe Polanco, Amy Trebes, Richard Copley, Simon Fiddy, Russell Grocock, Edouard Hatton, Chris Holmes, Linda Hughes, Peter Humburg, Alexander Kanapin, Stefano Lise, Hilary Martin, Lisa Murray, Davis McCarthy, Andy Rimmer, Natasha Sahgal, Ben Wright, and Chris Yau
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2014
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42. Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

Author: Elinor Sawyer, Rebecca Roylance, Christos Petridis, Mark N Brook, Salpie Nowinski, Efterpi Papouli, Olivia Fletcher, Sarah Pinder, Andrew Hanby, Kelly Kohut, Patricia Gorman, Michele Caneppele, Julian Peto, Isabel Dos Santos Silva, Nichola Johnson, Ruth Swann, Miriam Dwek, Katherine-Anne Perkins, Cheryl Gillett, Richard Houlston, Gillian Ross, Paolo De Ieso, Melissa C Southey, John L Hopper, Elena Provenzano, Carmel Apicella, Jelle Wesseling, Sten Cornelissen, Renske Keeman, Peter A Fasching, Sebastian M Jud, Arif B Ekici, Matthias W Beckmann, Michael J Kerin, Federick Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Therese Truong, Pierre Laurent-Puig, Pierre Kerbrat, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, Primitiva Menéndez, Javier Benitez, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K Schmutzler, Magdalena Lochmann, Hiltrud Brauch, Hans-Peter Fischer, Yon-Dschun Ko, GENICA Network, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Natalia V Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Georgia Chenevix-Trench, KConFab Investigators, Diether Lambrechts, Caroline Weltens, Erik Van Limbergen, Sigrid Hatse, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Graham G Giles, Gianluca Severi, Laura Baglietto, Catriona A McLean, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Vessela Kristensen, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Peter Devillee, Rob A E M Tollenaar, Caroline M Seynaeve, Mieke Kriege, Jonine Figueroa, Stephen J Chanock, Mark E Sherman, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Carolien H M van Deurzen, Jingmei Li, Kamila Czene, Keith Humphreys, Angela Cox, Simon S Cross, Malcolm W R Reed, Mitul Shah, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Anthony Swerdlow, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Fergus J Couch, Emily Hallberg, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Daniel C Tessier, Daniel Vincent, Francois Bacot, Manjeet K Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Alison M Dunning, Per Hall, Doug Easton, Paul Pharoah, Marjanka K Schmidt, Ian Tomlinson, and Montserrat Garcia-Closas
Subjects: Genetics, QH426-470
Abstract: Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P
Published: 2014
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43. Colorectal tumors from APC*I1307K carriers principally harbor somatic APC mutations outside the A8 tract.

Author: Peter Zauber, Timothy Bishop, Claire Taylor, Marlene Sabbath-Solitare, Stephen Marotta, and Ian Tomlinson
Subjects: Medicine, Science
Abstract: APC*I1307K (c.3920T>A) is an inherited variant associated with colorectal tumour risk found almost exclusively in those of Ashkenazi Jewish ancestry. A single nucleotide substitution creates an oligo-adenine tract (A8) that appears to be inherently prone to further mis-pairing and slippage. The reported multiple tumor phenotype of carriers is not easily reconciled with molecular and population genetics data. We postulated that some c.3920T>A carriers with multiple adenomas have other unidentified APC germ line or somatic mutations.DNA from 82 colonic tumours and accompanying normal tissue collected from 29 carriers with multiple colorectal tumors was directly sequenced between codons 716 and 1604. We also assessed APC gene loss of heterozygosity.One patient (3.4%) was found to have an additional APC germ line mutation. Twenty-five of the tumours showed no significant somatic molecular change, 36 showed one change, 20 showed two, and one tumour showed more than 2 changes. Our data suggest a correlation between advancing histology and fewer beta-catenin binding sites remaining in the mutant proteins.There were no other common germ line variants identified within the region of the APC gene examined, suggesting that any effect from this region on tumour production is attributable to the c.3920T>A allele. Our findings further suggest the only somatic genetic change clearly attributable to the c.3920T>A mutation is the c.3924_3925insA.
Published: 2014
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44. Association between CASP8 -652 6N del polymorphism (rs3834129) and colorectal cancer risk: results from a multi-centric study.

Author: Barbara Pardini, Paolo Verderio, Sara Pizzamiglio, Carmela Nici, Maria Valeria Maiorana, Alessio Naccarati, Ludmila Vodickova, Veronika Vymetalkova, Silvia Veneroni, Maria Grazia Daidone, Fernando Ravagnani, Tiziana Bianchi, Luis Bujanda, Angel Carracedo, Antoni Castells, Clara Ruiz-Ponte, Hans Morreau, Kimberley Howarth, Angela Jones, Sergi Castellví-Bel, Li Li, Ian Tomlinson, Tom Van Wezel, Pavel Vodicka, Paolo Radice, Paolo Peterlongo, and EPICOLON Consortium
Subjects: Medicine, Science
Abstract: The common -652 6N del variant in the CASP8 promoter (rs3834129) has been described as a putative low-penetrance risk factor for different cancer types. In particular, some studies suggested that the deleted allele (del) was inversely associated with CRC risk while other analyses failed to confirm this. Hence, to better understand the role of this variant in the risk of developing CRC, we performed a multi-centric case-control study. In the study, the variant -652 6N del was genotyped in a total of 6,733 CRC cases and 7,576 controls recruited by six different centers located in Spain, Italy, USA, England, Czech Republic and the Netherlands collaborating to the international consortium COGENT (COlorectal cancer GENeTics). Our analysis indicated that rs3834129 was not associated with CRC risk in the full data set. However, the del allele was under-represented in one set of cases with a family history of CRC (per allele model OR = 0.79, 95% CI = 0.69-0.90) suggesting this allele might be a protective factor versus familial CRC. Since this multi-centric case-control study was performed on a very large sample size, it provided robust clarification of the effect of rs3834129 on the risk of developing CRC in Caucasians.
Published: 2014
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45. MicroRNA related polymorphisms and breast cancer risk.

Author: Sofia Khan, Dario Greco, Kyriaki Michailidou, Roger L Milne, Taru A Muranen, Tuomas Heikkinen, Kirsimari Aaltonen, Joe Dennis, Manjeet K Bolla, Jianjun Liu, Per Hall, Astrid Irwanto, Keith Humphreys, Jingmei Li, Kamila Czene, Jenny Chang-Claude, Rebecca Hein, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Olivia Fletcher, Julian Peto, Isabel dos Santos Silva, Nichola Johnson, Lorna Gibson, Zoe Aitken, John L Hopper, Helen Tsimiklis, Minh Bui, Enes Makalic, Daniel F Schmidt, Melissa C Southey, Carmel Apicella, Jennifer Stone, Quinten Waisfisz, Hanne Meijers-Heijboer, Muriel A Adank, Rob B van der Luijt, Alfons Meindl, Rita K Schmutzler, Bertram Müller-Myhsok, Peter Lichtner, Clare Turnbull, Nazneen Rahman, Stephen J Chanock, David J Hunter, Angela Cox, Simon S Cross, Malcolm W R Reed, Marjanka K Schmidt, Annegien Broeks, Laura J Van't Veer, Frans B Hogervorst, Peter A Fasching, Michael G Schrauder, Arif B Ekici, Matthias W Beckmann, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Javier Benitez, Pilar M Zamora, Jose I A Perez, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Paul D P Pharoah, Alison M Dunning, Mitul Shah, Robert Luben, Judith Brown, Fergus J Couch, Xianshu Wang, Celine Vachon, Janet E Olson, Diether Lambrechts, Matthieu Moisse, Robert Paridaens, Marie-Rose Christiaens, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Claire Mulot, Frederick Marme, Barbara Burwinkel, Andreas Schneeweiss, Christof Sohn, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Irene L Andrulis, Julia A Knight, Sandrine Tchatchou, Anna Marie Mulligan, Thilo Dörk, Natalia V Bogdanova, Natalia N Antonenkova, Hoda Anton-Culver, Hatef Darabi, Mikael Eriksson, Montserrat Garcia-Closas, Jonine Figueroa, Jolanta Lissowska, Louise Brinton, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Christi J van Asperen, Vessela N Kristensen, kConFab Investigators, Australian Ovarian Cancer Study Group, Susan Slager, Amanda E Toland, Christine B Ambrosone, Drakoulis Yannoukakos, Annika Lindblom, Sara Margolin, Paolo Radice, Paolo Peterlongo, Monica Barile, Paolo Mariani, Maartje J Hooning, John W M Martens, J Margriet Collée, Agnes Jager, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Graham G Giles, Catriona McLean, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, GENICA Network, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Michael Jones, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Arto Mannermaa, Ute Hamann, Georgia Chenevix-Trench, Carl Blomqvist, Kristiina Aittomäki, Douglas F Easton, and Heli Nevanlinna
Subjects: Medicine, Science
Abstract: Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
Published: 2014
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46. Expression Profiling of Proliferation and Apoptotic Markers along the Adenoma-Carcinoma Sequence in Familial Adenomatous Polyposis Patients

Author: Jayson Wang, Nabil El-Masry, Ian Talbot, Ian Tomlinson, Malcolm R. Alison, and Mona El-Bahrawy
Subjects: Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Introduction. Familial adenomatous polyposis (FAP) patients have a germline mutation in the adenomatous polyposis coli (APC) gene. The APC protein interacts with beta-catenin, resulting in the activation of the Wnt signalling pathway. This results in alterations in cell proliferation and apoptosis. We investigated the expression of beta-catenin and related proliferation and apoptotic factors in FAP patients, exploring the expression along the adenoma-carcinoma sequence. Methods. The expression of beta-catenin, p53, bcl-2, cyclin-D1, caspase-3, CD10, and Ki-67 proteins was studied by immunohistochemistry in samples of colonic nonneoplastic mucosa (n=71), adenomas (n=152), and adenocarcinomas (n=19) from each of the16 FAP patients. Results. The expression of beta-catenin, caspase-3, cyclin-D1, and Ki-67 was increased in both adenomas and carcinomas in FAP patients, compared with normal mucosa. p53 and CD10 expression was only slightly increased in adenomas, but more frequently expressed in carcinomas. Bcl-2 expression was increased in adenomas, but decreased in carcinomas. Conclusion. This is the first study investigating collectively the expression of these molecules together in nonneoplastic mucosa, adenomas, and carcinomas from FAP patients. We find that beta-catenin and related proliferative and apoptotic factors (cyclin-D1, bcl-2, caspase-3, and Ki-67) are expressed early in the sequence, in adenomas. However, p53 and CD10 are often expressed later in the sequence, in carcinomas.
Published: 2013
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47. Meta-analysis of mismatch repair polymorphisms within the cogent consortium for colorectal cancer susceptibility.

Author: Simone Picelli, Justo Lorenzo Bermejo, Jenny Chang-Claude, Michael Hoffmeister, Ceres Fernández-Rozadilla, Angel Carracedo, Antoni Castells, Sergi Castellví-Bel, Memebers of EPICOLON Consortium-Gastrointestinal Oncology Group of the Spanish Gastroenterological Association, Alessio Naccarati, Barbara Pardini, Ludmila Vodickova, Heiko Müller, Bente A Talseth-Palmer, Geoffrey Stibbard, Paolo Peterlongo, Carmela Nici, Silvia Veneroni, Li Li, Graham Casey, Albert Tenesa, Susan M Farrington, Ian Tomlinson, Victor Moreno, Tom van Wezel, Juul Wijnen, Malcolm Dunlop, Paolo Radice, Rodney J Scott, Pavel Vodicka, Clara Ruiz-Ponte, Hermann Brenner, Stephan Buch, Henry Völzke, Jochen Hampe, Clemens Schafmayer, and Annika Lindblom
Subjects: Medicine, Science
Abstract: In the last four years, Genome-Wide Association Studies (GWAS) have identified sixteen low-penetrance polymorphisms on fourteen different loci associated with colorectal cancer (CRC). Due to the low risks conferred by known common variants, most of the 35% broad-sense heritability estimated by twin studies remains unexplained. Recently our group performed a case-control study for eight Single Nucleotide Polymorphisms (SNPs) in 4 CRC genes. The present investigation is a follow-up of that study. We have genotyped six SNPs that showed a positive association and carried out a meta-analysis based on eight additional studies comprising in total more than 8000 cases and 6000 controls. The estimated recessive odds ratio for one of the SNPs, rs3219489 (MUTYH Q338H), decreased from 1.52 in the original Swedish study, to 1.18 in the Swedish replication, and to 1.08 in the initial meta-analysis. Since the corresponding summary probability value was 0.06, we decided to retrieve additional information for this polymorphism. The incorporation of six further studies resulted in around 13000 cases and 13000 controls. The newly updated OR was 1.03. The results from the present large, multicenter study illustrate the possibility of decreasing effect sizes with increasing samples sizes. Phenotypic heterogeneity, differential environmental exposures, and population specific linkage disequilibrium patterns may explain the observed difference of genetic effects between Sweden and the other investigated cohorts.
Published: 2013
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48. Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).

Author: Rebecca Hein, Melanie Maranian, John L Hopper, Miroslaw K Kapuscinski, Melissa C Southey, Daniel J Park, Marjanka K Schmidt, Annegien Broeks, Frans B L Hogervorst, H Bas Bueno-de-Mesquita, Kenneth R Muir, Artitaya Lophatananon, Suthee Rattanamongkongul, Puttisak Puttawibul, Peter A Fasching, Alexander Hein, Arif B Ekici, Matthias W Beckmann, Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Julian Peto, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Frederick Marmee, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Emilie Cordina-Duverger, Florence Menegaux, Thérèse Truong, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, M Pilar Zamora, Javier Benítez, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina A Clarke, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Nazneen Rahman, Sheila Seal, Clare Turnbull, Anthony Renwick, Alfons Meindl, Sarah Schott, Claus R Bartram, Rita K Schmutzler, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, GENICA Network, Shan Wang-Gohrke, Thilo Dörk, Peter Schürmann, Johann H Karstens, Peter Hillemanns, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Natalia V Bogdanova, Iosif V Zalutsky, Natalia N Antonenkova, Marina Bermisheva, Darya Prokovieva, Albina Farahtdinova, Elza Khusnutdinova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana Hartikainen, Xiaoqing Chen, Jonathan Beesley, Kconfab Investigators, AOCS Group, Diether Lambrechts, Hui Zhao, Patrick Neven, Hans Wildiers, Stefan Nickels, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Fergus J Couch, Janet E Olson, Xianshu Wang, Zachary Fredericksen, Graham G Giles, Laura Baglietto, Catriona A McLean, Gianluca Severi, Kenneth Offit, Mark Robson, Mia M Gaudet, Joseph Vijai, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børresen-Dale, Esther M John, Alexander Miron, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Jonine D Figueroa, Montserrat García-Closas, Jolanta Lissowska, Mark E Sherman, Maartje Hooning, John W M Martens, Caroline Seynaeve, Margriet Collée, Per Hall, Keith Humpreys, Kamila Czene, Jianjun Liu, Angela Cox, Ian W Brock, Simon S Cross, Malcolm W R Reed, Shahana Ahmed, Maya Ghoussaini, Paul D P Pharoah, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Anna Jakubowska, Katarzyna Jaworska, Katarzyna Durda, Elżbieta Złowocka, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Chen-Yang Shen, Jyh-Cherng Yu, Huan-Ming Hsu, Ming-Feng Hou, Nick Orr, Minouk Schoemaker, Alan Ashworth, Anthony Swerdlow, Amy Trentham-Dietz, Polly A Newcomb, Linda Titus, Kathleen M Egan, Georgia Chenevix-Trench, Antonis C Antoniou, Manjeet K Humphreys, Jonathan Morrison, Jenny Chang-Claude, Douglas F Easton, and Alison M Dunning
Subjects: Medicine, Science
Abstract: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.
Published: 2012
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49. Correction: Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).

Author: Rebecca Hein, Melanie Maranian, John L. Hopper, Miroslaw K. Kapuscinski, Melissa C. Southey, Daniel J. Park, Marjanka K. Schmidt, Annegien Broeks, Frans B. L. Hogervorst, H. Bas Bueno-de-Mesquit, Kenneth R. Muir, Artitaya Lophatananon, Suthee Rattanamongkongul, Puttisak Puttawibul, Peter A. Fasching, Alexander Hein, Arif B. Ekici, Matthias W. Beckmann, Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Julian Peto, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Frederick Marmee, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Emilie Cordina-Duverger, Florence Menegaux, Thérèse Truong, Stig E. Bojesen, Børge G. Nordestgaard, Henrik Flyger, Roger L. Milne, Jose Ignacio Arias Perez, M. Pilar Zamora, Javier Benítez, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina A. Clarke, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Nazneen Rahman, Sheila Seal, Clare Turnbull, Anthony Renwick, Alfons Meindl, Sarah Schott, Claus R. Bartram, Rita K. Schmutzler, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, Shan Wang-Gohrke, Thilo Dörk, Peter Schürmann, Johann H. Karstens, Peter Hillemanns, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Natalia V. Bogdanova, Iosif V. Zalutsky, Natalia N. Antonenkova, Marina Bermisheva, Darya Prokovieva, Albina Farahtdinova, Elza Khusnutdinova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana Hartikainen, Xiaoqing Chen, Jonathan Beesley, kConFab Investigators, Diether Lambrechts, Hui Zhao, Patrick Neven, Hans Wildiers, Stefan Nickels, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Fergus J. Couch, Janet E. Olson, Xianshu Wang, Zachary Fredericksen, Graham G. Giles, Laura Baglietto, Catriona A. McLean, Gianluca Severi, Kenneth Offit, Mark Robson, Mia M. Gaudet, Joseph Vijai, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børresen-Dale, Esther M. John, Alexander Miron, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Jonine D. Figueroa, Montserrat García-Closas, Jolanta Lissowska, Mark E. Sherman, Maartje Hooning, John W. M. Martens, Caroline Seynaeve, Margriet Collée, Per Hall, Keith Humpreys, Kamila Czene, Jianjun Liu, Angela Cox, Ian W. Brock, Simon S. Cross, Malcolm W. R. Reed, Shahana Ahmed, Maya Ghoussaini, Paul DP. Pharoah, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Anna Jakubowska, Katarzyna Jaworska, Katarzyna Durda, Elżbieta Złowocka, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Chen-Yang Shen, Jyh-Cherng Yu, Huan-Ming Hsu, Ming-Feng Hou, Nick Orr, Minouk Schoemaker, Alan Ashworth, Anthony Swerdlow, Amy Trentham-Dietz, Polly A. Newcomb, Linda Titus, Kathleen M. Egan, Georgia Chenevix-Trench, Antonis C. Antoniou, Manjeet K. Humphreys, Jonathan Morrison, Jenny Chang-Claude, Douglas F. Easton, and Alison M. Dunning
Subjects: Medicine, Science
Published: 2012
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50. Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH mutations in glioblastoma.

Author: Daniel Krell, Mawuelikem Assoku, Malcolm Galloway, Paul Mulholland, Ian Tomlinson, and Chiara Bardella
Subjects: Medicine, Science
Abstract: Isocitrate dehydrogenases (IDHs) catalyse oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). IDH1 functions in the cytosol and peroxisomes, whereas IDH2 and IDH3 are both localized in the mitochondria. Heterozygous somatic mutations in IDH1 occur at codon 132 in 70% of grade II-III gliomas and secondary glioblastomas (GBMs), and in 5% of primary GBMs. Mutations in IDH2 at codon 172 are present in grade II-III gliomas at a low frequency. IDH1 and IDH2 mutations cause both loss of normal enzyme function and gain-of-function, causing reduction of α-KG to D-2-hydroxyglutarate (D-2HG) which accumulates. Excess hydroxyglutarate (2HG) can also be caused by germline mutations in D- and L-2-hydroxyglutarate dehydrogenases (D2HGDH and L2HGDH). If loss of IDH function is critical for tumourigenesis, we might expect some tumours to acquire somatic IDH3 mutations. Alternatively, if 2HG accumulation is critical, some tumours might acquire somatic D2HGDH or L2HGDH mutations. We therefore screened 47 glioblastoma samples looking for changes in these genes. Although IDH1 R132H was identified in 12% of samples, no mutations were identified in any of the other genes. This suggests that mutations in IDH3, D2HGDH and L2HGDH do not occur at an appreciable frequency in GBM. One explanation is simply that mono-allelic IDH1 and IDH2 mutations occur more frequently by chance than the bi-allelic mutations expected at IDH3, D2HGDH and L2HGDH. Alternatively, both loss of IDH function and 2HG accumulation might be required for tumourigenesis, and only IDH1 and IDH2 mutations have these dual effects.
Published: 2011
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