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1. Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel

Author

Parsons, Michael T, de la Hoya, Miguel, Richardson, Marcy E, Tudini, Emma, Anderson, Michael, Berkofsky-Fessler, Windy, Caputo, Sandrine M, Chan, Raymond C, Cline, Melissa S, Feng, Bing-Jian, Fortuno, Cristina, Gomez-Garcia, Encarna, Hadler, Johanna, Hiraki, Susan, Holdren, Megan, Houdayer, Claude, Hruska, Kathleen, James, Paul, Karam, Rachid, Leong, Huei San, Martins, Alexandra, Mensenkamp, Arjen R, Monteiro, Alvaro N, Nathan, Vaishnavi, O'Connor, Robert, Pedersen, Inge Sokilde, Pesaran, Tina, Radice, Paolo, Schmidt, Gunnar, Southey, Melissa, Tavtigian, Sean, Thompson, Bryony A, Toland, Amanda E, Turnbull, Clare, Vogel, Maartje J, Weyandt, Jamie, Wiggins, George AR, Zec, Lauren, Couch, Fergus J, Walker, Logan C, Vreeswijk, Maaike PG, Goldgar, David E, and Spurdle, Amanda B

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Women's Health, Breast Cancer, Ovarian Cancer, Cancer, Rare Diseases, Good Health and Well Being, ACMG/AMP variant curation guidelines, BRCA1, BRCA2, ClinGen, ClinVar, VCEP, Humans, BRCA2 Protein, BRCA1 Protein, Female, Genetic Variation, Breast Neoplasms, Genomics, Databases, Genetic, Ovarian Neoplasms, Genetic Predisposition to Disease, Genetic Testing, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.

Published
2024

2. Unrecognised actionability for breast cancer risk variants identified in a national-level review of Australian familial cancer centres

Author

Fortuno, Cristina, Cops, Elisa J., Davidson, Aimee L., Hadler, Johanna, Innella, Giovanni, McKenzie, Maddison E., Parsons, Michael, Campbell, Ainsley M., Dubowsky, Andrew, Fargas, Verna, Field, Michael J., Mar Fan, Helen G., Nichols, Cassandra B., Poplawski, Nicola K., Warwick, Linda, Williams, Rachel, Beshay, Victoria, Edwards, Caitlin, Johns, Andrea, McPhillips, Mary, Kumar, Vanessa Siva, Scott, Rodney, Williams, Mark, Scott, Hamish, James, Paul A., and Spurdle, Amanda B.

Published
2024
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3. Germline copy number variants and endometrial cancer risk

Author

Stylianou, Cassie E., Wiggins, George A. R., Lau, Vanessa L., Dennis, Joe, Shelling, Andrew N., Wilson, Michelle, Sykes, Peter, Amant, Frederic, Annibali, Daniela, De Wispelaere, Wout, Easton, Douglas F., Fasching, Peter A., Glubb, Dylan M., Goode, Ellen L., Lambrechts, Diether, Pharoah, Paul D. P., Scott, Rodney J., Tham, Emma, Tomlinson, Ian, Bolla, Manjeet K., Couch, Fergus J., Czene, Kamila, Dörk, Thilo, Dunning, Alison M., Fletcher, Olivia, García-Closas, Montserrat, Hoppe, Reiner, Jernström, Helena, Kaaks, Rudolf, Michailidou, Kyriaki, Obi, Nadia, Southey, Melissa C., Stone, Jennifer, Wang, Qin, Spurdle, Amanda B., O’Mara, Tracy A., Pearson, John, and Walker, Logan C.

Published
2024
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5. A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer

Author

Srinivasan, Srilakshmi, Kryza, Thomas, Bock, Nathalie, Tse, Brian W. C., Sokolowski, Kamil A., Janaththani, Panchadsaram, Fernando, Achala, Moya, Leire, Stephens, Carson, Dong, Ying, Röhl, Joan, Alinezhad, Saeid, Vela, Ian, Perry-Keene, Joanna L., Buzacott, Katie, Nica, Robert, Gago-Dominguez, Manuela, Schleutker, Johanna, Maier, Christiane, Muir, Kenneth, Tangen, Catherine M., Gronberg, Henrik, Pashayan, Nora, Albanes, Demetrius, Wolk, Alicja, Stanford, Janet L., Berndt, Sonja I., Mucci, Lorelei A., Koutros, Stella, Cussenot, Olivier, Sorensen, Karina Dalsgaard, Grindedal, Eli Marie, Travis, Ruth C., Haiman, Christopher A., MacInnis, Robert J., Vega, Ana, Wiklund, Fredrik, Neal, David E., Kogevinas, Manolis, Penney, Kathryn L., Nordestgaard, Børge G., Brenner, Hermann, John, Esther M., Gamulin, Marija, Claessens, Frank, Melander, Olle, Dahlin, Anders, Stattin, Pär, Hallmans, Göran, Häggström, Christel, Johansson, Robert, Thysell, Elin, Rönn, Ann-Charlotte, Li, Weiqiang, Brown, Nigel, Dimeski, Goce, Shepherd, Benjamin, Dadaev, Tokhir, Brook, Mark N., Spurdle, Amanda B., Stenman, Ulf-Håkan, Koistinen, Hannu, Kote-Jarai, Zsofia, Klein, Robert J., Lilja, Hans, Ecker, Rupert C., Eeles, Rosalind, Clements, Judith, and Batra, Jyotsna

Published
2024
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6. Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant

Author

Block, Ines, Mateu-Regué, Àngels, Do, Thi Tuyet Nhu, Miceikaite, Ieva, Sdogati, Daniel, Larsen, Martin J., Hao, Qin, Nielsen, Henriette Roed, Boonen, Susanne E., Skytte, Anne-Bine, Jensen, Uffe Birk, Høffding, Louise K., De Nicolo, Arcangela, Viel, Alessandra, Tudini, Emma, Parsons, Michael T., Hansen, Thomas V. O., Rossing, Maria, Kruse, Torben A., Spurdle, Amanda B., and Thomassen, Mads

Published
2024
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7. A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer

Author

Srilakshmi Srinivasan, Thomas Kryza, Nathalie Bock, Brian W. C. Tse, Kamil A. Sokolowski, Panchadsaram Janaththani, Achala Fernando, Leire Moya, Carson Stephens, Ying Dong, Joan Röhl, Saeid Alinezhad, Ian Vela, Joanna L. Perry-Keene, Katie Buzacott, Robert Nica, The IMPACT Study, Manuela Gago-Dominguez, The PROFILE Study Steering Committee, Johanna Schleutker, Christiane Maier, Kenneth Muir, Catherine M. Tangen, Henrik Gronberg, Nora Pashayan, Demetrius Albanes, Alicja Wolk, Janet L. Stanford, Sonja I. Berndt, Lorelei A. Mucci, Stella Koutros, Olivier Cussenot, Karina Dalsgaard Sorensen, Eli Marie Grindedal, Ruth C. Travis, Christopher A. Haiman, Robert J. MacInnis, Ana Vega, Fredrik Wiklund, David E. Neal, Manolis Kogevinas, Kathryn L. Penney, Børge G. Nordestgaard, Hermann Brenner, Esther M. John, Marija Gamulin, Frank Claessens, Olle Melander, Anders Dahlin, Pär Stattin, Göran Hallmans, Christel Häggström, Robert Johansson, Elin Thysell, Ann-Charlotte Rönn, Weiqiang Li, Nigel Brown, Goce Dimeski, Benjamin Shepherd, Tokhir Dadaev, Mark N. Brook, Amanda B. Spurdle, Ulf-Håkan Stenman, Hannu Koistinen, Zsofia Kote-Jarai, Robert J. Klein, Hans Lilja, Rupert C. Ecker, Rosalind Eeles, The Practical Consortium, The Australian Prostate Cancer BioResource, Judith Clements, and Jyotsna Batra

Subjects
Science
Abstract

Abstract Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The ‘Thr’ PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, ‘Thr’ PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.

Published
2024
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8. Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome)

Author

Buchanan DD, Rosty C, Clendenning M, Spurdle AB, and Win AK

Subjects
Medicine (General), R5-920, Genetics, QH426-470
Abstract

Daniel D Buchanan,1,2 Christophe Rosty,1,3,4 Mark Clendenning,1 Amanda B Spurdle,5 Aung Ko Win2 1Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia; 2Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia; 3Envoi Specialist Pathologists, Herston, QLD, Australia; 4School of Medicine, University of Queensland, Herston, QLD, Australia; 5Molecular Cancer Epidemiology Laboratory, Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Herston, QLD, AustraliaAbstract: Carriers of a germline mutation in one of the DNA mismatch repair (MMR) genes have a high risk of developing numerous different cancers, predominantly colorectal cancer and endometrial cancer (known as Lynch syndrome). MMR gene mutation carriers develop tumors with MMR deficiency identified by tumor microsatellite instability or immunohistochemical loss of MMR protein expression. Tumor MMR deficiency is used to identify individuals most likely to carry an MMR gene mutation. However, MMR deficiency can also result from somatic inactivation, most commonly methylation of the MLH1 gene promoter. As tumor MMR testing of all incident colorectal and endometrial cancers (universal screening) is becoming increasingly adopted, a growing clinical problem is emerging for individuals who have tumors that show MMR deficiency who are subsequently found not to carry an MMR gene mutation after genetic testing using the current diagnostic approaches (Sanger sequencing and multiplex ligation-dependent probe amplification) and who also show no evidence of MLH1 methylation. The inability to determine the underlying cause of tumor MMR deficiency in these "Lynch-like" or "suspected Lynch syndrome" cases has significant implications on the clinical management of these individuals and their relatives. When the data from published studies are combined, 59% (95% confidence interval [CI]: 55% to 64%) of colorectal cancers and 52% (95% CI: 41% to 62%) of endometrial cancers with MMR deficiency were identified as suspected Lynch syndrome. Recent studies estimated that colorectal cancer risk for relatives of suspected Lynch syndrome cases is lower than for relatives of those with MMR gene mutations, but higher than for relatives of those with tumor MMR deficiency resulting from methylation of the MLH1 gene promoter. The cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely due to either unidentified germline MMR gene mutations, somatic cell mosaicism, or biallelic somatic inactivation. Determining the underlying cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely to reshape the current triaging schemes used to identify germline MMR gene mutations in cancer-affected individuals and their relatives.Keywords: Lynch syndrome, cancer risk, screening, somatic mutation, germline mutation

Published
2014

9. Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

Author

O’Mahony, Denise G, Ramus, Susan J, Southey, Melissa C, Meagher, Nicola S, Hadjisavvas, Andreas, John, Esther M, Hamann, Ute, Imyanitov, Evgeny N, Andrulis, Irene L, Sharma, Priyanka, Daly, Mary B, Hake, Christopher R, Weitzel, Jeffrey N, Jakubowska, Anna, Godwin, Andrew K, Arason, Adalgeir, Bane, Anita, Simard, Jacques, Soucy, Penny, Caligo, Maria A, Mai, Phuong L, Claes, Kathleen BM, Teixeira, Manuel R, Chung, Wendy K, Lazaro, Conxi, Hulick, Peter J, Toland, Amanda E, Pedersen, Inge Sokilde, Neuhausen, Susan L, Vega, Ana, de la Hoya, Miguel, Nevanlinna, Heli, Dhawan, Mallika, Zampiga, Valentina, Danesi, Rita, Varesco, Liliana, Gismondi, Viviana, Vellone, Valerio Gaetano, James, Paul A, Janavicius, Ramunas, Nikitina-Zake, Liene, Nielsen, Finn Cilius, van Overeem Hansen, Thomas, Pejovic, Tanja, Borg, Ake, Rantala, Johanna, Offit, Kenneth, Montagna, Marco, Nathanson, Katherine L, Domchek, Susan M, Osorio, Ana, García, María J, Karlan, Beth Y, De Fazio, Anna, Bowtell, David, McGuffog, Lesley, Leslie, Goska, Parsons, Michael T, Dörk, Thilo, Speith, Lisa-Marie, dos Santos, Elizabeth Santana, da Costa, Alexandre André BA, Radice, Paolo, Peterlongo, Paolo, Papi, Laura, Engel, Christoph, Hahnen, Eric, Schmutzler, Rita K, Wappenschmidt, Barbara, Easton, Douglas F, Tischkowitz, Marc, Singer, Christian F, Tan, Yen Yen, Whittemore, Alice S, Sieh, Weiva, Brenton, James D, Yannoukakos, Drakoulis, Fostira, Florentia, Konstantopoulou, Irene, Soukupova, Jana, Vocka, Michal, Chenevix-Trench, Georgia, Pharoah, Paul DP, Antoniou, Antonis C, Goldgar, David E, Spurdle, Amanda B, and Michailidou, Kyriaki

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Cancer, Breast Cancer, Genetics, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Humans, Female, Virulence, BRCA1 Protein, BRCA2 Protein, Ovarian Neoplasms, Genetic Predisposition to Disease, Breast Neoplasms, HEBON Investigators, GEMO Study Collaborators, AOCS Group, CZECANCA Consortium, Consortium of Investigators of Modifiers of BRCA1/2, Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundThe distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system.MethodsData for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong).ResultsNo histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis.ConclusionsWe provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.

Published
2023

10. Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions

Author

Lindström, Sara, Wang, Lu, Feng, Helian, Majumdar, Arunabha, Huo, Sijia, Macdonald, James, Harrison, Tabitha, Turman, Constance, Chen, Hongjie, Mancuso, Nicholas, Bammler, Theo, Consortium, Breast Cancer Association, Gallinger, Steve, Gruber, Stephen B, Gunter, Marc J, Le Marchand, Loic, Moreno, Victor, Offit, Kenneth, Study, Genetics And Epidemiology Of Colorectal Cancer Consortium Colorectal Transdisciplinary Study Colon Cancer Family Registry, De Vivo, Immaculata, O’Mara, Tracy A, Spurdle, Amanda B, Tomlinson, Ian, Consortium, Endometrial Cancer Association, Fitzgerald, Rebecca, Gharahkhani, Puya, Gockel, Ines, Jankowski, Janusz, Macgregor, Stuart, Schumacher, Johannes, Barnholtz-Sloan, Jill, Bondy, Melissa L, Houlston, Richard S, Jenkins, Robert B, Melin, Beatrice, Wrensch, Margaret, Brennan, Paul, Christiani, David C, Johansson, Mattias, Mckay, James, Aldrich, Melinda C, Amos, Christopher I, Landi, Maria Teresa, Tardon, Adonina, Consortium, International Lung Cancer, Bishop, D Timothy, Demenais, Florence, Goldstein, Alisa M, Iles, Mark M, Kanetsky, Peter A, Law, Matthew H, Consortium, Ovarian Cancer Association, Amundadottir, Laufey T, Stolzenberg-Solomon, Rachael, Wolpin, Brian M, Consortium, Pancreatic Cancer Cohort, Klein, Alison, Petersen, Gloria, Risch, Harvey, Consortium, The PRACTICAL Consortium Pancreatic Cancer Case-Control, Chanock, Stephen J, Purdue, Mark P, Scelo, Ghislaine, Pharoah, Paul, Kar, Siddhartha, Hung, Rayjean J, Pasaniuc, Bogdan, and Kraft, Peter

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Human Genome, Genetics, Digestive Diseases, Prevention, Clinical Research, Urologic Diseases, Cancer, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Male, Humans, Genome-Wide Association Study, Genetic Predisposition to Disease, Neoplasms, Risk Factors, Transcriptome, Polymorphism, Single Nucleotide, Breast Cancer Association Consortium, Colorectal Transdisciplinary Study (CORECT), Colon Cancer Family Registry Study (CCFR), Genetics And Epidemiology Of Colorectal Cancer Consortium, Endometrial Cancer Association Consortium, International Lung Cancer Consortium, Ovarian Cancer Association Consortium, Pancreatic Cancer Cohort Consortium, Pancreatic Cancer Case-Control Consortium (Panc4), The PRACTICAL Consortium, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundThe shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.MethodsWe collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.ResultsWe observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci.ConclusionsOverall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

Published
2023

11. Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines

Author

Luo, Xi, Maciaszek, Jamie L, Thompson, Bryony A, San Leong, Huei, Dixon, Katherine, Sousa, Sónia, Anderson, Michael, Roberts, Maegan E, Lee, Kristy, Spurdle, Amanda B, Mensenkamp, Arjen R, Brannan, Terra, Pardo, Carolina, Zhang, Liying, Pesaran, Tina, Wei, Sainan, Fasaye, Grace-Ann, Kesserwan, Chimene, Shirts, Brian H, Davis, Jeremy L, Oliveira, Carla, Plon, Sharon E, Schrader, Kasmintan A, and Karam, Rachid

Subjects
Genetics, Cancer, Good Health and Well Being, Humans, Genetic Variation, Genetic Testing, Germ-Line Mutation, Stomach Neoplasms, Germ Cells, Antigens, CD, Cadherins, Genetic Predisposition to Disease, Gastrointestinal Diseases, Medical, ClinGen CDH1 Variant Curation Expert Panel, Genetics, Medical, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

BackgroundGermline pathogenic variants in CDH1 are associated with increased risk of diffuse gastric cancer and lobular breast cancer. Risk reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation of germline CDH1 variants critical for physicians deciding on these procedures. The Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications.MethodsCDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen and expert knowledge from ongoing CDH1 variant curations. The CDH1 VCEP reviewed 273 variants using updated CDH1 specifications and incorporated published and unpublished data provided by diagnostic laboratories.ResultsUpdated CDH1-specific interpretation guidelines include 11 major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36 of 37) of variants with ClinVar conflicting interpretations were resolved to benign, likely benign, likely pathogenic or pathogenic, and 35% (15 of 43) of VUS were resolved to benign or likely benign. Overall, 88% (239 of 273) of curated variants had non-VUS classifications. To date, variants classified as pathogenic are either nonsense, frameshift, splicing, or affecting the translation initiation codon, and the only missense variants classified as pathogenic or likely pathogenic have been shown to affect splicing.ConclusionsThe development and evolution of CDH1-specific criteria by the expert panel resulted in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene, which can ultimately lead to more effective clinical management recommendations.

Published
2023

12. Atypical cancer risk profile in carriers of Italian founder BRCA1 variant p.His1673del: Implications for classification and clinical management

Author

Giovanni Innella, Cristina Fortuno, Laura Caleca, Bing‐Jian Feng, Courtney Carroll, Michael T. Parsons, Sara Miccoli, Marco Montagna, Daniele Calistri, Laura Cortesi, Barbara Pasini, Siranoush Manoukian, Daniela Giachino, Laura Matricardi, Maria Cristina Foti, Valentina Zampiga, Claudia Piombino, Elena Barbieri, Francesca Vignolo Lutati, Jacopo Azzolini, Rita Danesi, Valentina Arcangeli, Sandrine M. Caputo, Nadia Boutry‐Kryza, Vincent Goussot, Susan Hiraki, Marcy Richardson, Hereditary Breast/Ovarian Cancer IOV network (HBOC IOVnet), Simona Ferrari, Paolo Radice, Amanda B. Spurdle, and Daniela Turchetti

Subjects
BRCA1, breast cancer, cancer risk, classification, clinical management, ovarian cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background BRCA1:c.5017_5019del (p.His1673del) is a founder variant relatively frequent in Northern Italy. Despite previous suggestion of pathogenicity, variant classification in public databases is still conflicting, needing additional evidence. Methods Maximum likelihood penetrance of breast/ovarian and other cancer types was estimated using full pedigree data from 53 informative Italian families. The effect of the variant on BRCA1‐ABRAXAS1 interaction was assessed using a GFP‐fragment reassembly‐based PPI assay. Results were combined with additional data from multiple sources to classify the variant according to ACMG/AMP classification rules specified for BRCA1/2. Results Variant‐carriers displayed increased risk for ovarian cancer (HR = 33.0, 95% CI = 7.0–155.0; cumulative risk at age 70 = 27.6%, 95% CI = 12.6–40.0%) but not for breast cancer (HR = 0.7, 95% CI = 0.2–2.2). An increased risk of uterine cancer (HR = 8.0, 95% CI = 1.03–61.6) emerged, warranting further evaluation. Likelihood‐ratio in favor of pathogenicity was 98898642.82 under assumption of standard BRCA1 breast and ovarian penetrance, and 104240832.84 after excluding breast cancer diagnoses (based on penetrance results). Functional analysis demonstrated that the variant abrogates the BRCA1‐ABRAXAS1 binding, supporting the PS3 code assignment within the ACMG/AMP rule‐based model. Collectively, these findings allowed to classify the variant as pathogenic. Conclusion Pathogenicity of BRCA1:c.5017_5019del(p.His1673del) has been confirmed; however, breast cancer risk in Italian families is not increased, unlike in families from other countries and in carriers of most BRCA1 pathogenic variants. The knowledge of atypical risk profiles for this and other variants will pave the way for personalized management based on specific genotype.

Published
2024
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13. Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline ATM sequence variants

Author

Richardson, Marcy E., Holdren, Megan, Brannan, Terra, de la Hoya, Miguel, Spurdle, Amanda B., Tavtigian, Sean V., Young, Colin C., Zec, Lauren, Hiraki, Susan, Anderson, Michael J., Walker, Logan C., McNulty, Shannon, Turnbull, Clare, Tischkowitz, Marc, Schon, Katherine, Slavin, Thomas, Foulkes, William D., Cline, Melissa, Monteiro, Alvaro N., Pesaran, Tina, and Couch, Fergus J.

Published
2024
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14. Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant

Author

Ines Block, Àngels Mateu-Regué, Thi Tuyet Nhu Do, Ieva Miceikaite, Daniel Sdogati, Martin J. Larsen, Qin Hao, Henriette Roed Nielsen, Susanne E. Boonen, Anne-Bine Skytte, Uffe Birk Jensen, Louise K. Høffding, Arcangela De Nicolo, Alessandra Viel, Emma Tudini, Michael T. Parsons, Thomas V. O. Hansen, Maria Rossing, Torben A. Kruse, Amanda B. Spurdle, and Mads Thomassen

Subjects
BRCA1, Dual carrier, Fanconi Anemia, Variant classification, Exon duplication, Transcription activation domain assay, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype. Methods We identified two families with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells. Results Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability. Conclusions This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.

Published
2024
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19. A multi-centre international quality control study comparing mRNA splicing assay protocols and reporting practices from the ENIGMA consortium

Author

Whiley P, Walker LC, De LA Hoya M, Wappenschmidt B, Becker A, Blanco A, Blok MJ, Caligo MA, Chatfield C, Couch F, Diez O, Fachal L, Guidugli L, Enríquez S, Hansen T, Houdayer C, Imrie S, Lafferty A, Lázaro C, Menéndez M, Montagna M, Montalbán G, Santamariña M, Pederson I, Southey M, Tancredi M, Tenès A, Thomassen M, Van Overeem Vega A, Spurdle AB, and Brown MA

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Published
2012
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21. RNA variant assessment using transactivation and transdifferentiation

Author

Azmanov, Dimitar N., Barnett, Christopher P., Barry, Simon C., Baynam, Gareth, Berkovic, Samuel F., Christodoulou, John, Coman, David J., Cooper, Sandra, Corbett, Mark A., Delatycki, Martin, Dudding, Tracy E., Fletcher, Sue, Gardner, Alison E., Gecz, Jozef, Higgins, Megan J., Hildebrand, Michael S., Jolly, Lachlan A., Lister, Ryan, McGaughran, Julie, Pflueger, Christian, Poulton, Cathryn, Roscioli, Tony, Hamish S. Scott, Ingrid Scheffer, Sinclair, Andrew H., Spurdle, Amanda B., Tan, Tiong Y., van Eyk, Clare L., Voineagu, Irina, Nicolas-Martinez, Emmylou C., Robinson, Olivia, Gardner, Alison, Ritchie, Tarin, Kroes, Thessa, Scheffer, Ingrid E., Barnier, Jean-Vianney, Rousseau, Véronique, Genevieve, David, Haushalter, Virginie, Piton, Amélie, Denommé-Pichon, Anne-Sophie, Bruel, Ange-Line, Nambot, Sophie, Isidor, Bertrand, Grigg, John, Gonzalez, Tina, Ghedia, Sondhya, Marchant, Rhett G., Bournazos, Adam, Wong, Wui-Kwan, Webster, Richard I., Evesson, Frances J., Jones, Kristi J., and Cooper, Sandra T.

Published
2024
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23. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Author

Li, Shuai, Silvestri, Valentina, Leslie, Goska, Rebbeck, Timothy R, Neuhausen, Susan L, Hopper, John L, Nielsen, Henriette Roed, Lee, Andrew, Yang, Xin, McGuffog, Lesley, Parsons, Michael T, Andrulis, Irene L, Arnold, Norbert, Belotti, Muriel, Borg, Åke, Buecher, Bruno, Buys, Saundra S, Caputo, Sandrine M, Chung, Wendy K, Colas, Chrystelle, Colonna, Sarah V, Cook, Jackie, Daly, Mary B, de la Hoya, Miguel, de Pauw, Antoine, Delhomelle, Hélène, Eason, Jacqueline, Engel, Christoph, Evans, D Gareth, Faust, Ulrike, Fehm, Tanja N, Fostira, Florentia, Fountzilas, George, Frone, Megan, Garcia-Barberan, Vanesa, Garre, Pilar, Gauthier-Villars, Marion, Gehrig, Andrea, Glendon, Gord, Goldgar, David E, Golmard, Lisa, Greene, Mark H, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hassan, Tiara, Hentschel, Julia, Horvath, Judit, Izatt, Louise, Janavicius, Ramunas, Jiao, Yue, John, Esther M, Karlan, Beth Y, Kim, Sung-Won, Konstantopoulou, Irene, Kwong, Ava, Laugé, Anthony, Lee, Jong Won, Lesueur, Fabienne, Mebirouk, Noura, Meindl, Alfons, Mouret-Fourme, Emmanuelle, Musgrave, Hannah, Yie, Joanne Ngeow Yuen, Niederacher, Dieter, Park, Sue K, Pedersen, Inge Sokilde, Ramser, Juliane, Ramus, Susan J, Rantala, Johanna, Rashid, Muhammad U, Reichl, Florian, Ritter, Julia, Rump, Andreas, Santamariña, Marta, Saule, Claire, Schmidt, Gunnar, Schmutzler, Rita K, Senter, Leigha, Shariff, Saba, Singer, Christian F, Southey, Melissa C, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen, Teo, Soo Hwang, Terry, Mary Beth, Thomassen, Mads, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Vega, Ana, Wagner, Sebastian A, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weber, Bernhard HF, Yannoukakos, Drakoulis, Spurdle, Amanda B, Easton, Douglas F, and Chenevix-Trench, Georgia

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Women's Health, Digestive Diseases, Breast Cancer, Ovarian Cancer, Pancreatic Cancer, Prevention, Cancer, Urologic Diseases, Rare Diseases, 2.1 Biological and endogenous factors, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Breast Neoplasms, Male, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Infant, Newborn, Male, Mutation, Ovarian Neoplasms, Pancreatic Neoplasms, Risk, Clinical Sciences, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

PurposeTo provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.MethodsWe used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.ResultsBRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.ConclusionIn addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.

Published
2022

24. Federated analysis of BRCA1 and BRCA2 variation in a Japanese cohort

Author

Casaletto, James, Parsons, Michael, Markello, Charles, Iwasaki, Yusuke, Momozawa, Yukihide, Spurdle, Amanda B, and Cline, Melissa

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Cancer, Breast Cancer, Human Genome, Good Health and Well Being
Abstract

More than 40% of the germline variants in ClinVar today are variants of uncertain significance (VUSs). These variants remain unclassified in part because the patient-level data needed for their interpretation is siloed. Federated analysis can overcome this problem by "bringing the code to the data": analyzing the sensitive patient-level data computationally within its secure home institution and providing researchers with valuable insights from data that would not otherwise be accessible. We tested this principle with a federated analysis of breast cancer clinical data at RIKEN, derived from the BioBank Japan repository. We were able to analyze these data within RIKEN's secure computational framework without the need to transfer the data, gathering evidence for the interpretation of several variants. This exercise represents an approach to help realize the core charter of the Global Alliance for Genomics and Health (GA4GH): to responsibly share genomic data for the benefit of human health.

Published
2022

25. Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum

Author

Fortuno, Cristina, Feng, Bing-Jian, Carroll, Courtney, Innella, Giovanni, Kohlmann, Wendy, Lázaro, Conxi, Brunet, Joan, Feliubadaló, Lidia, Iglesias, Silvia, Menéndez, Mireia, Teulé, Alex, Ballinger, Mandy L., Thomas, David M., Campbell, Ainsley, Field, Mike, Harris, Marion, Kirk, Judy, Pachter, Nicholas, Poplawski, Nicola, Susman, Rachel, Tucker, Kathy, Wallis, Mathew, Williams, Rachel, Cops, Elisa, Goldgar, David, James, Paul A., Spurdle, Amanda B., Amor, David, Andrews, Lesley, Antill, Yoland, Balleine, Rosemary, Beesley, Jonathan, Bennett, Ian, Bogwitz, Michael, Bodek, Simon, Botes, Leon, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burke, Jo, Butow, Phyllis, Caldon, Liz, Campbell, Ian, Cao, Michelle, Chakrabarti, Anannya, Chauhan, Deepa, Chauhan, Manisha, Chenevix-Trench, Georgia, Christian, Alice, Cohen, Paul, Colley, Alison, Crook, Ashley, Cui, James, Courtney, Eliza, Cummings, Margaret, Dawson, Sarah-Jane, deFazio, Anna, Delatycki, Martin, Dickson, Rebecca, Dixon, Joanne, Edkins, Ted, Edwards, Stacey, Farshid, Gelareh, Fellows, Andrew, Fenton, Georgina, Field, Michael, Flanagan, James, Fong, Peter, Forrest, Laura, Fox, Stephen, French, Juliet, Friedlander, Michael, Gaff, Clara, Gattas, Mike, George, Peter, Greening, Sian, Harris, Marion, Hart, Stewart, Hayward, Nick, Hopper, John, Hoskins, Cass, Hunt, Clare, James, Paul, Jenkins, Mark, Kidd, Alexa, Kirk, Judy, Koehler, Jessica, Kollias, James, Lakhani, Sunil, Lawrence, Mitchell, Lee, Jason, Li, Shuai, Lindeman, Geoff, Lippey, Jocelyn, Lipton, Lara, Lobb, Liz, Loi, Sherene, Mann, Graham, Marsh, Deborah, McLachlan, Sue Anne, Meiser, Bettina, Milne, Roger, Nightingale, Sophie, OʼConnell, Shona, OʼSullivan, Sarah, Ortega, David Gallego, Pachter, Nick, Pang, Jia-Min, Pathak, Gargi, Patterson, Briony, Pearn, Amy, Phillips, Kelly, Pieper, Ellen, Ramus, Susan, Rickard, Edwina, Robinson, Bridget, Saleh, Mona, Skandarajah, Anita, Salisbury, Elizabeth, Saunders, Christobel, Saunus, Jodi, Savas, Peter, Scott, Rodney, Scott, Clare, Sexton, Adrienne, Shaw, Joanne, Shelling, Andrew, Srinivasa, Shweta, Simpson, Peter, Southey, Melissa, Spurdle, Amanda, Taylor, Jessica, Taylor, Renea, Thorne, Heather, Trainer, Alison, Tucker, Kathy, Visvader, Jane, Walker, Logan, Williams, Rachael, Winship, Ingrid, Young, Mary Ann, and Zaheed, Milita

Published
2024
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27. The impact of coding germline variants on contralateral breast cancer risk and survival

Author

Sahlberg, Kristine K., Børresen-Dale, Anne-Lise, Gram, Inger Torhild, Olsen, Karina Standahl, Engebråten, Olav, Naume, Bjørn, Geisler, Jürgen, OSBREAC, Grenaker Alnæs, Grethe I., Amor, David, Andrews, Lesley, Antill, Yoland, Balleine, Rosemary, Beesley, Jonathan, Bennett, Ian, Bogwitz, Michael, Botes, Leon, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burke, Jo, Butow, Phyllis, Caldon, Liz, Campbell, Ian, Cao, Michelle, Chakrabarti, Anannya, Chauhan, Deepa, Chauhan, Manisha, Chenevix-Trench, Georgia, Christian, Alice, Cohen, Paul, Colley, Alison, Crook, Ashley, Cui, James, Courtney, Eliza, Cummings, Margaret, Dawson, Sarah-Jane, DeFazio, Anna, Delatycki, Martin, Dickson, Rebecca, Dixon, Joanne, Edkins, Ted, Edwards, Stacey, Farshid, Gelareh, Fellows, Andrew, Fenton, Georgina, Field, Michael, Flanagan, James, Fong, Peter, Forrest, Laura, Fox, Stephen, French, Juliet, Friedlander, Michael, Gaff, Clara, Gattas, Mike, George, Peter, Greening, Sian, Harris, Marion, Hart, Stewart, Hayward, Nick, Hopper, John, Hoskins, Cass, Hunt, Clare, James, Paul, Jenkins, Mark, Kidd, Alexa, Kirk, Judy, Koehler, Jessica, Kollias, James, Lakhani, Sunil, Lawrence, Mitchell, Lee, Jason, Li, Shuai, Lindeman, Geoff, Lipton, Lara, Lobb, Liz, Loi, Sherene, Mann, Graham, Marsh, Deborah, McLachlan, Sue Anne, Meiser, Bettina, Milne, Roger, Nightingale, Sophie, O'Connell, Shona, O'Sullivan, Sarah, Ortega, David Gallego, Pachter, Nick, Pang, Jia-Min, Pathak, Gargi, Patterson, Briony, Pearn, Amy, Phillips, Kelly, Pieper, Ellen, Ramus, Susan, Rickard, Edwina, Robinson, Bridget, Saleh, Mona, Skandarajah, Anita, Salisbury, Elizabeth, Saunders, Christobel, Saunus, Jodi, Scott, Rodney, Scott, Clare, Sexton, Adrienne, Shelling, Andrew, Simpson, Peter, Southey, Melissa, Spurdle, Amanda, Taylor, Jessica, Taylor, Renea, Thorne, Heather, Trainer, Alison, Tucker, Kathy, Visvader, Jane, Walker, Logan, Williams, Rachael, Winship, Ingrid, Young, Mary Ann, Zaheed, Milita, Morra, Anna, Mavaddat, Nasim, Muranen, Taru A., Ahearn, Thomas U., Allen, Jamie, Andrulis, Irene L., Auvinen, Päivi, Becher, Heiko, Behrens, Sabine, Blomqvist, Carl, Bojesen, Stig E., Bolla, Manjeet K., Brauch, Hiltrud, Camp, Nicola J., Carvalho, Sara, Castelao, Jose E., Cessna, Melissa H., Chang-Claude, Jenny, Czene, Kamila, Decker, Brennan, Dennis, Joe, Dörk, Thilo, Dorling, Leila, Dunning, Alison M., Ekici, Arif B., Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine D., Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, Geurts-Giele, Willemina R.R., Giles, Graham G., Guénel, Pascal, Gündert, Melanie, Hahnen, Eric, Hall, Per, Hamann, Ute, Harrington, Patricia A., He, Wei, Heikkilä, Päivi, Hooning, Maartje J., Hoppe, Reiner, Howell, Anthony, Humphreys, Keith, Jakubowska, Anna, Jung, Audrey Y., Keeman, Renske, Kristensen, Vessela N., Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Mavroudis, Dimitrios, Milne, Roger L., Mulligan, Anna Marie, Newman, William G., Park-Simon, Tjoung-Won, Peterlongo, Paolo, Pharoah, Paul D.P., Rhenius, Valerie, Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Shah, Mitul, Spurdle, Amanda B., Tomlinson, Ian, Truong, Thérèse, van Veen, Elke M., Vreeswijk, Maaike P.G., Wang, Qin, Wendt, Camilla, Yang, Xiaohong R., Nevanlinna, Heli, Devilee, Peter, Easton, Douglas F., and Schmidt, Marjanka K.

Published
2023
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28. Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group

Author

Byrne, Alicia, Spurdle, Amanda, Palculict, Blake, Coe, Bradley, Deqiong, Ma, Lyon, Elaine, Groopman, Emily, Qian, Emily, Puffenberger, Erik, Riggs, Erin, Couch, Fergus, Maston, Glenn, Dziadzio, Hannah, Harraway, James, Mester, Jessica, Garcia, John, Lerner-Ellis, Jordan, Benson, Katherine, Avello, Kayleigh, McGoldrick, Kelly, Conlin, Laura, Zec, Lauren, Steeves, Marcie, Richardson, Marcy, Lebo, Matt, Kelly, Melissa, Gollob, Michael, Luo, Minjie, Ganapathi, Mythily, Watkins, Nicholas, Niu, Nifang, Sergouniotis, Panagiotis, Bayrak-Toydemir, Pinar, Schmidt, Ryan, Schilit, Samantha, Richards, Sarah, Pesaran, Tina, Pollin, Toni, Jobanputra, Vaidehi, Zhang, Wenying, Chen, Wuyan, Fan, Yuxin, Schmidt, Ryan J., Benson, Katherine A., Coe, Bradley P., Conlin, Laura K., Gollob, Michael H., Ma, Deqiong, Palculict, T. Blake, Pollin, Toni I., Rehm, Heidi L., Riggs, Erin R., Schilit, Samantha L.P., Sergouniotis, Panagiotis I., Tvrdik, Tatiana, and Lebo, Matthew S.

Published
2024
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30. The clinical utility and costs of whole-genome sequencing to detect cancer susceptibility variants—a multi-site prospective cohort study

Author

Aimee L. Davidson, Uwe Dressel, Sarah Norris, Daffodil M. Canson, Dylan M. Glubb, Cristina Fortuno, Georgina E. Hollway, Michael T. Parsons, Miranda E. Vidgen, Oliver Holmes, Lambros T. Koufariotis, Vanessa Lakis, Conrad Leonard, Scott Wood, Qinying Xu, Amy E. McCart Reed, Hilda A. Pickett, Mohammad K. Al-Shinnag, Rachel L. Austin, Jo Burke, Elisa J. Cops, Cassandra B. Nichols, Annabel Goodwin, Marion T. Harris, Megan J. Higgins, Emilia L. Ip, Catherine Kiraly-Borri, Chiyan Lau, Julia L. Mansour, Michael W. Millward, Melissa J. Monnik, Nicholas S. Pachter, Abiramy Ragunathan, Rachel D. Susman, Sharron L. Townshend, Alison H. Trainer, Simon L. Troth, Katherine M. Tucker, Mathew J. Wallis, Maie Walsh, Rachel A. Williams, Ingrid M. Winship, Felicity Newell, Emma Tudini, John V. Pearson, Nicola K. Poplawski, Helen G. Mar Fan, Paul A. James, Amanda B. Spurdle, Nicola Waddell, and Robyn L. Ward

Subjects
Familial cancer, Genetics, Variants, Whole-genome sequencing, Diagnostic testing, Health economics, Medicine, QH426-470
Abstract

Abstract Background Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer predisposition genes and be at higher risk for developing cancer. Methods This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken. Results Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing. Conclusions These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability.

Published
2023
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32. The clinical utility and costs of whole-genome sequencing to detect cancer susceptibility variants—a multi-site prospective cohort study

Author

Davidson, Aimee L., Dressel, Uwe, Norris, Sarah, Canson, Daffodil M., Glubb, Dylan M., Fortuno, Cristina, Hollway, Georgina E., Parsons, Michael T., Vidgen, Miranda E., Holmes, Oliver, Koufariotis, Lambros T., Lakis, Vanessa, Leonard, Conrad, Wood, Scott, Xu, Qinying, McCart Reed, Amy E., Pickett, Hilda A., Al-Shinnag, Mohammad K., Austin, Rachel L., Burke, Jo, Cops, Elisa J., Nichols, Cassandra B., Goodwin, Annabel, Harris, Marion T., Higgins, Megan J., Ip, Emilia L., Kiraly-Borri, Catherine, Lau, Chiyan, Mansour, Julia L., Millward, Michael W., Monnik, Melissa J., Pachter, Nicholas S., Ragunathan, Abiramy, Susman, Rachel D., Townshend, Sharron L., Trainer, Alison H., Troth, Simon L., Tucker, Katherine M., Wallis, Mathew J., Walsh, Maie, Williams, Rachel A., Winship, Ingrid M., Newell, Felicity, Tudini, Emma, Pearson, John V., Poplawski, Nicola K., Mar Fan, Helen G., James, Paul A., Spurdle, Amanda B., Waddell, Nicola, and Ward, Robyn L.

Published
2023
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33. A Kallikrein 15 (KLK15) single nucleotide polymorphism located close to a novel exon shows evidence of association with poor ovarian cancer survival

Author

Song Honglin, Bolton Kelly L, Srinivasan Srilakshmi, Skeie Lene, Lose Felicity, Tan Olivia L, Dong Ying, Higgins Melanie, O'Mara Tracy, Nagle Christina M, Batra Jyotsna, Ramus Susan J, Gayther Simon A, Pharoah Paul DP, Kedda Mary-Anne, Spurdle Amanda B, and Clements Judith A

Subjects
Kallikrein 15, single nucleotide polymorphisms, ovarian cancer, splice variants, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background KLK15 over-expression is reported to be a significant predictor of reduced progression-free survival and overall survival in ovarian cancer. Our aim was to analyse the KLK15 gene for putative functional single nucleotide polymorphisms (SNPs) and assess the association of these and KLK15 HapMap tag SNPs with ovarian cancer survival. Results In silico analysis was performed to identify KLK15 regulatory elements and to classify potentially functional SNPs in these regions. After SNP validation and identification by DNA sequencing of ovarian cancer cell lines and aggressive ovarian cancer patients, 9 SNPs were shortlisted and genotyped using the Sequenom iPLEX Mass Array platform in a cohort of Australian ovarian cancer patients (N = 319). In the Australian dataset we observed significantly worse survival for the KLK15 rs266851 SNP in a dominant model (Hazard Ratio (HR) 1.42, 95% CI 1.02-1.96). This association was observed in the same direction in two independent datasets, with a combined HR for the three studies of 1.16 (1.00-1.34). This SNP lies 15bp downstream of a novel exon and is predicted to be involved in mRNA splicing. The mutant allele is also predicted to abrogate an HSF-2 binding site. Conclusions We provide evidence of association for the SNP rs266851 with ovarian cancer survival. Our results provide the impetus for downstream functional assays and additional independent validation studies to assess the role of KLK15 regulatory SNPs and KLK15 isoforms with alternative intracellular functional roles in ovarian cancer survival.

Published
2011
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34. Effect of BRCA2 sequence variants predicted to disrupt exonic splice enhancers on BRCA2 transcripts

Author

Brewster Brooke L, Pettigrew Christopher A, Whiley Phillip J, Walker Logan C, Spurdle Amanda B, and Brown Melissa A

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Genetic screening of breast cancer patients and their families have identified a number of variants of unknown clinical significance in the breast cancer susceptibility genes, BRCA1 and BRCA2. Evaluation of such unclassified variants may be assisted by web-based bioinformatic prediction tools, although accurate prediction of aberrant splicing by unclassified variants affecting exonic splice enhancers (ESEs) remains a challenge. Methods This study used a combination of RT-PCR analysis and splicing reporter minigene assays to assess five unclassified variants in the BRCA2 gene that we had previously predicted to disrupt an ESE using bioinformatic approaches. Results Analysis of BRCA2 c.8308 G > A (p.Ala2770Thr) by mRNA analysis, and BRCA2 c.8962A > G (p.Ser2988Gly), BRCA2 c.8972G > A (p.Arg2991His), BRCA2 c.9172A > G (p.Ser3058Gly), and BRCA2 c.9213G > T (p.Glu3071Asp) by a minigene assay, revealed no evidence for aberrant splicing. Conclusions These results illustrate the need for improved methods for predicting functional ESEs and the potential consequences of sequence variants contained therein.

Published
2010
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35. Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants

Author

Fortuno, Cristina, Lee, Kristy, Olivier, Magali, Pesaran, Tina, Mai, Phuong L, Andrade, Kelvin C, Attardi, Laura D, Crowley, Stephanie, Evans, D Gareth, Feng, Bing‐Jian, Foreman, Ann KM, Frone, Megan N, Huether, Robert, James, Paul A, McGoldrick, Kelly, Mester, Jessica, Seifert, Bryce A, Slavin, Thomas P, Witkowski, Leora, Zhang, Liying, Plon, Sharon E, Spurdle, Amanda B, Savage, Sharon A, and Panel, the ClinGen TP53 Variant Curation Expert

Subjects
Human Genome, Prevention, Genetics, Cancer, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Genetic Testing, Genetic Variation, Germ Cells, Humans, Li-Fraumeni Syndrome, Tumor Suppressor Protein p53, United States, cancer, pathogenic variant, TP53, variant curation, ClinGen TP53 Variant Curation Expert Panel, Clinical Sciences, Genetics & Heredity
Abstract

Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, including early-onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were developed for 20 ACMG/AMP criteria, while nine were deemed not applicable. The original strength level for the 10 criteria was also adjusted due to current evidence. Use of TP53-specific guidelines and sharing of clinical data among experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53-specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification.

Published
2021

36. Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup

Author

Biesecker, Leslie G., Harrison, Steven M., Tayoun, Ahmad A., Berg, Jonathan S., Brenner, Steven E., Cutting, Garry R., Ellard, Sian, Greenblatt, Marc S., Kang, Peter, Karbassi, Izabela, Karchin, Rachel, Mester, Jessica, O’Donnell-Luria, Anne, Pesaran, Tina, Plon, Sharon E., Rehm, Heidi L., Strande, Natasha T., Tavtigian, Sean V., Topper, Scott, Walker, Logan C., Hoya, Miguel de la, Wiggins, George A.R., Lindy, Amanda, Vincent, Lisa M., Parsons, Michael T., Canson, Daffodil M., Bis-Brewer, Dana, Cass, Ashley, Tchourbanov, Alexander, Zimmermann, Heather, Byrne, Alicia B., Karam, Rachid, and Spurdle, Amanda B.

Published
2023
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37. The effect of sample size on polygenic hazard models for prostate cancer

Author

Karunamuni, Roshan A, Huynh-Le, Minh-Phuong, Fan, Chun C, Eeles, Rosalind A, Easton, Douglas F, Kote-Jarai, ZSofia, Amin Al Olama, Ali, Benlloch Garcia, Sara, Muir, Kenneth, Gronberg, Henrik, Wiklund, Fredrik, Aly, Markus, Schleutker, Johanna, Sipeky, Csilla, Tammela, Teuvo LJ, Nordestgaard, Børge G, Key, Tim J, Travis, Ruth C, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Pharoah, Paul, Pashayan, Nora, Khaw, Kay-Tee, Thibodeau, Stephen N, McDonnell, Shannon K, Schaid, Daniel J, Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S, Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Brenner, Hermann, Schöttker, Ben, Holleczek, Bernd, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Clements, Judith A, Spurdle, Amanda, Teixeira, Manuel R, Paulo, Paula, Maia, Sofia, Pandha, Hardev, Michael, Agnieszka, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, and Seibert, Tyler M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Cancer, Aging, Urologic Diseases, Clinical Trials as Topic, Genome-Wide Association Study, Humans, Male, Models, Genetic, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Proportional Hazards Models, Prostatic Neoplasms, Sample Size, Australian Prostate Cancer BioResource, PRACTICAL Consortium, Genetics, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

Published
2020

38. A Genetic Risk Score to Personalize Prostate Cancer Screening, Applied to Population Data

Author

Huynh-Le, Minh-Phuong, Fan, Chun Chieh, Karunamuni, Roshan, Walsh, Eleanor I, Turner, Emma L, Lane, J Athene, Martin, Richard M, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Parsons, J Kellogg, Eeles, Rosalind A, Easton, Douglas F, Kote-Jarai, Zsofia, Al Olama, Ali Amin, Garcia, Sara Benlloch, Muir, Kenneth, Grönberg, Henrik, Wiklund, Fredrik, Aly, Markus, Schleutker, Johanna, Sipeky, Csilla, Tammela, Teuvo LJ, Nordestgaard, Børge Grønne, Key, Timothy J, Travis, Ruth C, Pharoah, Paul DP, Pashayan, Nora, Khaw, Kay-Tee, Thibodeau, Stephen N, McDonnell, Shannon K, Schaid, Daniel J, Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S, Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa A, Brenner, Hermann, Schöttker, Ben, Holleczek, Bernd, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Slavov, Chavdar Kroumov, Kaneva, Radka P, Mitev, Vanio I, Batra, Jyotsna, Clements, Judith A, Spurdle, Amanda B, BioResource, for the Australian Prostate Cancer, Teixeira, Manuel R, Paulo, Paula, Maia, Sofia, Pandha, Hardev, Michael, Agnieszka, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, Seibert, Tyler M, and Consortium, for the PRACTICAL

Subjects
Biomedical and Clinical Sciences, Health Sciences, Clinical Sciences, Oncology and Carcinogenesis, Aging, Prostate Cancer, Cancer, Prevention, Urologic Diseases, Good Health and Well Being, Aged, Early Detection of Cancer, Humans, Male, Middle Aged, Neoplasm Grading, Population Control, Prostatic Neoplasms, Australian Prostate Cancer BioResource, PRACTICAL Consortium, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundA polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.MethodsUnited Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups.ResultsThe expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age.ConclusionsPHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS.ImpactPersonalized genetic risk assessments could inform prostate cancer screening decisions.

Published
2020

39. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Author

Zhang, Yan Dora, Hurson, Amber N, Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F, Milne, Roger L, Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K, Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T, Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B, Casey, Graham, Schmit, Stephanie L, O'Mara, Tracy A, Spurdle, Amanda B, Thompson, Deborah J, Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H, Iles, Mark M, Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D Timothy, Ward, Sarah V, Bondy, Melissa L, Houlston, Richard, Wiencke, John K, Melin, Beatrice, Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R, Amos, Christopher I, Hung, Rayjean J, Brennan, Paul, McKay, James, Caporaso, Neil E, Berndt, Sonja I, Birmann, Brenda M, Camp, Nicola J, Kraft, Peter, Rothman, Nathaniel, Slager, Susan L, Berchuck, Andrew, Pharoah, Paul DP, Sellers, Thomas A, Gayther, Simon A, Pearce, Celeste L, Goode, Ellen L, Schildkraut, Joellen M, Moysich, Kirsten B, Amundadottir, Laufey T, Jacobs, Eric J, Klein, Alison P, Petersen, Gloria M, Risch, Harvey A, Stolzenberg-Solomon, Rachel Z, Wolpin, Brian M, Li, Donghui, Eeles, Rosalind A, Haiman, Christopher A, Kote-Jarai, Zsofia, Schumacher, Fredrick R, Al Olama, Ali Amin, Purdue, Mark P, Scelo, Ghislaine, Dalgaard, Marlene D, Greene, Mark H, Grotmol, Tom, Kanetsky, Peter A, McGlynn, Katherine A, Nathanson, Katherine L, Turnbull, Clare, Wiklund, Fredrik, 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), and Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL)

Subjects
Breast Cancer Association Consortium, Barrett’s and Esophageal Adenocarcinoma Consortium, Colon Cancer Family Registry, Transdisciplinary Studies of Genetic Variation in Colorectal Cancer, Endometrial Cancer Association Consortium, Genetics and Epidemiology of Colorectal Cancer Consortium, Melanoma Genetics Consortium, Glioma International Case-Control Study, International Lung Cancer Consortium, Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies, Ovarian Cancer Association Consortium, Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium, Pancreatic Cancer Cohort Consortium, Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome, Renal Cancer GWAS, Testicular Cancer Consortium, Animals, Humans, Neoplasms, Genetic Predisposition to Disease, Incidence, Risk Assessment, Risk Factors, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Models, Genetic, Female, Male, Genome-Wide Association Study, Human Genome, Prevention, Cancer, Prostate Cancer, Genetics, Urologic Diseases, 2.1 Biological and endogenous factors
Abstract

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

Published
2020

41. The association between genetically elevated polyunsaturated fatty acids and risk of cancer

Author

Tintle, Nathan, Rice, Terri, Cheng, Iona, Jenkins, Mark, Gallinger, Steve, Cornish, Alex J., Sud, Amit, Vijayakrishnan, Jayaram, Wrensch, Margaret, Johansson, Mattias, Norman, Aaron D., Klein, Alison, Clay-Gilmour, Alyssa, Franke, Andre, Ardisson Korat, Andres V., Wheeler, Bill, Nilsson, Björn, Smith, Caren, Heng, Chew-Kiat, Song, Ci, Riadi, David, Claus, Elizabeth B., Ellinghaus, Eva, Ostroumova, Evgenia, Hosnijeh, de Vathaire, Florent, Cugliari, Giovanni, Matullo, Giuseppe, Oi-Lin Ng, Irene, Passow, Jeanette E., Foo, Jia Nee, Han, Jiali, Liu, Jianjun, Barnholtz-Sloan, Jill, Schildkraut, Joellen M., Maris, John, Wiemels, Joseph L., Hemminki, Kari, Yang, Keming, Kiemeney, Lambertus A., Wu, Lang, Amundadottir, Laufey, Stern, Marc-Henri, Boutron, Marie-Christine, Iles, Mark Martin, Purdue, Mark P., Stanulla, Martin, Bondy, Melissa, Gaudet, Mia, Mobuchon, Lenha, Camp, Nicola J., Sham, Pak Chung, Guénel, Pascal, Brennan, Paul, Taylor, Philip R., Ostrom, Quinn, Stolzenberg-Solomon, Rachael, Dorajoo, Rajkumar, Houlston, Richard, Jenkins, Robert B., Diskin, Sharon, Berndt, Sonja I., Tsavachidis, Spiridon, Channock, Stephen J., Harrison, Tabitha, Galesloot, Tessel, Gyllensten, Ulf, Joseph, Vijai, Shi, Y., Yang, Wenjian, Lin, Yi, Van Den Eeden, Stephen K., Haycock, Philip C., Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N., Burgess, Stephen, Khankari, Nikhil K., Tsilidis, Konstantinos K., Gaunt, Tom R., Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M., OMara, Tracy, Spurdle, Amanda B., Iles, Mark M., Law, Matthew H., Slager, Susan L., Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R., Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C., Block, Robert C., Amos, Christopher I., Hung, Rayjean J., Zheng, Wei, Gunter, Marc J., Smith, George Davey, Relton, Caroline, and Martin, Richard M.

Published
2023
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42. Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare

Author

Stark, Zornitza, Boughtwood, Tiffany, Haas, Matilda, Braithwaite, Jeffrey, Gaff, Clara L., Goranitis, Ilias, Spurdle, Amanda B., Hansen, David P., Hofmann, Oliver, Laing, Nigel, Metcalfe, Sylvia, Newson, Ainsley J., Scott, Hamish S., Thorne, Natalie, Ward, Robyn L., Dinger, Marcel E., Best, Stephanie, Long, Janet C., Grimmond, Sean M., Pearson, John, Waddell, Nicola, Barnett, Christopher P., Cook, Matthew, Field, Michael, Fielding, David, Fox, Stephen B., Gecz, Jozef, Jaffe, Adam, Leventer, Richard J., Lockhart, Paul J., Lunke, Sebastian, Mallett, Andrew J., McGaughran, Julie, Mileshkin, Linda, Nones, Katia, Roscioli, Tony, Scheffer, Ingrid E., Semsarian, Christopher, Simons, Cas, Thomas, David M., Thorburn, David R., Tothill, Richard, White, Deborah, Dunwoodie, Sally, Simpson, Peter T., Phillips, Peta, Brion, Marie-Jo, Finlay, Keri, Quinn, Michael CJ., Mattiske, Tessa, Tudini, Emma, Boggs, Kirsten, Murray, Sean, Wells, Kathy, Cannings, John, Sinclair, Andrew H., Christodoulou, John, and North, Kathryn N.

Published
2023
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43. Assessment of blind predictions of the clinical significance of BRCA1 and BRCA2 variants

Author

Cline, Melissa S, Babbi, Giulia, Bonache, Sandra, Cao, Yue, Casadio, Rita, de la Cruz, Xavier, Díez, Orland, Gutiérrez‐Enríquez, Sara, Katsonis, Panagiotis, Lai, Carmen, Lichtarge, Olivier, Martelli, Pier L, Mishne, Gilad, Moles‐Fernández, Alejandro, Montalban, Gemma, Mooney, Sean D, O'Conner, Robert, Ootes, Lars, Özkan, Selen, Padilla, Natalia, Pagel, Kymberleigh A, Pejaver, Vikas, Radivojac, Predrag, Riera, Casandra, Savojardo, Castrense, Shen, Yang, Sun, Yuanfei, Topper, Scott, Parsons, Michael T, Spurdle, Amanda B, Goldgar, David E, and Consortium, The ENIGMA

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Breast Cancer, Cancer, Ovarian Cancer, Rare Diseases, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Computational Biology, Early Detection of Cancer, Female, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Humans, Models, Genetic, Ovarian Neoplasms, BRCA, BRCA1, BRCA2, CAGI, CAGI5, variant interpretation, ENIGMA Consortium, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

Testing for variation in BRCA1 and BRCA2 (commonly referred to as BRCA1/2), has emerged as a standard clinical practice and is helping countless women better understand and manage their heritable risk of breast and ovarian cancer. Yet the increased rate of BRCA1/2 testing has led to an increasing number of Variants of Uncertain Significance (VUS), and the rate of VUS discovery currently outpaces the rate of clinical variant interpretation. Computational prediction is a key component of the variant interpretation pipeline. In the CAGI5 ENIGMA Challenge, six prediction teams submitted predictions on 326 newly-interpreted variants from the ENIGMA Consortium. By evaluating these predictions against the new interpretations, we have gained a number of insights on the state of the art of variant prediction and specific steps to further advance this state of the art.

Published
2019

44. Shariant platform: Enabling evidence sharing across Australian clinical genetic-testing laboratories to support variant interpretation

Author

Akesson, Lauren, Allcock, Richard, Ashton, Katie, Bell, Damon A., Brown, Anna, Buckley, Michael, Burnett, John R., Burrows, Linda, Byrne, Alicia, Chan, Eva, Cliffe, Corrina, Clifton-Bligh, Roderick, Dooley, Susan, Fernandez, Miriam Fanjul, Farnsworth, Elizabeth, Ha, Thuong, Henry, Denae, Holds, Duncan, Holman, Katherine, Jackson, Matilda, Kang, Sinlay, Luxford, Catherine, McManus, Sam, Mehrtens, Rachael, Meldrum, Cliff, Mossman, David, Pantaleo, Sarah-Jane, Phelan, Dean, Pontikinas, Electra, Ravine, Anja, Roscioli, Tony, Scott, Rodney, Simons, Keryn, Vanwageningen, Oliver, Tudini, Emma, Andrews, James, Lawrence, David M., King-Smith, Sarah L., Baker, Naomi, Baxter, Leanne, Beilby, John, Bennetts, Bruce, Beshay, Victoria, Black, Michael, Boughtwood, Tiffany F., Brion, Kristian, Cheong, Pak Leng, Christie, Michael, Christodoulou, John, Chong, Belinda, Cox, Kathy, Davis, Mark R., Dejong, Lucas, Dinger, Marcel E., Doig, Kenneth D., Douglas, Evelyn, Dubowsky, Andrew, Ellul, Melissa, Fellowes, Andrew, Fisk, Katrina, Fortuno, Cristina, Friend, Kathryn, Gallagher, Renee L., Gao, Song, Hackett, Emma, Hadler, Johanna, Hipwell, Michael, Ho, Gladys, Hollway, Georgina, Hooper, Amanda J., Kassahn, Karin S., Krishnaraj, Rahul, Lau, Chiyan, Le, Huong, San Leong, Huei, Lundie, Ben, Lunke, Sebastian, Marty, Anthony, McPhillips, Mary, Nguyen, Lan T., Nones, Katia, Palmer, Kristen, Pearson, John V., Quinn, Michael C.J., Rawlings, Lesley H., Sadedin, Simon, Sanchez, Louisa, Schreiber, Andreas W., Sigalas, Emanouil, Simsek, Aygul, Soubrier, Julien, Stark, Zornitza, Thompson, Bryony A., U, James, Vakulin, Cassandra G., Wells, Amanda V., Wise, Cheryl A., Woods, Rick, Ziolkowski, Andrew, Brion, Marie-Jo, Scott, Hamish S., Thorne, Natalie P., and Spurdle, Amanda B.

Published
2022
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45. Coffee consumption and risk of endometrial cancer: a pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium (E2C2)

Author

Crous-Bou, Marta, Du, Mengmeng, Gunter, Marc J, Setiawan, Veronica W, Schouten, Leo J, Shu, Xiao-ou, Wentzensen, Nicolas, Bertrand, Kimberly A, Cook, Linda S, Friedenreich, Christine M, Gapstur, Susan M, Goodman, Marc T, Ibiebele, Torukiri I, La Vecchia, Carlo, Levi, Fabio, Liao, Linda M, Negri, Eva, McCann, Susan E, O’Connell, Kelly, Palmer, Julie R, Patel, Alpa V, Ponte, Jeanette, Reynolds, Peggy, Sacerdote, Carlotta, Sinha, Rashmi, Spurdle, Amanda B, Trabert, Britton, van den Brandt, Piet A, Webb, Penelope M, Petruzella, Stacey, Olson, Sara H, and De Vivo, Immaculata

Published
2022
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46. 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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47. The association between genetically elevated polyunsaturated fatty acids and risk of cancerResearch in context

Author

Philip C. Haycock, Maria Carolina Borges, Kimberley Burrows, Rozenn N. Lemaitre, Stephen Burgess, Nikhil K. Khankari, Konstantinos K. Tsilidis, Tom R. Gaunt, Gibran Hemani, Jie Zheng, Therese Truong, Brenda M. Birmann, Tracy OMara, Amanda B. Spurdle, Mark M. Iles, Matthew H. Law, Susan L. Slager, Fatemeh Saberi Hosnijeh, Daniela Mariosa, Michelle Cotterchio, James R. Cerhan, Ulrike Peters, Stefan Enroth, Puya Gharahkhani, Loic Le Marchand, Ann C. Williams, Robert C. Block, Christopher I. Amos, Rayjean J. Hung, Wei Zheng, Marc J. Gunter, George Davey Smith, Caroline Relton, Richard M. Martin, Nathan Tintle, Terri Rice, Iona Cheng, Mark Jenkins, Steve Gallinger, Alex J. Cornish, Amit Sud, Jayaram Vijayakrishnan, Margaret Wrensch, Mattias Johansson, Aaron D. Norman, Alison Klein, Alyssa Clay-Gilmour, Andre Franke, Andres V. Ardisson Korat, Bill Wheeler, Björn Nilsson, Caren Smith, Chew-Kiat Heng, Ci Song, David Riadi, Elizabeth B. Claus, Eva Ellinghaus, Evgenia Ostroumova, Hosnijeh, Florent de Vathaire, Giovanni Cugliari, Giuseppe Matullo, Irene Oi-Lin Ng, Jeanette E. Passow, Jia Nee Foo, Jiali Han, Jianjun Liu, Jill Barnholtz-Sloan, Joellen M. Schildkraut, John Maris, Joseph L. Wiemels, Kari Hemminki, Keming Yang, Lambertus A. Kiemeney, Lang Wu, Laufey Amundadottir, Marc-Henri Stern, Marie-Christine Boutron, Mark Martin Iles, Mark P. Purdue, Martin Stanulla, Melissa Bondy, Mia Gaudet, Lenha Mobuchon, Nicola J. Camp, Pak Chung Sham, Pascal Guénel, Paul Brennan, Philip R. Taylor, Quinn Ostrom, Rachael Stolzenberg-Solomon, Rajkumar Dorajoo, Richard Houlston, Robert B. Jenkins, Sharon Diskin, Sonja I. Berndt, Spiridon Tsavachidis, Stephen J. Channock, Tabitha Harrison, Tessel Galesloot, Ulf Gyllensten, Vijai Joseph, Y. Shi, Wenjian Yang, Yi Lin, and Stephen K. Van Den Eeden

Subjects
Mendelian randomization, Cancer risk, Polyunsaturated fatty acids, Omega 3, Omega 6, Delta-5 desaturase, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. Methods: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. Findings: Genetically elevated PUFA desaturase activity was associated (P

Published
2023
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48. Splicing annotation of endometrial cancer GWAS risk loci reveals potentially causal variants and supports a role for NF1 and SKAP1 as susceptibility genes

Author

Daffodil M. Canson, Tracy A. O’Mara, Amanda B. Spurdle, and Dylan M. Glubb

Subjects
endometrial cancer, GWAS, splicing, spliceogenic, sQTL, NF1, Genetics, QH426-470
Abstract

Summary: Alternative splicing contributes to cancer development. Indeed, splicing analysis of cancer genome-wide association study (GWAS) risk variants has revealed likely causal variants. To systematically assess GWAS variants for splicing effects, we developed a prioritization workflow using a combination of splicing prediction tools, alternative transcript isoforms, and splicing quantitative trait locus (sQTL) annotations. Application of this workflow to candidate causal variants from 16 endometrial cancer GWAS risk loci highlighted single-nucleotide polymorphisms (SNPs) that were predicted to upregulate alternative transcripts. For two variants, sQTL data supported the predicted impact on splicing. At the 17q11.2 locus, the protective allele for rs7502834 was associated with increased splicing of an exon in a NF1 alternative transcript encoding a truncated protein in adipose tissue and is consistent with an endometrial cancer transcriptome-wide association study (TWAS) finding in adipose tissue. Notably, NF1 haploinsufficiency is protective for obesity, a well-established risk factor for endometrial cancer. At the 17q21.32 locus, the rs2278868 risk allele was predicted to upregulate a SKAP1 transcript that is subject to nonsense-mediated decay, concordant with a corresponding sQTL in lymphocytes. This is consistent with a TWAS finding that indicates decreased SKAP1 expression in blood increases endometrial cancer risk. As SKAP1 is involved in T cell immune responses, decreased SKAP1 expression may impact endometrial tumor immunosurveillance. In summary, our analysis has identified potentially causal endometrial cancer GWAS risk variants with plausible biological mechanisms and provides a splicing annotation workflow to aid interpretation of other GWAS datasets.

Published
2023
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49. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author

Barnes, Daniel R., Rookus, Matti A., McGuffog, Lesley, Leslie, Goska, Mooij, Thea M., Dennis, Joe, Mavaddat, Nasim, Adlard, Julian, Ahmed, Munaza, Aittomäki, Kristiina, Andrieu, Nadine, Andrulis, Irene L., Arnold, Norbert, Arun, Banu K., Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B., Barrowdale, Daniel, Benitez, Javier, Berthet, Pascaline, Białkowska, Katarzyna, Blanco, Amie M., Blok, Marinus J., Bonanni, Bernardo, Boonen, Susanne E., Borg, Åke, Bozsik, Aniko, Bradbury, Angela R., Brennan, Paul, Brewer, Carole, Brunet, Joan, Buys, Saundra S., Caldés, Trinidad, Caligo, Maria A., Campbell, Ian, Christensen, Lise Lotte, Chung, Wendy K., Claes, Kathleen B.M., Colas, Chrystelle, Collonge-Rame, Marie-Agnès, Delnatte, Capucine, Faivre, Laurence, Giraud, Sophie, Lasset, Christine, Mari, Véronique, Mebirouk, Noura, Mouret-Fourme, Emmanuelle, Schuster, Hélène, Stoppa-Lyonnet, Dominique, Antoniou, Antonis, Cook, Jackie, Davidson, Rosemarie, Easton, Douglas, Eeles, Ros, Evans, D. Gareth, Frost, Debra, Hanson, Helen, Izatt, Louise, Ong, Kai-ren, Side, Lucy, O’Shaughnessy-Kirwan, Aoife, Tischkowitz, Marc, Walker, Lisa, Daly, Mary B., de la Hoya, Miguel, de Putter, Robin, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M., Dorfling, Cecilia M., Dumont, Martine, Ejlertsen, Bent, Engel, Christoph, Foretova, Lenka, Fostira, Florentia, Friedlander, Michael, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gehrig, Andrea, Gerdes, Anne-Marie, Gesta, Paul, Glendon, Gord, Godwin, Andrew K., Goldgar, David E., González-Neira, Anna, Greene, Mark H., Gschwantler-Kaulich, Daphne, Hahnen, Eric, Hamann, Ute, Hentschel, Julia, Hogervorst, Frans B.L., Hooning, Maartje J., Horvath, Judit, Hu, Chunling, Hulick, Peter J., Imyanitov, Evgeny N., Chenevix-Trench, Georgia, Phillips, Kelly-Anne, Spurdle, Amanda, Blok, Marinus, Hogervorst, Frans, Hooning, Maartje, Koudijs, Marco, Mensenkamp, Arjen, Meijers-Heijboer, Hanne, Rookus, Matti, Engelen, Klaartje van, Noguès, Catherine, Isaacs, Claudine, Izquierdo, Angel, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, John, Esther M., Joseph, Vijai, Karlan, Beth Y., Kast, Karin, Kruse, Torben A., Kwong, Ava, Laitman, Yael, Lazaro, Conxi, Lester, Jenny, Lesueur, Fabienne, Liljegren, Annelie, Loud, Jennifer T., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Meijers-Heijboer, Hanne E.J., Meindl, Alfons, Mensenkamp, Arjen R., Miller, Austin, Montagna, Marco, Mukherjee, Semanti, Mulligan, Anna Marie, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Niederacher, Dieter, Nielsen, Finn Cilius, Nikitina-Zake, Liene, Olah, Edith, Olopade, Olufunmilayo I., Osorio, Ana, Ott, Claus-Eric, Papi, Laura, Park, Sue K., Parsons, Michael T., Pedersen, Inge Sokilde, Peissel, Bernard, Peixoto, Ana, Peterlongo, Paolo, Pfeiler, Georg, Prajzendanc, Karolina, Pujana, Miquel Angel, Radice, Paolo, Ramser, Juliane, Ramus, Susan J., Rantala, Johanna, Rennert, Gad, Risch, Harvey A., Robson, Mark, Rønlund, Karina, Salani, Ritu, Senter, Leigha, Shah, Payal D., Sharma, Priyanka, Side, Lucy E., Singer, Christian F., Slavin, Thomas P., Soucy, Penny, Southey, Melissa C., Spurdle, Amanda B., Steinemann, Doris, Steinsnyder, Zoe, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Thull, Darcy L., Tognazzo, Silvia, Toland, Amanda E., Trainer, Alison H., Tung, Nadine, van Engelen, Klaartje, van Rensburg, Elizabeth J., Vega, Ana, Vierstraete, Jeroen, Wagner, Gabriel, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Yadav, Siddhartha, Yang, Xin, Yannoukakos, Drakoulis, Zimbalatti, Dario, Offit, Kenneth, Thomassen, Mads, Couch, Fergus J., Schmutzler, Rita K., Simard, Jacques, Easton, Douglas F., and Antoniou, Antonis C.

Published
2020
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