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1. A two-phase case–control study for colorectal cancer genetic susceptibility: candidate genes from chromosomal regions 9q22 and 3q22

Author

Abulí, A, Fernández-Rozadilla, C, Giráldez, MD, Muñoz, J, Gonzalo, V, Bessa, X, Bujanda, L, Reñé, JM, Lanas, A, García, AM, Saló, J, Argüello, L, Vilella, À, Carreño, R, Jover, R, Xicola, RM, Llor, X, Carvajal-Carmona, L, Tomlinson, IPM, Kerr, DJ, Houlston, RS, Piqué, JM, Carracedo, A, Castells, A, Andreu, M, Ruiz-Ponte, C, Castellví-Bel, S, and for the Gastrointestinal Oncology Group of the Spanish Gastroenterological Association

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Prevention, Digestive Diseases, Colo-Rectal Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, Aged, Antigens, CD, Carrier Proteins, Case-Control Studies, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 9, Colorectal Neoplasms, DNA-Binding Proteins, GPI-Linked Proteins, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Nuclear Proteins, Polymorphism, Single Nucleotide, Semaphorins, colorectal neoplasm, genetic predisposition to disease, single-nucleotide polymorphism, genetic association study, Gastrointestinal Oncology Group of the Spanish Gastroenterological Association, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundColorectal cancer (CRC) is the second cause of cancer-related death in the Western world. Much of the CRC genetic risk remains unidentified and may be attributable to a large number of common, low-penetrance genetic variants. Genetic linkage studies in CRC families have reported additional association with regions 9q22-31, 3q21-24, 7q31, 11q, 14q and 22q. There are several plausible candidate genes for CRC susceptibility within the aforementioned linkage regions including PTCH1, XPA and TGFBR1 in 9q22-31, and EPHB1 and MRAS in 3q21-q24.MethodsCRC cases and matched controls were from EPICOLON, a prospective, multicentre, nationwide Spanish initiative, composed of two independent phases. Phase 1 corresponded to 515 CRC cases and 515 controls, whereas phase 2 consisted of 901 CRC cases and 909 controls. Genotyping was performed for 172 single-nucleotide polymorphisms (SNPs) in 84 genes located within regions 9q22-31 and 3q21-q24.ResultsNone of the 172 SNPs analysed in our study could be formally associated with CRC risk. However, rs1444601 (TOPBP1) and rs13088006 (CDV3) in region 3q22 showed interesting results and may have an effect on CRC risk.ConclusionsTOPBP1 and CDV3 genetic variants on region 3q22 may modulate CRC risk. Further validation and meta-analysis should be undertaken in larger CRC cohorts.

Published
2011

2. Replication study of SNP associations for colorectal cancer in Hong Kong Chinese

Author

Ho, JW, Choi, S-C, Lee, Y-F, Hui, TC, Cherny, SS, Garcia-Barceló, M-M, Carvajal-Carmona, L, Liu, R, To, S-H, Yau, T-K, Chung, CC, Yau, CC, Hui, SM, Lau, PY, Yuen, C-H, Wong, Y-W, Ho, S, Fung, SS, Tomlinson, IP, Houlston, RS, Cheng, KK, and Sham, PC

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Aging, Digestive Diseases, Prevention, Genetics, Human Genome, Cancer, Colo-Rectal Cancer, Aged, Case-Control Studies, Colorectal Neoplasms, Female, Hong Kong, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, colorectal cancer, genetic, association, replication, Chinese, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundRecent genome-wide association studies of colorectal cancer (CRC) have identified common single-nucleotide polymorphisms (SNPs) mapping to 10 independent loci that confer modest increased risk. These studies have been conducted in European populations and it is unclear whether these observations generalise to populations with different ethnicities and rates of CRC.MethodsAn association study was performed on 892 CRC cases and 890 controls recruited from the Hong Kong Chinese population, genotyping 32 SNPs, which were either associated with CRC in previous studies or are in close proximity to previously reported risk SNPs.ResultsTwelve of the SNPs showed evidence of an association. The strongest associations were provided by rs10795668 on 10p14, rs4779584 on 15q14 and rs12953717 on 18q21.2. There was significant linear association between CRC risk and the number of independent risk variants possessed by an individual (P=2.29 × 10(-5)).ConclusionThese results indicate that some previously reported SNP associations also impact on CRC risk in the Chinese population. Possible reasons for failure of replication for some loci include inadequate study power, differences in allele frequency, linkage disequilibrium structure or effect size between populations. Our results suggest that many associations for CRC are likely to generalise across populations.

Published
2011

3. COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

Author

Tomlinson, IPM, Dunlop, M, Campbell, H, Zanke, B, Gallinger, S, Hudson, T, Koessler, T, Pharoah, PD, Niittymäkix, I, Tuupanenx, S, Aaltonen, LA, Hemminki, K, Lindblom, A, Försti, A, Sieber, O, Lipton, L, van Wezel, T, Morreau, H, Wijnen, JT, Devilee, P, Matsuda, K, Nakamura, Y, Castellví-Bel, S, Ruiz-Ponte, C, Castells, A, Carracedo, A, Ho, JWC, Sham, P, Hofstra, RMW, Vodicka, P, Brenner, H, Hampe, J, Schafmayer, C, Tepel, J, Schreiber, S, Völzke, H, Lerch, MM, Schmidt, CA, Buch, S, Moreno, V, Villanueva, CM, Peterlongo, P, Radice, P, Echeverry, MM, Velez, A, Carvajal-Carmona, L, Scott, R, Penegar, S, Broderick, P, Tenesa, A, and Houlston, RS

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Digestive Diseases, Genetics, Colo-Rectal Cancer, Cancer, Prevention, Aetiology, 2.1 Biological and endogenous factors, Colorectal Neoplasms, Genetic Predisposition to Disease, Humans, Penetrance, Polymorphism, Genetic, Prognosis, Risk, Risk Factors, colorectal cancer, association, polymorphism, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT.

Published
2010

4. Microarray comparative genomic hybridisation analysis of intraocular uveal melanomas identifies distinctive imbalances associated with loss of chromosome 3

Author

Hughes, S, Damato, BE, Giddings, I, Hiscott, PS, Humphreys, J, and Houlston, RS

Subjects
Human Genome, Genetics, Cancer, Adult, Aged, Aged, 80 and over, Chromosome Deletion, Chromosomes, Human, Pair 3, Eye Neoplasms, Female, Genome, Human, Humans, Male, Melanoma, Middle Aged, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

Defining regions of genomic imbalance can identify genes involved in tumour development. Conventional cytogenetics has identified several nonrandom copy number alterations (CNA) in uveal melanomas (UVM), which include monosomy 3, chromosome 6 abnormalities and gain of 8q. To gain further insight into the CNAs and define the regions involved more precisely we analysed 18 primary UVMs using 1 Mb BAC microarray comparative genomic hybridisation (CGH). Our analysis showed that the most common genomic imbalances were 8q gain (78%), 6p gain (67%) and monosomy 3 (56%). Two distinct CGH profiles could be delineated on the basis of the chromosome 3 status. The most common genetic changes in monosomy 3 tumours, in our study, were gain of 8q11.21-q24.3, 6p25.1-p21.2, 21q21.2-q21.3 and 21q22.13-q22.3 and loss of 1p36.33-p34.3, 1p31.1-p21.2, 6q16.2-q25.3 and 8p23.3-p11.23. In contrast, disomy 3 tumours showed recurrent gains of only 6p25.3-p22.3 and 8q23.2-q24.3. Our approach allowed definition of the smallest overlapping regions of imbalance, which may be important in the development of UVM.

Published
2005

5. Role of MC1R variants in uveal melanoma

Author

Hearle, N, Humphreys, J, Damato, BE, Wort, R, Talaban, R, Wixey, J, Green, H, Easton, DF, and Houlston, RS

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Rare Diseases, Human Genome, Cancer, Genetics, Skin, Adult, Age of Onset, Aged, Aged, 80 and over, Cohort Studies, DNA Primers, Female, Genetic Predisposition to Disease, Genetic Variation, Germ-Line Mutation, Hair Color, Humans, Male, Melanoma, Middle Aged, Receptor, Melanocortin, Type 1, Risk Factors, Uveal Neoplasms, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Variants of the melanocortin-1 receptor (MC1R) gene have been linked to sun-sensitive skin types and hair colour, and may independently play a role in susceptibility to cutaneous melanoma. To assess the role of MC1R variants in uveal melanoma, we have analysed a cohort of 350 patients for the changes within the major region of the gene displaying sequence variation. Eight variants were detected - V60L, D84E, V92M, R151C, I155T, R160W, R163Q and D294H - 63% of these patients being hetero- or homozygous for at least one variant. Standard melanoma risk factor data were available on 119 of the patients. MC1R variants were significantly associated with hair colour (P=0.03) but not skin or eye colour. The frequency of the variants detected in the 350 patients was comparable with those in the general population, and comparison of the cumulative tumour distribution by age at diagnosis in carriers and noncarriers provided no evidence that MC1R variants confer an increased risk of uveal melanoma. We interpret the data as indicating that MC1R variants do not appear to be major determinants of susceptibility to uveal melanoma.

Published
2003

6. A Likelihood Ratio Approach for Utilizing Case-Control Data in the Clinical Classification of Rare Sequence Variants: Application to BRCA1 and BRCA2

Author

Cutting, G, Zanti, M, O'Mahony, DG, Parsons, MT, Li, H, Dennis, J, Aittomakkiki, K, Andrulis, IL, Anton-Culver, H, Aronson, KJ, Augustinsson, A, Becher, H, Bojesen, SE, Bolla, MK, Brenner, H, Brown, MA, Buys, SS, Canzian, F, Caputo, SM, Castelao, JE, Chang-Claude, J, Czene, K, Daly, MB, De Nicolo, A, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Eccles, DM, Engel, C, Evans, DG, Fasching, PA, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Gentry-Maharaj, A, Geurts-Giele, WRR, Giles, GG, Glendon, G, Goldberg, MS, Garcia, EBG, Guendert, M, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Hopper, JL, Houdayer, C, Houlston, RS, Howell, A, Investigators, A, Jakimovska, M, Jakubowska, A, Jernstrom, H, John, EM, Kaaks, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Leone, M, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Menon, U, Milne, RL, Monteiro, AN, Murphy, RA, Neuhausen, SL, Nevanlinna, H, Newman, WG, Offit, K, Park, SK, James, P, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Punie, K, Radice, P, Rashid, MU, Rennert, G, Romero, A, Rosenberg, EH, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Shu, X-O, Simard, J, Southey, MC, Stone, J, Stoppa-Lyonnet, D, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Thomassen, M, Troester, MA, Vachon, CM, Vega, A, Vreeswijk, MPG, Wang, Q, Wappenschmidt, B, Weinberg, CR, Wolk, A, Zheng, W, Feng, B, Couch, FJ, Spurdle, AB, Easton, DF, Goldgar, DE, Michailidou, K, Cutting, G, Zanti, M, O'Mahony, DG, Parsons, MT, Li, H, Dennis, J, Aittomakkiki, K, Andrulis, IL, Anton-Culver, H, Aronson, KJ, Augustinsson, A, Becher, H, Bojesen, SE, Bolla, MK, Brenner, H, Brown, MA, Buys, SS, Canzian, F, Caputo, SM, Castelao, JE, Chang-Claude, J, Czene, K, Daly, MB, De Nicolo, A, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Eccles, DM, Engel, C, Evans, DG, Fasching, PA, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Gentry-Maharaj, A, Geurts-Giele, WRR, Giles, GG, Glendon, G, Goldberg, MS, Garcia, EBG, Guendert, M, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Hopper, JL, Houdayer, C, Houlston, RS, Howell, A, Investigators, A, Jakimovska, M, Jakubowska, A, Jernstrom, H, John, EM, Kaaks, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Leone, M, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Menon, U, Milne, RL, Monteiro, AN, Murphy, RA, Neuhausen, SL, Nevanlinna, H, Newman, WG, Offit, K, Park, SK, James, P, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Punie, K, Radice, P, Rashid, MU, Rennert, G, Romero, A, Rosenberg, EH, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Shu, X-O, Simard, J, Southey, MC, Stone, J, Stoppa-Lyonnet, D, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Thomassen, M, Troester, MA, Vachon, CM, Vega, A, Vreeswijk, MPG, Wang, Q, Wappenschmidt, B, Weinberg, CR, Wolk, A, Zheng, W, Feng, B, Couch, FJ, Spurdle, AB, Easton, DF, Goldgar, DE, and Michailidou, K

Abstract

A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.

Published
2023

7. Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Author

Mueller, SH, Lai, AG, Valkovskaya, M, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Abu-Ful, Z, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baert, T, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Brucker, SY, Buys, SS, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Chung, WK, Colonna, S, Cornelissen, S, Couch, FJ, Czene, K, Daly, MB, Devilee, P, Dork, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Gago-Dominguez, M, Gao, Y-T, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Gentry-Maharaj, A, Grassmann, F, Guenel, P, Gundert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Harkness, EF, Harrington, PA, Hartikainen, JM, Hartman, M, Hein, A, Ho, W-K, Hooning, MJ, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Huo, D, Investigators, A, Ito, H, Iwasaki, M, Jakubowska, A, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kang, D, Khusnutdinova, EK, Kim, S-W, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Linet, M, Lo, W-Y, Long, J, Lophatananon, A, Mannermaa, A, Manoochehri, M, Margolin, S, Matsuo, K, Mavroudis, D, Menon, U, Muir, K, Murphy, RA, Nevanlinna, H, Newman, WG, Niederacher, D, O'Brien, KM, Obi, N, Offit, K, Olopade, O, Olshan, AF, Olsson, H, Park, SK, Patel, A, Perou, CM, Peto, J, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Ramachandran, D, Rashid, MU, Rennert, G, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneider, MO, Scott, C, Shah, M, Sharma, P, Shen, C-Y, Shu, X-O, Simard, J, Surowy, H, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Toland, AE, Tollenaar, RAEM, Torres, D, Torres-Mejia, G, Troester, MA, Truong, T, Vachon, CM, Vijai, J, Weinberg, CR, Wendt, C, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Yang, XR, Yu, J-C, Zheng, W, Ziogas, A, Ziv, E, Dunning, AM, Easton, DF, Hemingway, H, Hamann, U, Kuchenbaecker, KB, Mueller, SH, Lai, AG, Valkovskaya, M, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Abu-Ful, Z, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baert, T, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Brucker, SY, Buys, SS, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Chung, WK, Colonna, S, Cornelissen, S, Couch, FJ, Czene, K, Daly, MB, Devilee, P, Dork, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Gago-Dominguez, M, Gao, Y-T, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Gentry-Maharaj, A, Grassmann, F, Guenel, P, Gundert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Harkness, EF, Harrington, PA, Hartikainen, JM, Hartman, M, Hein, A, Ho, W-K, Hooning, MJ, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Huo, D, Investigators, A, Ito, H, Iwasaki, M, Jakubowska, A, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kang, D, Khusnutdinova, EK, Kim, S-W, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Linet, M, Lo, W-Y, Long, J, Lophatananon, A, Mannermaa, A, Manoochehri, M, Margolin, S, Matsuo, K, Mavroudis, D, Menon, U, Muir, K, Murphy, RA, Nevanlinna, H, Newman, WG, Niederacher, D, O'Brien, KM, Obi, N, Offit, K, Olopade, O, Olshan, AF, Olsson, H, Park, SK, Patel, A, Perou, CM, Peto, J, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Ramachandran, D, Rashid, MU, Rennert, G, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneider, MO, Scott, C, Shah, M, Sharma, P, Shen, C-Y, Shu, X-O, Simard, J, Surowy, H, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Toland, AE, Tollenaar, RAEM, Torres, D, Torres-Mejia, G, Troester, MA, Truong, T, Vachon, CM, Vijai, J, Weinberg, CR, Wendt, C, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Yang, XR, Yu, J-C, Zheng, W, Ziogas, A, Ziv, E, Dunning, AM, Easton, DF, Hemingway, H, Hamann, U, and Kuchenbaecker, KB

Abstract

BACKGROUND: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. RESULTS: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. CONCLUSIONS: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts.

Published
2023

8. Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.

Author

Morra, A, Schreurs, MAC, Andrulis, IL, Anton-Culver, H, Augustinsson, A, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brauch, H, Broeks, A, Buys, SS, Camp, NJ, Castelao, JE, Cessna, MH, Chang-Claude, J, Chung, WK, Collaborators, N, Colonna, SV, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dörk, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Eriksson, M, Evans, DG, Fasching, PA, Fehm, TN, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, Genkinger, J, Grassmann, F, Gündert, M, Hahnen, E, Haiman, CA, Hamann, U, Harrington, PA, Hartikainen, JM, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Investigators, A, Investigators, K, Jakubowska, A, Janni, W, Jernström, H, John, EM, Johnson, N, Jones, ME, Kristensen, VN, Kurian, AW, Lambrechts, D, Marchand, LL, Lindblom, A, Lubiński, J, Lux, MP, Mannermaa, A, Mavroudis, D, Mulligan, AM, Muranen, TA, Nevanlinna, H, Nevelsteen, I, Neven, P, Newman, WG, Obi, N, Offit, K, Olshan, AF, Park-Simon, T-W, Patel, AV, Peterlongo, P, Phillips, K-A, Plaseska-Karanfilska, D, Polley, EC, Presneau, N, Pylkäs, K, Rack, B, Radice, P, Rashid, MU, Rhenius, V, Robson, M, Romero, A, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schuetze, S, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Tapper, WJ, Teras, LR, Tollenaar, RAEM, Tomczyk, K, Tomlinson, I, Troester, MA, Vachon, CM, van Veen, EM, Wang, Q, Wendt, C, Wildiers, H, Winqvist, R, Ziogas, A, Hall, P, Pharoah, PDP, Adank, MA, Hollestelle, A, Schmidt, MK, Hooning, MJ, Morra, A, Schreurs, MAC, Andrulis, IL, Anton-Culver, H, Augustinsson, A, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brauch, H, Broeks, A, Buys, SS, Camp, NJ, Castelao, JE, Cessna, MH, Chang-Claude, J, Chung, WK, Collaborators, N, Colonna, SV, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dörk, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Eriksson, M, Evans, DG, Fasching, PA, Fehm, TN, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, Genkinger, J, Grassmann, F, Gündert, M, Hahnen, E, Haiman, CA, Hamann, U, Harrington, PA, Hartikainen, JM, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Investigators, A, Investigators, K, Jakubowska, A, Janni, W, Jernström, H, John, EM, Johnson, N, Jones, ME, Kristensen, VN, Kurian, AW, Lambrechts, D, Marchand, LL, Lindblom, A, Lubiński, J, Lux, MP, Mannermaa, A, Mavroudis, D, Mulligan, AM, Muranen, TA, Nevanlinna, H, Nevelsteen, I, Neven, P, Newman, WG, Obi, N, Offit, K, Olshan, AF, Park-Simon, T-W, Patel, AV, Peterlongo, P, Phillips, K-A, Plaseska-Karanfilska, D, Polley, EC, Presneau, N, Pylkäs, K, Rack, B, Radice, P, Rashid, MU, Rhenius, V, Robson, M, Romero, A, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schuetze, S, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Tapper, WJ, Teras, LR, Tollenaar, RAEM, Tomczyk, K, Tomlinson, I, Troester, MA, Vachon, CM, van Veen, EM, Wang, Q, Wendt, C, Wildiers, H, Winqvist, R, Ziogas, A, Hall, P, Pharoah, PDP, Adank, MA, Hollestelle, A, Schmidt, MK, and Hooning, MJ

Abstract

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. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of 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. 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)]. In 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. (Main MS: 3201 words).

Published
2023

9. A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Author

Middha, PK, Wang, X, Behrens, S, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baert, T, Freeman, LEB, Becher, H, Beckmann, MW, Benitez, J, Bojesen, SE, Brauch, H, Brenner, H, Brooks-Wilson, A, Campa, D, Canzian, F, Carracedo, A, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Cordina-Duverger, E, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dossus, L, Dugue, P-A, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Giles, GG, Gonzalez-Neira, A, Grassmann, F, Grundy, A, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hankinson, SE, Harkness, EF, Holleczek, B, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Ingvar, C, Isaksson, K, Jernstroem, H, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lacey, JV, Lambrechts, D, Larson, NL, Larsson, S, Le Marchand, L, Lejbkowicz, F, Li, S, Linet, M, Lissowska, J, Martinez, ME, Maurer, T, Mulligan, AM, Mulot, C, Murphy, RA, Newman, WG, Nielsen, SF, Nordestgaard, BG, Norman, A, O'Brien, KM, Olson, JE, Patel, AV, Prentice, R, Rees-Punia, E, Rennert, G, Rhenius, V, Ruddy, KJ, Sandler, DP, Scott, CG, Shah, MT, Shu, X-O, Smeets, A, Southey, MC, Stone, J, Tamimi, RM, Taylor, JA, Teras, LR, Tomczyk, K, Troester, MA, Truong, T, Vachon, CM, Wang, SS, Weinberg, CR, Wildiers, H, Willett, W, Winham, SJ, Wolk, A, Yang, X, Zamora, MP, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Garcia-Closas, M, Schmidt, MK, Kraft, P, Milne, RL, Lindstroem, S, Easton, DF, Chang-Claude, J, Middha, PK, Wang, X, Behrens, S, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baert, T, Freeman, LEB, Becher, H, Beckmann, MW, Benitez, J, Bojesen, SE, Brauch, H, Brenner, H, Brooks-Wilson, A, Campa, D, Canzian, F, Carracedo, A, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Cordina-Duverger, E, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dossus, L, Dugue, P-A, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Giles, GG, Gonzalez-Neira, A, Grassmann, F, Grundy, A, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hankinson, SE, Harkness, EF, Holleczek, B, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Ingvar, C, Isaksson, K, Jernstroem, H, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lacey, JV, Lambrechts, D, Larson, NL, Larsson, S, Le Marchand, L, Lejbkowicz, F, Li, S, Linet, M, Lissowska, J, Martinez, ME, Maurer, T, Mulligan, AM, Mulot, C, Murphy, RA, Newman, WG, Nielsen, SF, Nordestgaard, BG, Norman, A, O'Brien, KM, Olson, JE, Patel, AV, Prentice, R, Rees-Punia, E, Rennert, G, Rhenius, V, Ruddy, KJ, Sandler, DP, Scott, CG, Shah, MT, Shu, X-O, Smeets, A, Southey, MC, Stone, J, Tamimi, RM, Taylor, JA, Teras, LR, Tomczyk, K, Troester, MA, Truong, T, Vachon, CM, Wang, SS, Weinberg, CR, Wildiers, H, Willett, W, Winham, SJ, Wolk, A, Yang, X, Zamora, MP, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Garcia-Closas, M, Schmidt, MK, Kraft, P, Milne, RL, Lindstroem, S, Easton, DF, and Chang-Claude, J

Abstract

BACKGROUND: Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. METHODS: Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. RESULTS: Assuming a 1 × 10-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). CONCLUSIONS: Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer.

Published
2023

10. Elongin C (ELOC/TCEB1) associated von Hippel-Lindau disease

Author

Andreou, A, Yngvadottir, B, Bassaganyas, L, Clarke, G, Martin, E, Whitworth, J, Cornish, AJ, Genomics England Research Consortium, Houlston, RS, Rich, P, Egan, C, Hodgson, SV, Warren, AY, Snape, K, and Maher, ER

Abstract

BACKGROUND: Around 95% of patients with clinical features diagnostic of Von Hippel-Lindau disease (VHL) have a detectable inactivating germline variant in VHL. The VHL protein (pVHL) functions as part of the VCB-CR complex which plays a key role in oxygen sensing and degradation of hypoxia inducible factors. To date, only variants in VHL has been shown to cause VHL disease. MATERIALS AND METHODS: We undertook trio analysis by Whole-exome sequencing (WES) in a proband with VHL disease but without a detectable VHL mutation. Molecular studies were also performed on paired DNA extracted from the proband's kidney tumour and blood and bioinformatics analysis of sporadic renal cell carcinoma data set was undertaken. RESULTS: A de novo pathogenic variant in ELOC (NM_005648.4:c.236A > G [p.Tyr79Cys]) gene was identified in the proband. ELOC encodes elongin C, a key component [C] of the VCB-CR complex. The p.Tyr79Cys substitution is a mutational hotspot in sporadic VHL-competent renal cell carcinoma (RCC) and has previously been shown to mimic the effects of pVHL deficiency on hypoxic signalling. Analysis of a RCC from the proband showed similar findings to that in somatically ELOC mutated RCC (expression of hypoxia responsive proteins, no somatic VHL variants and chromosome 8 loss). CONCLUSIONS: These findings are consistent with pathogenic ELOC variants being a novel cause for VHL disease and suggest that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease with no detectable VHL variant.

Published
2022

11. Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

Author

Loveday, C, Garrett, A, Law, P, Hanks, S, Poyastro-Pearson, E, Adlard, JW, Barwell, J, Berg, J, Brady, AF, Brewer, C, Chapman, C, Cook, J, Davidson, R, Donaldson, A, Douglas, F, Greenhalgh, L, Henderson, A, Izatt, L, Kumar, A, Lalloo, F, Miedzybrodzka, Z, Morrison, PJ, Paterson, J, Porteous, M, Rogers, MT, Walker, L, Breast and Ovarian Cancer Susceptibility Collaboration, Eccles, D, Evans, DG, Snape, K, Hanson, H, Houlston, RS, Turnbull, C, Loveday, C, Garrett, A, Law, P, Hanks, S, Poyastro-Pearson, E, Adlard, JW, Barwell, J, Berg, J, Brady, AF, Brewer, C, Chapman, C, Cook, J, Davidson, R, Donaldson, A, Douglas, F, Greenhalgh, L, Henderson, A, Izatt, L, Kumar, A, Lalloo, F, Miedzybrodzka, Z, Morrison, PJ, Paterson, J, Porteous, M, Rogers, MT, Walker, L, Breast and Ovarian Cancer Susceptibility Collaboration, Eccles, D, Evans, DG, Snape, K, Hanson, H, Houlston, RS, and Turnbull, C

Abstract

BACKGROUND: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. PATIENTS AND METHODS: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. ELIGIBILITY CRITERIA: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. RESULTS: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10-4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. CONCLUSIONS: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of

Published
2022

12. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Author

Chen, H, Majumdar, A, Wang, L, Kar, S, Brown, KM, Feng, H, Turman, C, Dennis, J, Easton, D, Michailidou, K, Simard, J, Breast Cancer Association Consortium (BCAC), Bishop, T, Cheng, IC, Huyghe, JR, Schmit, SL, Colorectal Transdisciplinary Study (CORECT), Colon Cancer Family Registry Study (CCFR), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO, O'Mara, TA, Spurdle, AB, Endometrial Cancer Association Consortium (ECAC), Gharahkhani, P, Schumacher, J, Jankowski, J, Gockel, I, Esophageal Cancer GWAS Consortium, Bondy, ML, Houlston, RS, Jenkins, RB, Melin, B, Glioma International Case Control Consortium (GICC), Lesseur, C, Ness, AR, Diergaarde, B, Olshan, AF, Head-Neck Cancer GWAS Consortium, Amos, CI, Christiani, DC, Landi, MT, McKay, JD, International Lung Cancer Consortium (ILCCO), Brossard, M, Iles, MM, Law, MH, MacGregor, S, Melanoma GWAS Consortium, Beesley, J, Jones, MR, Tyrer, J, Winham, SJ, Ovarian Cancer Association Consortium (OCAC), Klein, AP, Petersen, G, Li, D, Wolpin, BM, Pancreatic Cancer Case-Control Consortium (PANC4), Pancreatic Cancer Cohort Consortium (PanScan), Eeles, RA, Haiman, CA, Kote-Jarai, Z, Schumacher, FR, PRACTICAL consortium, CRUK, BPC3, CAPS, PEGASUS, Brennan, P, Chanock, SJ, Gaborieau, V, Purdue, MP, Renal Cancer GWAS Consortium, Pharoah, P, Hung, RJ, Amundadottir, LT, Kraft, P, Pasaniuc, B, and Lindström, S

Abstract

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.

Published
2021

13. Association analyses identify 31 new risk loci for colorectal cancer susceptibility

Author

Law, PJ, Timofeeva, M, Fernandez-Rozadilla, C, Broderick, P, Studd, J, Fernandez-Tajes, J, Farrington, S, Svinti, V, Palles, C, Orlando, G, Sud, A, Holroyd, A, Penegar, S, Theodoratou, E, Vaughan-Shaw, P, Campbell, H, Zgaga, L, Hayward, C, Campbell, A, Harris, S, Deary, IJ, Starr, J, Gatcombe, L, Pinna, M, Briggs, S, Martin, L, Jaeger, E, Sharma-Oates, A, East, J, Leedham, S, Arnold, R, Johnstone, E, Wang, H, Kerr, D, Kerr, R, Maughan, T, Kaplan, R, Al-Tassan, N, Palin, K, Hänninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Renkonen-Sinisalo, L, Lepistö, A, Böhm, J, Mecklin, J-P, Buchanan, DD, Win, A-K, Hopper, J, Jenkins, ME, Lindor, NM, Newcomb, PA, Gallinger, S, Duggan, D, Casey, G, Hoffmann, P, Nöthen, MM, Jöckel, K-H, Easton, DF, Pharoah, PDP, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Consortium, Practical, Harkin, A, Allan, K, McQueen, J, Paul, J, Iveson, T, Saunders, M, Butterbach, K, Chang-Claude, J, Hoffmeister, M, Brenner, H, Kirac, I, Matošević, P, Hofer, P, Brezina, S, Gsur, A, Cheadle, JP, Aaltonen, LA, Tomlinson, I, Houlston, RS, Dunlop, MG, Law, Philip J [0000-0001-9663-4611], Timofeeva, Maria [0000-0002-2503-4253], Fernandez-Rozadilla, Ceres [0000-0001-7330-4804], Broderick, Peter [0000-0002-8348-5829], Studd, James [0000-0002-7157-754X], Farrington, Susan [0000-0001-5955-7389], Svinti, Victoria [0000-0001-9926-0416], Sud, Amit [0000-0002-6133-0164], Hayward, Caroline [0000-0002-9405-9550], Campbell, Archie [0000-0003-0198-5078], Martin, Lynn [0000-0003-3962-389X], East, James [0000-0001-8035-3700], Kaplan, Richard [0000-0002-0189-8348], Al-Tassan, Nada [0000-0001-9076-0334], Palin, Kimmo [0000-0002-4621-6128], Salomaa, Veikko [0000-0001-7563-5324], Buchanan, Daniel D [0000-0003-2225-6675], Win, Aung-Ko [0000-0002-2794-5261], Jenkins, Mark E [0000-0002-8964-6160], Easton, Douglas F [0000-0003-2444-3247], Pharoah, Paul DP [0000-0001-8494-732X], Eeles, Rosalind A [0000-0002-3698-6241], Muir, Kenneth [0000-0001-6429-988X], Pashayan, Nora [0000-0003-0843-2468], Harkin, Andrea [0000-0002-8831-7381], Paul, James [0000-0001-7367-5816], Hofer, Philipp [0000-0003-2550-6019], Brezina, Stefanie [0000-0001-5238-6900], Cheadle, Jeremy P [0000-0001-9453-8458], Tomlinson, Ian [0000-0003-3037-1470], Houlston, Richard S [0000-0002-5268-0242], and Apollo - University of Cambridge Repository

Subjects
Male, Science, Inheritance Patterns, cancer genetics, Datasets as Topic, colorectal cancer, Genome-wide association studies, Polymorphism, Single Nucleotide, Article, White People, Asian People, Risk Factors, Cancer genomics, Humans, Genetic Predisposition to Disease, lcsh:Science, Cancer genetics, neoplasms, cancer genomics, genomiikka, Middle Aged, Colorectal cancer, digestive system diseases, peräsuolisyöpä, syöpägeenit, Genetic Loci, Case-Control Studies, genome-wide association studies, lcsh:Q, syöpätaudit, Female, Colorectal Neoplasms, Genome-Wide Association Study
Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention., 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

14. Runs of homozygosity and testicular cancer risk

Author

Loveday, C, Sud, A, Litchfield, K, Levy, M, Holroyd, A, Broderick, P, Kote-Jarai, Z, Dunning, AM, Muir, K, Peto, J, Eeles, R, Easton, DF, Dudakia, D, Orr, N, Pashayan, N, Rustin, Gordon, Srihari, Narayanan N, Cole, David, Askill, Colin, Bertelli, Gianfilippo, Barber, James, Gilby, Ed, White, Jeff, Baybrooke, Jeremy, Leahy, Michael, Welch, Richard, Chakraborti, Prabir, Joffe, Johnathan, Brown, Richard, Faust, Guy, Simmonds, Peter, Mazhar, Danish, Stockdale, Andrew, Hrounda, David, Humber, Caroline, Appel, Wiebke, Hong, Anne, Howard, Grahame, Douglas, Fiona, Bloomfield, David, Butt, Mohammad, Kelly, Kay, Mehra, Rakesh, Rogers, Paul, Hatton, Matthew, Hennig, Ivo, McAteer, John, Savage, Philip, Seckl, Michael, Gale, Joanna, Clark, Peter, Woby, Steve, Rathmell, Adrian, Lamont, Alan, Sarwar, Naveed, Stuart, Nick, Chowdhury, Simon, Beesley, Sharon, Winkler, Mathius, Hamid, Abdel, Pathak, Sanjeev, Madhavan, Krishnaswamy, Highley, Martin, Money-Kryle, Julian, Brock, Cathryn, Sreenivasan, Thiagarajan, Henderson, Brian E, Haiman, Christopher A, Schumacher, Fredrick R, Al Olama, Ali Amin, Benlloch, Sara, Berndt, Sonja I, Conti, David V, Wiklund, Fredrik, Chanock, Stephen, Gapster, Susan, Stevens, Victoria L, Tangen, Catherine M, Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Schleutker, Johanna, Albanes, Demetrius, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Cancel-Tassin, Geraldine, Koutros, Stella, Sorensen, Karina Dalsgaard, Maehle, Lovise, Neal, David E, Hamdy, Freddie C, Donovan, Jenny L, Travis, Ruth C, Hamilton, Robert J, Ingles, Sue Ann, Rosenstein, Barry S, Lu, Yong-Jie, Giles, Graham G, Kibel, Adam S, Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L, Park, Jong Y, Stanford, Janet L, Cybulski, Cezary, Nordestgaard, Borge G, Brenner, Hermann, Maier, Christiane, Kim, Jeri, John, Esther M, Teixeira, Manuel R, Neuhausen, Susan L, De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F, Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A, Dominguez, Manuela Gago, Roobol, Monique J, Menegaux, Florence, Khaw, Kay-Tee, Cannon-Albrigh, Lisa, Pandha, Hardev, Thibodeau, Stephen N, Reid, A, Huddart, RA, Houlston, RS, Turnbull, C, and Urology

Subjects
Oncology, Male, Endocrinology, Diabetes and Metabolism, LOCI, Genome-wide association study, Runs of Homozygosity, SUSCEPTIBILITY, VARIANTS, 0302 clinical medicine, Endocrinology, testicular germ cell tumour, Risk Factors, Genotype, genetics, Andrology, 030219 obstetrics & reproductive medicine, Genome, Homozygote, Neoplasms, Germ Cell and Embryonal, Disease gene identification, homozygosity mapping, Life Sciences & Biomedicine, RECENT POSITIVE SELECTION, medicine.medical_specialty, Urology, Biology, BREAST, Polymorphism, Single Nucleotide, 03 medical and health sciences, Endocrinology & Metabolism, Testicular Neoplasms, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Genetic predisposition, cancer, Humans, Allele, GENOME-WIDE ASSOCIATION, SEX DETERMINATION, runs of homozygosity, Science & Technology, IDENTIFICATION, Cancer, recessive, medicine.disease, GERM-CELL TUMOR, CONSANGUINITY, Reproductive Medicine, Relative risk, genome-wide association studies, Genome-Wide Association Study
Abstract

BACKGROUND: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. OBJECTIVE: To examine whether RoH are associated with TGCT risk. METHODS: We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. RESULTS: Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p

Published
2019

15. Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Author

Lin WY, Fordham SE, Hungate E, Sunter NJ, Elstob C, Xu Y, Park C, Quante A, Strauch K, Gieger C, Skol A, Rahman T, Sucheston-Campbell L, Wang J, Hahn T, Clay-Gilmour AI, Jones GL, Marr HJ, Jackson GH, Menne T, Collin M, Ivey A, Hills RK, Burnett AK, Russell NH, Fitzgibbon J, Larson RA, Le Beau MM, Stock W, Heidenreich O, Alharbi A, Allsup DJ, Houlston RS, Norden J, Dickinson AM, Douglas E, Lendrem C, Daly AK, Palm L, Piechocki K, Jeffries S, Bornhäuser M, Röllig C, Altmann H, Ruhnke L, Kunadt D, Wagenführ L, Cordell HJ, Darlay R, Andersen MK, Fontana MC, Martinelli G, Marconi G, Sanz MA, Cervera J, Gómez-Seguí I, Cluzeau T, Moreilhon C, Raynaud S, Sill H, Voso MT, Lo-Coco F, Dombret H, Cheok M, Preudhomme C, Gale RE, Linch D, Gaal-Wesinger J, Masszi A, Nowak D, Hofmann WK, Gilkes A, Porkka K, Milosevic Feenstra JD, Kralovics R, Grimwade D, Meggendorfer M, Haferlach T, Krizsán S, Bödör C, Stölzel F, Onel K, and Allan JM

Subjects
RISK, HLA, OLDER PATIENTS, AML, hemic and lymphatic diseases, HUMAN-LEUKOCYTE ANTIGEN, HIF-1-ALPHA, IMMUNE ESCAPE, CLONAL EVOLUTION, CANCER, GENE-MUTATIONS
Abstract

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10 -8 ; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10 -10 ; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).

Published
2021

16. Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer: a Mendelian randomisation analysis

Author

Culliford, R, Cornish, AJ, Law, PJ, Farrington, SM, Palin, K, Jenkins, MA, Casey, G, Hoffmeister, M, Brenner, H, Chang-Claude, J, Kirac, I, Maughan, T, Brezina, S, Gsur, A, Cheadle, JP, Aaltonen, LA, Dunlop, MG, Houlston, RS, Culliford, R, Cornish, AJ, Law, PJ, Farrington, SM, Palin, K, Jenkins, MA, Casey, G, Hoffmeister, M, Brenner, H, Chang-Claude, J, Kirac, I, Maughan, T, Brezina, S, Gsur, A, Cheadle, JP, Aaltonen, LA, Dunlop, MG, and Houlston, RS

Abstract

BACKGROUND: Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR). METHODS: We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (ORSD) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions. RESULTS: No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (ORSD = 1.00, 95% confidence interval (CI) = 0.96-1.03, P value = 0.90) with CRC was shown. CONCLUSIONS: Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.

Published
2021

18. Modifiable pathways for colorectal cancer: a mendelian randomisation analysis

Author

Cornish, AJ, Law, PJ, Timofeeva, M, Palin, K, Farrington, SM, Palles, C, Jenkins, MA, Casey, G, Brenner, H, Chang-Claude, J, Hoffmeister, M, Kirac, I, Maughan, T, Brezina, S, Gsur, A, Cheadle, JP, Aaltonen, LA, Tomlinson, I, Dunlop, MG, Houlston, RS, Cornish, AJ, Law, PJ, Timofeeva, M, Palin, K, Farrington, SM, Palles, C, Jenkins, MA, Casey, G, Brenner, H, Chang-Claude, J, Hoffmeister, M, Kirac, I, Maughan, T, Brezina, S, Gsur, A, Cheadle, JP, Aaltonen, LA, Tomlinson, I, Dunlop, MG, and Houlston, RS

Abstract

BACKGROUND: Epidemiological studies have linked lifestyle, cardiometabolic, reproductive, developmental, and inflammatory factors to the risk of colorectal cancer. However, which specific factors affect risk and the strength of these effects are unknown. We aimed to examine the relationship between potentially modifiable risk factors and colorectal cancer. METHODS: We used a random-effects model to examine the relationship between 39 potentially modifiable risk factors and colorectal cancer in 26 397 patients with colorectal cancer and 41 481 controls (ie, people without colorectal cancer). These population data came from a genome-wide association study of people of European ancestry, which was amended to exclude UK BioBank data. In the model, we used genetic variants as instruments via two-sample mendelian randomisation to limit bias from confounding and reverse causation. We calculated odds ratios per genetically predicted SD unit increase in each putative risk factor (ORSD) for colorectal cancer risk. We did mendelian randomisation Egger regressions to identify evidence of potential violations of mendelian randomisation assumptions. A Bonferroni-corrected threshold of p=1·3 × 10-3 was considered significant, and p values less than 0·05 were considered to be suggestive of an association. FINDINGS: No putative risk factors were significantly associated with colorectal cancer risk after correction for multiple testing. However, suggestive associations with increased risk were noted for genetically predicted body fat percentage (ORSD 1·14 [95% CI 1·03-1·25]; p=0·0086), body-mass index (1·09 [1·01-1·17]; p=0·023), waist circumference (1·13 [1·02-1·26]; p=0·018), basal metabolic rate (1·10 [1·03-1·18]; p=0·0079), and concentrations of LDL cholesterol (1·14 [1·04-1·25]; p=0·0056), total cholesterol (1·09 [1·01-1·18]; p=0·025), circulating serum iron (1·17 [1·00-1·36]; p=0·049), and serum vitamin B12 (1·21 [1·04-1·42]; p=0·016), although potential pleiotropy among geneti

Published
2020

22. Subclonal TP53 copy number is associated with prognosis in multiple myeloma

Author

Shah, V, Johnson, DC, Sherborne, AL, Ellis, S, Aldridge, FM, Howard-Reeves, J, Begum, F, Price, A, Kendall, J, Chiecchio, L, Savola, S, Jenner, MW, Drayson, MT, Owen, RG, Gregory, WM, Morgan, GJ, Davies, FE, Houlston, RS, Cook, G, Cairns, DA, Jackson, G, and Kaiser, MF

Subjects
Male, Survival Rate, Lymphoid Neoplasia, Gene Dosage, Humans, Female, Tumor Suppressor Protein p53, Multiple Myeloma, Disease-Free Survival, Gene Deletion, Genomic Instability
Abstract

Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of TP53 copy number, we profiled tumors from 1777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Subclonal TP53 deletions were independently associated with shorter overall survival, with a hazard ratio of 1.8 (95% confidence interval, 1.2-2.8; P = .01). Clonal, but not subclonal, TP53 deletions were associated with clinical markers of advanced disease, specifically lower platelet counts (P < .001) and increased lactate dehydrogenase (P < .001), as well as a higher frequency of features indicative of genomic instability, del(13q) (P = .002) or del(1p) (P = .006). Biallelic TP53 loss-of-function by mutation and deletion was rare (2.4%) and associated with advanced disease. We present a framework for identifying subclonal TP53 deletions by MLPA, to improve patient stratification in MM and tailor therapy, enabling management strategies.

Published
2018

23. Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Author

Went, M, Sud, A, Försti, A, Halvarsson, BM, Weinhold, N, Kimber, S, van Duin, M, Thorleifsson, G, Holroyd, A, Johnson, DC, Li, N, Orlando, G, Law, PJ, Ali, M, Chen, B, Mitchell, JS, Gudbjartsson, DF, Kuiper, R, Stephens, OW, Bertsch, U, Broderick, P, Campo, C, Bandapalli, OR, Einsele, H, Gregory, WA, Gullberg, U, Hillengass, J, Hoffmann, P, Jackson, GH, Jöckel, KH, Johnsson, E, Kristinsson, SY, Mellqvist, UH, Nahi, H, Easton, D, Pharoah, P, Dunning, A, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, ZS, Muir, K, Pashayan, N, Nickel, J, Nöthen, MM, Rafnar, T, Ross, FM, da Silva Filho, MI, Thomsen, H, Turesson, I, Vangsted, A, Andersen, NF, Waage, A, Walker, BA, Wihlborg, AK, Broyl, A, Davies, FE, Thorsteinsdottir, U, Langer, C, Hansson, M, Goldschmidt, H, Kaiser, M, Sonneveld, P, Stefansson, K, Morgan, GJ, Hemminki, K, Nilsson, B, Houlston, RS, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Olama, AAA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, The PRACTICAL Consortium, and Claessens, Frank

Subjects
Male, Quality Control, Risk, Chromatin Immunoprecipitation, Genotype, European Continental Ancestry Group, Quantitative Trait Loci, Bayes Theorem, Polymorphism, Single Nucleotide, Chromatin, Gene Expression Regulation, Humans, Female, Genetic Predisposition to Disease, Multiple Myeloma, Promoter Regions, Genetic, Genome-Wide Association Study
Abstract

© 2018, The Author(s). Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM. ispartof: Nature Communications vol:9 issue:1 ispartof: location:England status: published

Published
2018

24. Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia

Author

Vijayakrishnan, J, Studd, J, Broderick, P, Kinnersley, B, Holroyd, A, Law, PJ, Kumar, R, Allan, JM, Harrison, CJ, Moorman, AV, Vora, A, Roman, E, Rachakonda, S, Kinsey, SE, Sheridan, E, Thompson, PD, Irving, JA, Koehler, R, Hoffmann, P, Nöthen, MM, Heilmann-Heimbach, S, Jöckel, KH, Easton, DF, Pharaoh, PDP, Dunning, AM, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Greaves, M, Zimmerman, M, Bartram, CR, Schrappe, M, Stanulla, M, Hemminki, K, Houlston, RS, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Olama, AAA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, YJ, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, The PRACTICAL Consortium, and Claessens, Frank

Subjects
Male, Oncogene Proteins, Fusion, Glycosyltransferases, Prognosis, Polymorphism, Single Nucleotide, HLA Antigens, Risk Factors, Child, Preschool, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Core Binding Factor Alpha 2 Subunit, Humans, Female, Genetic Predisposition to Disease, Child, Genome-Wide Association Study
Abstract

© 2018 The Author(s). Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology. ispartof: Nature Communications vol:9 issue:1 ispartof: location:England status: published

Published
2018

25. Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia (vol 9, 1340, 2018)

Author

Vijayakrishnan, J, Studd, J, Broderick, P, Kinnersley, B, Holroyd, A, Law, PJ, Kumar, R, Allan, JM, Harrison, CJ, Moorman, AV, Vora, A, Roman, E, Rachakonda, S, Kinsey, SE, Sheridan, E, Thompson, PD, Irving, JA, Koehler, R, Hoffmann, P, Noethen, MM, Heilmann-Heimbach, S, Joeckel, K-H, Easton, DF, Pharaoh, PDP, Dunning, AM, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Al Olama, AA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, John, EM, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Greaves, M, Zimmerman, M, Bartram, CR, Schrappe, M, Stanulla, M, Hemminki, K, Houlston, RS, Vijayakrishnan, J, Studd, J, Broderick, P, Kinnersley, B, Holroyd, A, Law, PJ, Kumar, R, Allan, JM, Harrison, CJ, Moorman, AV, Vora, A, Roman, E, Rachakonda, S, Kinsey, SE, Sheridan, E, Thompson, PD, Irving, JA, Koehler, R, Hoffmann, P, Noethen, MM, Heilmann-Heimbach, S, Joeckel, K-H, Easton, DF, Pharaoh, PDP, Dunning, AM, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Al Olama, AA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, John, EM, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Greaves, M, Zimmerman, M, Bartram, CR, Schrappe, M, Stanulla, M, Hemminki, K, and Houlston, RS

Abstract

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

Published
2019

26. Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma (vol 9, 3707, 2018)

Author

Went, M, Sud, A, Foersti, A, Halvarsson, B-M, Weinhold, N, Kimber, S, van Duin, M, Thorleifsson, G, Holroyd, A, Johnson, DC, Li, N, Orlando, G, Law, PJ, Ali, M, Chen, B, Mitchell, JS, Gudbjartsson, DF, Kuiper, R, Stephens, OW, Bertsch, U, Broderick, P, Campo, C, Bandapalli, OR, Einsele, H, Gregory, WA, Gullberg, U, Hillengass, J, Hoffmann, P, Jackson, GH, Joeckel, K-H, Johnsson, E, Kristinsson, SY, Mellqvist, U-H, Nahi, H, Easton, D, Pharoah, P, Dunning, A, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Al Olama, AA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Grindedal, EM, Neal, DE, Hamdy, FC, Donovan, JL, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, John, EM, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Khaw, K-T, Cannon-Albright, L, Pandha, H, Thibodeau, SN, Nickel, J, Noethen, MM, Rafnar, T, Ross, FM, Filho, MIDS, Thomsen, H, Turesson, I, Vangsted, A, Andersen, NF, Waage, A, Walker, BA, Wihlborg, A-K, Broyl, A, Davies, FE, Thorsteinsdottir, U, Langer, C, Hansson, M, Goldschmidt, H, Kaiser, M, Sonneveld, P, Stefansson, K, Morgan, GJ, Hemminki, K, Nilsson, B, Houlston, RS, Went, M, Sud, A, Foersti, A, Halvarsson, B-M, Weinhold, N, Kimber, S, van Duin, M, Thorleifsson, G, Holroyd, A, Johnson, DC, Li, N, Orlando, G, Law, PJ, Ali, M, Chen, B, Mitchell, JS, Gudbjartsson, DF, Kuiper, R, Stephens, OW, Bertsch, U, Broderick, P, Campo, C, Bandapalli, OR, Einsele, H, Gregory, WA, Gullberg, U, Hillengass, J, Hoffmann, P, Jackson, GH, Joeckel, K-H, Johnsson, E, Kristinsson, SY, Mellqvist, U-H, Nahi, H, Easton, D, Pharoah, P, Dunning, A, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Al Olama, AA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Grindedal, EM, Neal, DE, Hamdy, FC, Donovan, JL, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, John, EM, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Khaw, K-T, Cannon-Albright, L, Pandha, H, Thibodeau, SN, Nickel, J, Noethen, MM, Rafnar, T, Ross, FM, Filho, MIDS, Thomsen, H, Turesson, I, Vangsted, A, Andersen, NF, Waage, A, Walker, BA, Wihlborg, A-K, Broyl, A, Davies, FE, Thorsteinsdottir, U, Langer, C, Hansson, M, Goldschmidt, H, Kaiser, M, Sonneveld, P, Stefansson, K, Morgan, GJ, Hemminki, K, Nilsson, B, and Houlston, RS

Abstract

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

Published
2019

27. Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility (vol 8, 1892, 2017)

Author

Sud, A, Thomsen, H, Law, PJ, Foersti, A, Filho, MIDS, Holroyd, A, Broderick, P, Orlando, G, Lenive, O, Wright, L, Cooke, R, Easton, D, Pharoah, P, Dunning, A, Peto, J, Canzian, F, Eeles, R, Kote-Jarai, Z, Muir, K, Pashayan, N, Hoffmann, P, Noethen, MM, Joeckel, K-H, von Strandmann, EP, Lightfoot, T, Kane, E, Roman, E, Lake, A, Montgomery, D, Jarrett, RF, Swerdlow, AJ, Engert, A, Orr, N, Hemminki, K, Houlston, RS, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Al Olama, AA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, John, EM, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Sud, A, Thomsen, H, Law, PJ, Foersti, A, Filho, MIDS, Holroyd, A, Broderick, P, Orlando, G, Lenive, O, Wright, L, Cooke, R, Easton, D, Pharoah, P, Dunning, A, Peto, J, Canzian, F, Eeles, R, Kote-Jarai, Z, Muir, K, Pashayan, N, Hoffmann, P, Noethen, MM, Joeckel, K-H, von Strandmann, EP, Lightfoot, T, Kane, E, Roman, E, Lake, A, Montgomery, D, Jarrett, RF, Swerdlow, AJ, Engert, A, Orr, N, Hemminki, K, Houlston, RS, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Al Olama, AA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, John, EM, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, and Menegaux, F

Abstract

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

28. Transcriptome-wide association study of multiple myeloma identifies candidate susceptibility genes

Author

Went, M, Kinnersley, B, Sud, A, Johnson, DC, Weinhold, N, Forsti, A, van Duin, Mark, Orlando, G, Mitchell, JS, Kuiper, Ronella, Walker, BA, Gregory, WM, Hoffmann, P, Jackson, GH, Nothen, MM, da Silva, MI, Thomsen, H, Broijl, A., Davies, FE, Thorsteinsdottir, U, Hansson, M, Kaiser, M, Sonneveld, Pieter, Goldschmidt, H, Stefansson, K, Hemminki, K, Nilsson, B, Morgan, GJ, Houlston, RS, Went, M, Kinnersley, B, Sud, A, Johnson, DC, Weinhold, N, Forsti, A, van Duin, Mark, Orlando, G, Mitchell, JS, Kuiper, Ronella, Walker, BA, Gregory, WM, Hoffmann, P, Jackson, GH, Nothen, MM, da Silva, MI, Thomsen, H, Broijl, A., Davies, FE, Thorsteinsdottir, U, Hansson, M, Kaiser, M, Sonneveld, Pieter, Goldschmidt, H, Stefansson, K, Hemminki, K, Nilsson, B, Morgan, GJ, and Houlston, RS

Published
2019

31. Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility

Author

Sud, A, Thomsen, H, Law, PJ, Försti, A, da Silva Filho, MI, Holroyd, A, Broderick, P, Orlando, G, Lenive, O, Wright, L, Cooke, R, Easton, D, Pharaoh, P, Dunning, A, Peto, J, Canzian, F, Eeles, R, Kote-Jarai, S, Muir, K, Pashayan, N, the PRACTICAL consortium, Hoffman, P, Nöthen, MM, Jöckel, K-H, von Strandmann, EP, Lightfoot, T, Kane, E, Roman, E, Lake, A, Montgomery, D, Jarrett, RF, Swerdlow, AJ, Engert, A, Orr, N, Hemminki, K, Houlston, RS, Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository

Subjects
Humans, Genetic Predisposition to Disease, Hodgkin Disease, Polymorphism, Single Nucleotide, Alleles, HLA-DP beta-Chains, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract

Several susceptibility loci for classical Hodgkin lymphoma (cHL) have been reported, however much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies (GWAS), a new GWAS, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all cHL at 6q22.33 (rs9482849, P=1.52 × 10-8) and for nodular sclerosis HL (NSHL) at 3q28 (rs4459895, P=9.43 × 10-17), 6q23.3 (rs6928977, P=4.62 × 10-55 11), 10p14 (rs3781093, P=9.49 × 10-13), 13q34 (rs112998813, P=4.58 × 10-8) and 16p13.13 (rs34972832, P=2.12 × 10-8). Additionally, independent loci within the HLA region are observed for NSHL (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity HL (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response.

Published
2017

32. Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21.

Author

Ostrom, QT, Kinnersley, B, Wrensch, MR, Eckel-Passow, JE, Armstrong, G, Rice, T, Chen, Y, Wiencke, JK, McCoy, LS, Hansen, HM, Amos, CI, Bernstein, JL, Claus, EB, Il'yasova, D, Johansen, C, Lachance, DH, Lai, RK, Merrell, RT, Olson, SH, Sadetzki, S, Schildkraut, JM, Shete, S, Rubin, JB, Lathia, JD, Berens, ME, Andersson, U, Rajaraman, P, Chanock, SJ, Linet, MS, Wang, Z, Yeager, M, GliomaScan consortium, Houlston, RS, Jenkins, RB, Melin, B, Bondy, ML, Barnholtz-Sloan, JS, Ostrom, QT, Kinnersley, B, Wrensch, MR, Eckel-Passow, JE, Armstrong, G, Rice, T, Chen, Y, Wiencke, JK, McCoy, LS, Hansen, HM, Amos, CI, Bernstein, JL, Claus, EB, Il'yasova, D, Johansen, C, Lachance, DH, Lai, RK, Merrell, RT, Olson, SH, Sadetzki, S, Schildkraut, JM, Shete, S, Rubin, JB, Lathia, JD, Berens, ME, Andersson, U, Rajaraman, P, Chanock, SJ, Linet, MS, Wang, Z, Yeager, M, GliomaScan consortium, Houlston, RS, Jenkins, RB, Melin, B, Bondy, ML, and Barnholtz-Sloan, JS

Abstract

Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.

Published
2018

33. Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci

Author

Tanskanen, T, van den Berg, L, Valimaki, N, Aavikko, M, Ness-Jensen, E, Hveem, K, Wettergren, Y, Lindskog, EB, Tonisson, N, Metspalu, A, Silander, K, Orlando, G, Law, PJ, Tuupanen, S, Gylfe, AE, Hanninen, UA, Cajuso, T, Kondelin, J, Sarin, A-P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Tenesa, A, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, MA, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, FR, Casey, G, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Houlston, RS, Palin, K, Aaltonen, LA, Tanskanen, T, van den Berg, L, Valimaki, N, Aavikko, M, Ness-Jensen, E, Hveem, K, Wettergren, Y, Lindskog, EB, Tonisson, N, Metspalu, A, Silander, K, Orlando, G, Law, PJ, Tuupanen, S, Gylfe, AE, Hanninen, UA, Cajuso, T, Kondelin, J, Sarin, A-P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Tenesa, A, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, MA, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, FR, Casey, G, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Houlston, RS, Palin, K, and Aaltonen, LA

Abstract

Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10-4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10-9 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.

Published
2018

34. Neutral tumor evolution in myeloma is associated with poor prognosis

Author

Johnson, DC, Lenive, O, Mitchell, J, Jackson, G, Owen, R, Drayson, M, Cook, G, Jones, JR, Pawlyn, C, Davies, FE, Walker, BA, Wardell, C, Gregory, WM, Cairns, D, Morgan, GJ, Houlston, RS, and Kaiser, MF

Abstract

Recent studies suggest that the evolutionary history of a cancer is important in forecasting clinical outlook. To gain insight into the clonal dynamics of multiple myeloma (MM) and its possible influence on patient outcome we analysed whole exome sequencing tumor data for 333 patients from Myeloma XI, a UK phase III trial and 434 patients from the CoMMpass study, all of which had received immunomodulatory therapy (IMiD). By analysing mutant allele frequency distributions in tumors we found that 17-20% of MM is under neutral evolutionary dynamics. These tumors are associated with poorer patient survival in non-intensively treated patients, consistent with reduced therapeutic efficacy of micro-environment modulating IMiD drugs. Our findings provide evidence that knowledge of the evolutionary history of MM has relevance for predicting patient outcome and personalising therapy.

Published
2017

35. Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer

Author

Zuber, V, Bettella, F, Witoelar, A, Andreassen, OA, Mills, IG, Urbanucci, A, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Weischer, M, Travis, RC, Neal, D, Pharoah, P, Khaw, KT, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Chenevix-Trench, G, Humphreys, M, Hung, RJ, Han, Y, Brennan, P, Bickeböller, H, Rosenberger, A, Houlston, RS, Caporaso, N, Landi, MT, Heinrich, J, Risch, A, Wu, X, Ye, Y, Christiani, DC, Amos, CI, Easton, DF, Michailidou, K, Bolla, MK, Wang, Q, Berchuck, A, Antoniou, A, McGuffog, L, Couch, F, Offit, K, Dennis, J, Dunning, AM, Lee, A, Dicks, E, Luccarini, C, Benitez, J, Gonzalez-Neira, A, Simard, J, Tessier, DC, Bacot, F, Vincent, D, LaBoissière, S, Zuber, Verena [0000-0001-9827-1877], Pharoah, Paul [0000-0001-8494-732X], Khaw, Kay-Tee [0000-0002-8802-2903], Easton, Douglas [0000-0003-2444-3247], Wang, Jean [0000-0002-9139-0627], Antoniou, Antonis [0000-0001-9223-3116], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Lee, Andrew [0000-0003-0677-0252], Dicks, Ed [0000-0002-0617-0401], and Apollo - University of Cambridge Repository

Subjects
risk loci, schizophrenia, breast cancer risk, super-enhancer, genome-wide association studies, BRD4, chromatin, functional annotation, prostate cancer risk, SNPs
Abstract

$\textbf{Background:}$ Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs. $\textbf{Results:}$ Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia. $\textbf{Conclusions:}$ This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.

Published
2017
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36. Genome-wide association study identifies multiple risk loci for renal cell carcinoma

Author

Scelo, G, Purdue, MP, Brown, KM, Johansson, M, Wang, Z, Eckel-Passow, JE, Ye, Y, Hoffman, JN, Choi, J, Foll, M, Gaborieau, V, Machiela, MJ, Colli, LM, Li, P, Sampson, JN, Abedi-Ardekani, B, Besse, C, Blanche, H, Boland, A, Burdette, L, Charbrier, A, Durand, G, Le Calvez-Kelm, F, Prokhortchouk, E, Robinot, N, Skyrabin, KG, Wozniak, MB, Yeager, M, Basta-Jovanovich, G, Dzamic, Z, Foretova, L, Holcatova, I, Janout, V, Mates, D, Mukeriya, A, Rascu, S, Zaridze, D, Bencko, V, Cybulski, C, Fabianova, E, Jinga, V, Lissowska, J, Lubinski, J, Navratilova, M, Rudnai, P, Szeszenia-Dabrowska, N, Benhamou, S, Cancel-Tassin, G, Cussenot, O, Baglietto, L, Boeing, H, Khaw, K-T, Weiderpass, E, Ljungberg, B, Sitaram, RT, Bruinsma, F, Jordan, SJ, Severi, G, Winship, I, Hveem, K, Vatten, LJ, Fletcher, T, Koppova, K, Larsson, SC, Wolk, A, Banks, RE, Selby, PJ, Easton, DF, Pharoah, P, Andreotti, G, Beane Freeman, LE, Koutros, S, Albanes, D, Mannisto, S, Weinstein, S, Clark, PE, Edwards, TL, Lipworth, L, Gapstur, SM, Stevens, VL, Carol, H, Freedman, ML, Pomerantz, MM, Cho, E, Kraft, P, Preston, MA, Wilson, KM, Gaziano, JM, Sesso, HD, Black, A, Freedman, ND, Huang, WY, Anema, JG, Kahnoski, RJ, Lane, BR, Noyes, SL, Petillo, D, Teh, BT, Peters, U, White, E, Anderson, GL, Johnson, L, Luo, J, Buring, J, Lee, I-M, Chow, W-H, Moore, LE, Wood, C, Eisen, T, Henrion, M, Larkin, J, Barman, P, Leibovich, BC, Choueiri, TK, Lathrop, GM, Rothman, N, Deleuze, J-F, McKay, JD, Parker, AS, Wu, X, Houlston, RS, Brennan, P, and Chanock, SJ

Abstract

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10−10), 3p22.1 (rs67311347, P=2.5 × 10−8), 3q26.2 (rs10936602, P=8.8 × 10−9), 8p21.3 (rs2241261, P=5.8 × 10−9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10−8), 11q22.3 (rs74911261, P=2.1 × 10−10) and 14q24.2 (rs4903064, P=2.2 × 10−24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.

Published
2017

37. Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1,905 trial patients

Author

Shah, V, Sherborne, AL, Walker, BA, Johnson, DC, Boyle, EM, Ellis, S, Begum, DB, Proszek, PZ, Jones, JR, Pawlyn, C, Savola, S, Jenner, MW, Drayson, MT, Owen, RG, Houlston, RS, Cairns, DA, Gregory, WM, Cook, G, Davies, F, Jackson, GH, Morgan, GJ, and Kaiser, MF

Abstract

Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10−7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10−14) and 1.68 (P=2.18 × 10−14), respectively. Patients with ‘double-hit’ defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10−27) for all patients and 3.19 (P=1.23 × 10−18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10−15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P

Published
2017

38. Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

Author

Rodriguez-Broadbent, H, Law, PJ, Sud, A, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Ripatti, S, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Palotie, A, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Passarelli, MN, Figueiredo, JC, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Aaltonen, LA, Cheadle, JP, Tomlinson, IP, Dunlop, MG, Houlston, RS, Rodriguez-Broadbent, H, Law, PJ, Sud, A, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Ripatti, S, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Palotie, A, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Passarelli, MN, Figueiredo, JC, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Aaltonen, LA, Cheadle, JP, Tomlinson, IP, Dunlop, MG, and Houlston, RS

Abstract

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, p = 1.68 × 10-4 ). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, p = 0.49), 0.94 (95% CI: 0.84-1.05, p = 0.27), and 0.98 (95% CI: 0.85-1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49-0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.

Published
2017

39. Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs.

Author

Zhou, F, Wang, Y, Liu, H, Ready, N, Han, Y, Hung, RJ, Brhane, Y, McLaughlin, J, Brennan, P, Bickeböller, H, Rosenberger, A, Houlston, RS, Caporaso, N, Landi, MT, Brüske, I, Risch, A, Ye, Y, Wu, X, Christiani, DC, Goodman, G, Chen, C, Transdisciplinary Research in Cancer of the Lung (TRICL) Research Team, Amos, CI, Wei, Q, Zhou, F, Wang, Y, Liu, H, Ready, N, Han, Y, Hung, RJ, Brhane, Y, McLaughlin, J, Brennan, P, Bickeböller, H, Rosenberger, A, Houlston, RS, Caporaso, N, Landi, MT, Brüske, I, Risch, A, Ye, Y, Wu, X, Christiani, DC, Goodman, G, Chen, C, Transdisciplinary Research in Cancer of the Lung (TRICL) Research Team, Amos, CI, and Wei, Q

Published
2017

40. Pro-inflammatory fatty acid profile and colorectal cancer risk: A Mendelian randomisation analysis

Author

May-Wilson, S, Sud, A, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Fisher, D, Kerr, R, Kerr, D, Passarelli, MN, Figueiredo, JC, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Aaltonen, LA, Cheadle, JP, Tomlinson, IP, Dunlop, MG, Houlston, RS, May-Wilson, S, Sud, A, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Fisher, D, Kerr, R, Kerr, D, Passarelli, MN, Figueiredo, JC, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Aaltonen, LA, Cheadle, JP, Tomlinson, IP, Dunlop, MG, and Houlston, RS

Abstract

BACKGROUND: While dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk. METHODS: We analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels. RESULTS: Risk reduction was observed for oleic and palmitoleic MUFAs (OROA = 0.77, 95% CI: 0.65-0.92, P = 3.9 × 10-3; ORPOA = 0.36, 95% CI: 0.15-0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (ORLA = 0.95, 95% CI: 0.93-0.98, P = 3.7 × 10-4; ORAA = 1.05, 95% CI: 1.02-1.07, P = 1.7 × 10-4). The SFA stearic acid was associated with increased CRC risk (ORSA = 1.17, 95% CI: 1.01-1.35, P = 0.041). CONCLUSION: Results from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk.

Published
2017

41. Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia

Author

Gu, F, Zhang, H, Hyland, PL, Berndt, S, Gapstur, SM, Wheeler, W, Amos, CI, Bezieau, S, Bickeboller, H, Brenner, H, Brennan, P, Chang-Claude, J, Conti, DV, Doherty, JA, Gruber, SB, Harrison, TA, Hayes, RB, Hoffmeister, M, Houlston, RS, Hung, RJ, Jenkins, MA, Kraft, P, Lawrenson, K, Mckay, J, Markt, S, Mucci, L, Phelan, CM, Qu, C, Risch, A, Rossing, MA, Wichmann, H-E, Shi, J, Schernhammer, E, Yu, K, Landi, MT, Caporaso, NE, Gu, F, Zhang, H, Hyland, PL, Berndt, S, Gapstur, SM, Wheeler, W, Amos, CI, Bezieau, S, Bickeboller, H, Brenner, H, Brennan, P, Chang-Claude, J, Conti, DV, Doherty, JA, Gruber, SB, Harrison, TA, Hayes, RB, Hoffmeister, M, Houlston, RS, Hung, RJ, Jenkins, MA, Kraft, P, Lawrenson, K, Mckay, J, Markt, S, Mucci, L, Phelan, CM, Qu, C, Risch, A, Rossing, MA, Wichmann, H-E, Shi, J, Schernhammer, E, Yu, K, Landi, MT, and Caporaso, NE

Abstract

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (ppathway < 0.00625). The two most significant genes were NPAS2 (pgene = 0.0062) and AANAT (pgene = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (ppathway = 0.021); this association was not confirmed in GECCO (ppathway = 0.76) or the combined data (ppathway = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.

Published
2017

42. Apparent Mendelian inheritance of breast and colorectal cancer: chance, genetic heterogeneity or a new gene?

Author

Lipton, L, Thomas, HJ, Eeles, RA, Houlston, RS, Longmuir, M, Davison, R, Hodgson, SV, Murday, VA, Norbury, CG, Taylor, C, and Tomlinson, IP

Subjects
skin and connective tissue diseases
Abstract

It is not uncommon for cancer geneticists to be referred families with apparently Mendelian co-inheritance of breast and bowel cancer. Such families present a particular problem as regards the intensity of their screening for these diseases and the utility of genetic testing. Many 'breast-colon' cancer families probably result from chance clustering of two common cancers. Other 'breast-colon' cancer families may result from known cancer syndromes, such as hereditary breast-ovarian cancer or hereditary non-polyposis colon cancer, either by conferring a high risk of one cancer type and a slightly increased risk of the other, or through a predisposition to one of the two cancers and chance occurrence of the other. Anecdotally, however, many geneticists wonder about the existence of a distinct 'breast-colon cancer syndrome', since some families present good a priori evidence of genetic disease and yet cannot readily be accounted for by known genes or chance. The identification of unknown 'breast-colon cancer' genes is likely to be difficult, relying primarily on candidate gene analysis, including loci separately implicated in breast or colorectal cancer, or in other multiple cancer syndromes. Studies such as those on APC I1307K and CHEK2 1100delC may suggest the way forward for the identification of 'breast-colon cancer' genes.

Published
2016

45. Genome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma

Author

Johnson, DC, Weinhold, N, Mitchell, JS, Chen, B, Kaiser, M, Begum, DB, Hillengass, J, Bertsch, U, Gregory, WA, Cairns, D, Jackson, GH, Försti, A, Nickel, J, Hoffmann, P, Nöethen, MM, Stephens, OW, Barlogie, B, Davis, FE, Hemminki, K, Goldschmidt, H, Houlston, RS, and Morgan, GJ

Abstract

Survival following a diagnosis of multiple myeloma (MM) varies between patients and some of these differences may be a consequence of inherited genetic variation. In this study, to identify genetic markers associated with MM overall survival (MM-OS), we conduct a meta-analysis of four patient series of European ancestry, totalling 3,256 patients with 1,200 MM-associated deaths. Each series is genotyped for ∼600,000 single nucleotide polymorphisms across the genome; genotypes for six million common variants are imputed using 1000 Genomes Project and UK10K as the reference. The association between genotype and OS is assessed by Cox proportional hazards model adjusting for age, sex, International staging system and treatment. We identify a locus at 6q25.1 marked by rs12374648 associated with MM-OS (hazard ratio=1.34, 95% confidence interval=1.22-1.48, P=4.69 × 10 -9). Our findings have potential clinical implications since they demonstrate that inherited genotypes can provide prognostic information in addition to conventional tumor acquired prognostic factors.

Published
2016

46. Identification of four new susceptibility loci for testicular germ cell tumour

Author

Litchfield, K, Holroyd, A, Lloyd, A, Broderick, P, Nsengimana, J, Eeles, R, Easton, DF, Dudakia, D, UKTCC, Bishop, DT, Reid, A, Huddart, RA, Grotmol, T, Wiklund, F, Shipley, J, Houlston, RS, and Turnbull, C

Abstract

Genome wide association studies (GWAS) have identified multiple risk loci for testicular germ cell tumour (TGCT), revealing a polygenic model of disease susceptibility strongly influenced by common variation. To identify further SNPs associated with TGCT we conducted a multistage GWAS with combined dataset of >25,000 individuals (6,059 cases and 19,094 controls). We identified new risk loci for TGCT at 3q23 (rs11705932, TFDP2, P = 1.5 x 10-9), 11q14.1 (rs7107174, GAB2, P = 9.7 x 10-11), 16p13.13 (rs4561483, GSPT1, P = 1.6 x 10-8) and 16q24.2 (rs55637647, ZFPM1, P = 3.4 x 10-9). We additionally present detailed functional analysis of these loci, identifying a strong relationship between rs4561483 risk genotype and increased GSPT1 expression in TGCT patient samples. These findings provide additional support for a polygenic model of TGCT risk and further insight into the biologic basis of disease development.

Published
2015

47. Genome-wide association study identifies multiple susceptibility loci for glioma

Author

Kinnersley, B, Labussière, M, Holroyd, A, Di Stefano, A-L, Broderick, P, Vijayakrishnan, J, Mokhtari, K, Delattre, J-Y, Gousias, K, Schramm, J, Schoemaker, MJ, Fleming, SJ, Herms, S, Heilmann, S, Schreiber, S, Wichmann, H-E, Nöthen, MM, Swerdlow, A, Lathrop, M, Simon, M, Bondy, M, Sanson, M, and Houlston, RS

Abstract

Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 × 10−9) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 × 10−8), 11q23.2 (rs648044, near ZBTB16, P=6.26 × 10−11), 12q21.2 (rs12230172, P=7.53 × 10−11) and 15q24.2 (rs1801591, near ETFA, P=5.71 × 10−9). Our findings provide further insights into the genetic basis of the different glioma subtypes.

Published
2015

48. Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease

Author

Orlando, G, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Kaprio, J, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Tenesa, A, Farrington, S, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Taipale, J, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Aaltonen, LA, Houlston, RS, Orlando, G, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Kaprio, J, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Tenesa, A, Farrington, S, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Taipale, J, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Aaltonen, LA, and Houlston, RS

Abstract

To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 × 10-8, odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r2 = 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) < 0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.

Published
2016

49. Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer

Author

Jarvis, D, Mitchell, JS, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Kaprio, J, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Taipale, J, Aaltonen, LA, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Houlston, RS, Jarvis, D, Mitchell, JS, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Kaprio, J, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Taipale, J, Aaltonen, LA, Cheadle, JP, Dunlop, MG, Tomlinson, IP, and Houlston, RS

Abstract

BACKGROUND: Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC. METHODS: We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls. RESULTS: In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02-1.49, P=0.033), 1.59 (95% CI: 1.08-2.34, P=0.019) and 1.07 (95% CI: 1.03-1.13, P=0.018), respectively. There was no evidence for association between birth weight and CRC (OR=1.22, 95% CI: 0.89-1.67, P=0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10-1.44, P=7.7 × 10(-4)) and 1.40 (95% CI: 1.14-1.72, P=1.2 × 10(-3)), respectively. CONCLUSIONS: These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity.

Published
2016

50. Correspondence: SEMA4A variation and risk of colorectal cancer

Author

Kinnersley, B, Chubb, D, Dobbins, S E, Frampton, M, Buch, S, Timofeeva, MN, Castellvi-Bel, S, Farrington, SM, Forsti, A, Hampe, J, Hemminki, K, Hofstra, Robert, Northwood, E, Palles, C, Pinheiro, M, Ruiz-Ponte, C, Schafmayer, C, Teixeira, MR, Westers, H, van Wezel, T, Bishop, DT, Tomlinson, I, Dunlop, MG, Houlston, RS, Kinnersley, B, Chubb, D, Dobbins, S E, Frampton, M, Buch, S, Timofeeva, MN, Castellvi-Bel, S, Farrington, SM, Forsti, A, Hampe, J, Hemminki, K, Hofstra, Robert, Northwood, E, Palles, C, Pinheiro, M, Ruiz-Ponte, C, Schafmayer, C, Teixeira, MR, Westers, H, van Wezel, T, Bishop, DT, Tomlinson, I, Dunlop, MG, and Houlston, RS

Published
2016

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