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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.

ABSTRACT: A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

SUBMITTER: Lawrenson K

PROVIDER: S-EPMC5023955 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.

Lawrenson Kate K Kar Siddhartha S McCue Karen K Kuchenbaeker Karoline K Michailidou Kyriaki K Tyrer Jonathan J Beesley Jonathan J Ramus Susan J SJ Li Qiyuan Q Delgado Melissa K MK Lee Janet M JM Aittomäki Kristiina K Andrulis Irene L IL Anton-Culver Hoda H Arndt Volker V Arun Banu K BK Arver Brita B Bandera Elisa V EV Barile Monica M Barkardottir Rosa B RB Barrowdale Daniel D Beckmann Matthias W MW Benitez Javier J Berchuck Andrew A Bisogna Maria M Bjorge Line L Blomqvist Carl C Blot William W Bogdanova Natalia N Bojesen Anders A Bojesen Stig E SE Bolla Manjeet K MK Bonanni Bernardo B Børresen-Dale Anne-Lise AL Brauch Hiltrud H Brennan Paul P Brenner Hermann H Bruinsma Fiona F Brunet Joan J Buhari Shaik Ahmad SA Burwinkel Barbara B Butzow Ralf R Buys Saundra S SS Cai Qiuyin Q Caldes Trinidad T Campbell Ian I Canniotto Rikki R Chang-Claude Jenny J Chiquette Jocelyne J Choi Ji-Yeob JY Claes Kathleen B M KB Cook Linda S LS Cox Angela A Cramer Daniel W DW Cross Simon S SS Cybulski Cezary C Czene Kamila K Daly Mary B MB Damiola Francesca F Dansonka-Mieszkowska Agnieszka A Darabi Hatef H Dennis Joe J Devilee Peter P Diez Orland O Doherty Jennifer A JA Domchek Susan M SM Dorfling Cecilia M CM Dörk Thilo T Dumont Martine M Ehrencrona Hans H Ejlertsen Bent B Ellis Steve S Engel Christoph C Lee Eunjung E Evans D Gareth DG Fasching Peter A PA Feliubadalo Lidia L Figueroa Jonine J Flesch-Janys Dieter D Fletcher Olivia O Flyger Henrik H Foretova Lenka L Fostira Florentia F Foulkes William D WD Fridley Brooke L BL Friedman Eitan E Frost Debra D Gambino Gaetana G Ganz Patricia A PA Garber Judy J García-Closas Montserrat M Gentry-Maharaj Aleksandra A Ghoussaini Maya M Giles Graham G GG Glasspool Rosalind R Godwin Andrew K AK Goldberg Mark S MS Goldgar David E DE González-Neira Anna A Goode Ellen L EL Goodman Marc T MT Greene Mark H MH Gronwald Jacek J Guénel Pascal P Haiman Christopher A CA Hall Per P Hallberg Emily E Hamann Ute U Hansen Thomas V O TV Harrington Patricia A PA Hartman Mikael M Hassan Norhashimah N Healey Sue S Heitz Florian F Herzog Josef J Høgdall Estrid E Høgdall Claus K CK Hogervorst Frans B L FB Hollestelle Antoinette A Hopper John L JL Hulick Peter J PJ Huzarski Tomasz T Imyanitov Evgeny N EN Isaacs Claudine C Ito Hidemi H Jakubowska Anna A Janavicius Ramunas R Jensen Allan A John Esther M EM Johnson Nichola N Kabisch Maria M Kang Daehee D Kapuscinski Miroslav M Karlan Beth Y BY Khan Sofia S Kiemeney Lambertus A LA Kjaer Susanne Kruger SK Knight Julia A JA Konstantopoulou Irene I Kosma Veli-Matti VM Kristensen Vessela V Kupryjanczyk Jolanta J Kwong Ava A de la Hoya Miguel M Laitman Yael Y Lambrechts Diether D Le Nhu N De Leeneer Kim K Lester Jenny J Levine Douglas A DA Li Jingmei J Lindblom Annika A Long Jirong J Lophatananon Artitaya A Loud Jennifer T JT Lu Karen K Lubinski Jan J Mannermaa Arto A Manoukian Siranoush S Le Marchand Loic L Margolin Sara S Marme Frederik F Massuger Leon F A G LF Matsuo Keitaro K Mazoyer Sylvie S McGuffog Lesley L McLean Catriona C McNeish Iain I Meindl Alfons A Menon Usha U Mensenkamp Arjen R AR Milne Roger L RL Montagna Marco M Moysich Kirsten B KB Muir Kenneth K Mulligan Anna Marie AM Nathanson Katherine L KL Ness Roberta B RB Neuhausen Susan L SL Nevanlinna Heli H Nord Silje S Nussbaum Robert L RL Odunsi Kunle K Offit Kenneth K Olah Edith E Olopade Olufunmilayo I OI Olson Janet E JE Olswold Curtis C O'Malley David D Orlow Irene I Orr Nick N Osorio Ana A Park Sue Kyung SK Pearce Celeste L CL Pejovic Tanja T Peterlongo Paolo P Pfeiler Georg G Phelan Catherine M CM Poole Elizabeth M EM Pylkäs Katri K Radice Paolo P Rantala Johanna J Rashid Muhammad Usman MU Rennert Gad G Rhenius Valerie V Rhiem Kerstin K Risch Harvey A HA Rodriguez Gus G Rossing Mary Anne MA Rudolph Anja A Salvesen Helga B HB Sangrajrang Suleeporn S Sawyer Elinor J EJ Schildkraut Joellen M JM Schmidt Marjanka K MK Schmutzler Rita K RK Sellers Thomas A TA Seynaeve Caroline C Shah Mitul M Shen Chen-Yang CY Shu Xiao-Ou XO Sieh Weiva W Singer Christian F CF Sinilnikova Olga M OM Slager Susan S Song Honglin H Soucy Penny P Southey Melissa C MC Stenmark-Askmalm Marie M Stoppa-Lyonnet Dominique D Sutter Christian C Swerdlow Anthony A Tchatchou Sandrine S Teixeira Manuel R MR Teo Soo H SH Terry Kathryn L KL Terry Mary Beth MB Thomassen Mads M Tibiletti Maria Grazia MG Tihomirova Laima L Tognazzo Silvia S Toland Amanda Ewart AE Tomlinson Ian I Torres Diana D Truong Thérèse T Tseng Chiu-Chen CC Tung Nadine N Tworoger Shelley S SS Vachon Celine C van den Ouweland Ans M W AM van Doorn Helena C HC van Rensburg Elizabeth J EJ Van't Veer Laura J LJ Vanderstichele Adriaan A Vergote Ignace I Vijai Joseph J Wang Qin Q Wang-Gohrke Shan S Weitzel Jeffrey N JN Wentzensen Nicolas N Whittemore Alice S AS Wildiers Hans H Winqvist Robert R Wu Anna H AH Yannoukakos Drakoulis D Yoon Sook-Yee SY Yu Jyh-Cherng JC Zheng Wei W Zheng Ying Y Khanna Kum Kum KK Simard Jacques J Monteiro Alvaro N AN French Juliet D JD Couch Fergus J FJ Freedman Matthew L ML Easton Douglas F DF Dunning Alison M AM Pharoah Paul D PD Edwards Stacey L SL Chenevix-Trench Georgia G Antoniou Antonis C AC Gayther Simon A SA

Nature communications 20160907

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 ...[more]

PMID: 27601076

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Project description:Germline loss-of-function mutations in BRCA1 interacting protein C-terminal helicase 1 (BRIP1) are associated with ovarian carcinoma and may also contribute to breast cancer risk, particularly among patients who develop disease at an early age. Normal BRIP1 activity is required for DNA interstrand cross-link (ICL) repair and is thus central to the maintenance of genome stability. Although pathogenic mutations have been identified in BRIP1, genetic testing more often reveals missense variants, for which the impact on molecular function and subsequent roles in cancer risk are uncertain. Next-generation sequencing of germline DNA in 2,160 early-onset breast cancer and 1,199 patients with ovarian cancer revealed nearly 2% of patients carry a very rare missense variant (minor allele frequency < 0.0001) in BRIP1. This is 3-fold higher than the frequency of all rare BRIP1 missense alleles reported in more than 60,000 individuals of the general population (P < 0.0001, χ 2 test). Using CRISPR-Cas9 gene editing technology and rescue assays, we functionally characterized 20 of these missense variants, focusing on the altered protein's ability to repair ICL damage. A total of 75% of the characterized variants rendered the protein hypomorph or null. In a clinical cohort of >117,000 patients with breast and ovarian cancer who underwent panel testing, the combined OR associated with BRIP1 hypomorph or null missense carriers compared with the general population was 2.30 (95% confidence interval, 1.60-3.30; P < 0.0001). These findings suggest that novel missense variants within the helicase domain of BRIP1 may confer risk for both breast and ovarian cancer and highlight the importance of functional testing for additional variants. SIGNIFICANCE: Functional characterization of rare variants of uncertain significance in BRIP1 revealed that 75% demonstrate loss-of-function activity, suggesting rare missense alleles in BRIP1 confer risk for both breast and ovarian cancer.

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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.

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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.

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