Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.
Lawrenson K., Kar S., McCue K., Kuchenbaeker K., Michailidou K., Tyrer J., Beesley J., Ramus SJ., Li Q., Delgado MK., Lee JM., Aittomäki K., Andrulis IL., Anton-Culver H., Arndt V., Arun BK., Arver B., Bandera EV., Barile M., Barkardottir RB., Barrowdale D., Beckmann MW., Benitez J., Berchuck A., Bisogna M., Bjorge L., Blomqvist C., Blot W., Bogdanova N., Bojesen A., Bojesen SE., Bolla MK., Bonanni B., Børresen-Dale A-L., Brauch H., Brennan P., Brenner H., Bruinsma F., Brunet J., Buhari SA., Burwinkel B., Butzow R., Buys SS., Cai Q., Caldes T., Campbell I., Canniotto R., Chang-Claude J., Chiquette J., Choi J-Y., Claes KBM., GEMO Study Collaborators None., Cook LS., Cox A., Cramer DW., Cross SS., Cybulski C., Czene K., Daly MB., Damiola F., Dansonka-Mieszkowska A., Darabi H., Dennis J., Devilee P., Diez O., Doherty JA., Domchek SM., Dorfling CM., Dörk T., Dumont M., Ehrencrona H., Ejlertsen B., Ellis S., EMBRACE None., Engel C., Lee E., Evans DG., Fasching PA., Feliubadalo L., Figueroa J., Flesch-Janys D., Fletcher O., Flyger H., Foretova L., Fostira F., Foulkes WD., Fridley BL., Friedman E., Frost D., Gambino G., Ganz PA., Garber J., García-Closas M., Gentry-Maharaj A., Ghoussaini M., Giles GG., Glasspool R., Godwin AK., Goldberg MS., Goldgar DE., González-Neira A., Goode EL., Goodman MT., Greene MH., Gronwald J., Guénel P., Haiman CA., Hall P., Hallberg E., Hamann U., Hansen TVO., Harrington PA., Hartman M., Hassan N., Healey S., Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) None., Heitz F., Herzog J., Høgdall E., Høgdall CK., Hogervorst FBL., Hollestelle A., Hopper JL., Hulick PJ., Huzarski T., Imyanitov EN., KConFab Investigators None., Australian Ovarian Cancer Study Group None., Isaacs C., Ito H., Jakubowska A., Janavicius R., Jensen A., John EM., Johnson N., Kabisch M., Kang D., Kapuscinski M., Karlan BY., Khan S., Kiemeney LA., Kjaer SK., Knight JA., Konstantopoulou I., Kosma V-M., Kristensen V., Kupryjanczyk J., Kwong A., de la Hoya M., Laitman Y., Lambrechts D., Le N., De Leeneer K., Lester J., Levine DA., Li J., Lindblom A., Long J., Lophatananon A., Loud JT., Lu K., Lubinski J., Mannermaa A., Manoukian S., Le Marchand L., Margolin S., Marme F., Massuger LFAG., Matsuo K., Mazoyer S., McGuffog L., McLean C., McNeish I., Meindl A., Menon U., Mensenkamp AR., Milne RL., Montagna M., Moysich KB., Muir K., Mulligan AM., Nathanson KL., Ness RB., Neuhausen SL., Nevanlinna H., Nord S., Nussbaum RL., Odunsi K., Offit K., Olah E., Olopade OI., Olson JE., Olswold C., O'Malley D., Orlow I., Orr N., Osorio A., Park SK., Pearce CL., Pejovic T., Peterlongo P., Pfeiler G., Phelan CM., Poole EM., Pylkäs K., Radice P., Rantala J., Rashid MU., Rennert G., Rhenius V., Rhiem K., Risch HA., Rodriguez G., Rossing MA., Rudolph A., Salvesen HB., Sangrajrang S., Sawyer EJ., Schildkraut JM., Schmidt MK., Schmutzler RK., Sellers TA., Seynaeve C., Shah M., Shen C-Y., Shu X-O., Sieh W., Singer CF., Sinilnikova OM., Slager S., Song H., Soucy P., Southey MC., Stenmark-Askmalm M., Stoppa-Lyonnet D., Sutter C., Swerdlow A., Tchatchou S., Teixeira MR., Teo SH., Terry KL., Terry MB., Thomassen M., Tibiletti MG., Tihomirova L., Tognazzo S., Toland AE., Tomlinson I., Torres D., Truong T., Tseng C-C., Tung N., Tworoger SS., Vachon C., van den Ouweland AMW., van Doorn HC., van Rensburg EJ., Van't Veer LJ., Vanderstichele A., Vergote I., Vijai J., Wang Q., Wang-Gohrke S., Weitzel JN., Wentzensen N., Whittemore AS., Wildiers H., Winqvist R., Wu AH., Yannoukakos D., Yoon S-Y., Yu J-C., Zheng W., Zheng Y., Khanna KK., Simard J., Monteiro AN., French JD., Couch FJ., Freedman ML., Easton DF., Dunning AM., Pharoah PD., Edwards SL., Chenevix-Trench G., Antoniou AC., Gayther SA.
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.