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BRCA2 hypomorphic missense variants confer moderate risks of breast cancer.

Cancer Res. 2017 Mar 10. pii: canres.2568.2016. doi: 10.1158/0008-5472.CAN-16-2568. [Epub ahead of print]

BRCA2 hypomorphic missense variants confer moderate risks of breast cancer.

Shimelis H1, Mesman RL2, Von Nicolai C3, Ehlen A3, Guidugli L4, Martin C5, Calleja FM6, Meeks H7, Hallberg E8, Hinton J9, Lilyquist J9, Hu C10, Aalfs CM11, Aittomaki K12, Andrulis IL13, Anton-Culver H14, Arndt V15, Beckmann MW16, Benitez JJ17, Bogdanova N18, Bojesen SE19, Bolla MK20, Borresen-Dale AL21, Brauch H22, Brennan P23, Brenner H24, Broeks A25, Brouwers B26, Bruning T27, Burwinkel B28, Chang-Claude J29, Chenevix-Trench G30, Cheng CY31, Choi JY32, Collée JM33, Cox A34, Cross SS35, Czene K36, Darabi H36, Dennis J37, Dork T18, Dos Santos Silva I38, Dunning AM20, Fasching PA16, Figueroa JD39, Flyger H40, Garcia-Closas M41, Giles GG42, Glendon G43, Guenel P44, Haiman CA45, Hall P36, Hamann U46, Hartman M47, Hogervorst FB48, Hollestelle A49, Hopper JL50, Ito H51, Jakubowska A52, Kang D53, Kosma VM54, Kristensen V55, Lai KN56, Lambrechts D57, Le Marchand L58, Li J59, Lindblom A60, Lophatananon A61, Lubinski J52, Machackova E62, Mannermaa A54, Margolin S63, Marme F64, Matsuo K65, Miao H66, Michailidou K20, Milne RL42, Muir K67, Neuhausen SL68, Nevanlinna H69, Olson JE9, Olswold C70, Oosterwijk JC71, Osorio A72, Peterlongo P73, Peto J74, Pharoah PD75, Pylkäs K76, Radice P77, Rashid MU78, Rhenius V79, Rudolph A80, Sangrajrang S81, Sawyer EJ82, Schmidt MK83, Schoemaker MJ41, Seynaeve CM84, Shah M20, Shen CY85, Shrubsole MJ86, Shu XO87, Slager SL70, Southey MC88, Stram DO89, Swerdlow AJ41, Teo SH90, Tomlinson I91, Torres D92, Truong T93, van Asperen CJ94, van der Kolk LE95, Wang Q20, Winqvist R96, Wu AH97, Yu JC98, Zheng W87, Zheng Y99, Leary J100, Walker LC101, Foretova L102, Fostira F103, Claes K104, Varesco L105, Moghadasi S106, Easton DF20, Spurdle AB107, Devilee P108, Vrieling H109, Monteiro AN110, Goldgar DE111, Carreira A112, Vreeswijk MP113, Couch FJ114.

Abstract

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR=2.52, p=0.04) and BRCA1 c.5096G>A, p.Arg1699Gln (OR=4.29, p=0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR=2.68, p=0.004) and c.8187G>T, p.Lys2729Asn (OR=1.4, p=0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared to wildtype. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants.

PMID:
28283652
DOI:
10.1158/0008-5472.CAN-16-2568