JAMA oncology · 2017
Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer.
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Couch Fergus J, Shimelis Hermela, Hu Chunling, Hart Steven N, Polley Eric C, Na Jie, Hallberg Emily, Moore Raymond, Thomas Abigail, Lilyquist Jenna, Feng Bingjian, McFarland Rachel, Pesaran Tina, Huether Robert, LaDuca Holly, Chao Elizabeth C, Goldgar David E, Dolinsky Jill S
Аннотация
IMPORTANCE: Germline pathogenic variants in BRCA1 and BRCA2 predispose to an increased lifetime risk of breast cancer. However, the relevance of germline variants in other genes from multigene hereditary cancer testing panels is not well defined.
OBJECTIVE: To determine the risks of breast cancer associated with germline variants in cancer predisposition genes.
DESIGN, SETTING, AND PARTICIPANTS: A study population of 65 057 patients with breast cancer receiving germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels. Associations between pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes and breast cancer risk were estimated in a case-control analysis of patients with breast cancer and Exome Aggregation Consortium reference controls. The women underwent testing between March 15, 2012, and June 30, 2016.
MAIN OUTCOMES AND MEASURES: Breast cancer risk conferred by pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes.
RESULTS: The mean (SD) age at diagnosis for the 65 057 women included in the analysis was 48.5 (11.1) years. The frequency of pathogenic variants in 21 panel genes identified in 41 611 consecutively tested white women with breast cancer was estimated at 10.2%. After exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes were associated with high or moderately increased risks of breast cancer: ATM (OR, 2.78; 95% CI, 2.22-3.62), BARD1 (OR, 2.16; 95% CI, 1.31-3.63), CHEK2 (OR, 1.48; 95% CI, 1.31-1.67), PALB2 (OR, 7.46; 95% CI, 5.12-11.19), and RAD51D (OR, 3.07; 95% CI, 1.21-7.88). Conversely, variants in the BRIP1 and RAD51C ovarian cancer risk genes; the MRE11A, RAD50, and NBN MRN complex genes; the MLH1 and PMS2 mismatch repair genes; and NF1 were not associated with increased risks of breast cancer.
CONCLUSIONS AND RELEVANCE: This study establishes several panel genes as high- and moderate-risk breast cancer genes and provides estimates of breast cancer risk associated with pathogenic variants in these genes among individuals qualifying for clinical genetic testing.
OBJECTIVE: To determine the risks of breast cancer associated with germline variants in cancer predisposition genes.
DESIGN, SETTING, AND PARTICIPANTS: A study population of 65 057 patients with breast cancer receiving germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels. Associations between pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes and breast cancer risk were estimated in a case-control analysis of patients with breast cancer and Exome Aggregation Consortium reference controls. The women underwent testing between March 15, 2012, and June 30, 2016.
MAIN OUTCOMES AND MEASURES: Breast cancer risk conferred by pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes.
RESULTS: The mean (SD) age at diagnosis for the 65 057 women included in the analysis was 48.5 (11.1) years. The frequency of pathogenic variants in 21 panel genes identified in 41 611 consecutively tested white women with breast cancer was estimated at 10.2%. After exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes were associated with high or moderately increased risks of breast cancer: ATM (OR, 2.78; 95% CI, 2.22-3.62), BARD1 (OR, 2.16; 95% CI, 1.31-3.63), CHEK2 (OR, 1.48; 95% CI, 1.31-1.67), PALB2 (OR, 7.46; 95% CI, 5.12-11.19), and RAD51D (OR, 3.07; 95% CI, 1.21-7.88). Conversely, variants in the BRIP1 and RAD51C ovarian cancer risk genes; the MRE11A, RAD50, and NBN MRN complex genes; the MLH1 and PMS2 mismatch repair genes; and NF1 were not associated with increased risks of breast cancer.
CONCLUSIONS AND RELEVANCE: This study establishes several panel genes as high- and moderate-risk breast cancer genes and provides estimates of breast cancer risk associated with pathogenic variants in these genes among individuals qualifying for clinical genetic testing.
Предметные рубрики MeSH
Acid Anhydride HydrolasesAdultAtaxia Telangiectasia Mutated ProteinsBreast NeoplasmsCase-Control StudiesCell Cycle ProteinsCheckpoint Kinase 2Cyclin-Dependent Kinase Inhibitor p16Cyclin-Dependent Kinase Inhibitor p18DNA Repair EnzymesDNA-Binding ProteinsFanconi Anemia Complementation Group N ProteinFanconi Anemia Complementation Group ProteinsFemaleGenetic Predisposition to DiseaseGenetic TestingGerm-Line MutationHumansMRE11 Homologue ProteinMiddle AgedMismatch Repair Endonuclease PMS2MutL Protein Homolog 1MutS Homolog 2 ProteinNeurofibromin 1Nuclear ProteinsOvarian NeoplasmsPhenotypeRNA HelicasesRisk FactorsTumor Suppressor ProteinsUbiquitin-Protein LigasesWhite People