Risk of Breast Cancer in Women With a CHEK2 Mutation With and Without a Family History of Breast Cancer.

Cybulski C, Wokolorczyk D, Jakubowska A, Huzarski T, Byrski T, Gronwald J, Masojc B, Debniak T, Górski B, Blecharz P, Narod SA, Lubinski J.

Source

Cezary Cybulski, Dominika Wokołorczyk, Anna Jakubowska, Tomasz Huzarski, Tomasz Byrski, Jacek Gronwald, Bartłomiej Masojć, Tadeusz Dębniak, Bohdan Górski, and Jan Lubiński, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin; Paweł Blecharz, Maria Sklodowska-Curie Memorial Institute, Kraków, Poland; and Steven A. Narod, Women's College Research Institute, Toronto, Ontario, Canada.

Abstract

PURPOSETo estimate the risk of breast cancer in a woman who has a CHEK2 mutation depending on her family history of breast cancer. PATIENTS AND METHODSSeven thousand four hundred ninety-four BRCA1 mutation-negative patients with breast cancer and 4,346 control women were genotyped for four founder mutations in CHEK2 (del5395, IVS2+1G>A, 1100delC, and I157T).ResultsA truncating mutation (IVS2+1G>A, 1100delC, or del5395) was present in 227 patients (3.0%) and in 37 female controls (0.8%; odds ratio [OR], 3.6; 95% CI, 2.6 to 5.1). The OR was higher for women with a first- or second-degree relative with breast cancer (OR, 5.0; 95% CI, 3.3 to 7.6) than for women with no family history (OR, 3.3; 95% CI, 2.3 to 4.7). If both a first- and second-degree relative were affected with breast cancer, the OR was 7.3 (95% CI, 3.2 to 16.8). Assuming a baseline risk of 6%, we estimate the lifetime risks for carriers of CHEK2 truncating mutations to be 20% for a woman with no affected relative, 28% for a woman with one second-degree relative affected, 34% for a woman with one first-degree relative affected, and 44% for a woman with both a first- and second-degree relative affected. CONCLUSIONCHEK2 mutation screening detects a clinically meaningful risk of breast cancer and should be considered in all women with a family history of breast cancer. Women with a truncating mutation in CHEK2 and a positive family history of breast cancer have a lifetime risk of breast cancer of greater than 25% and are candidates for magnetic resonance imaging screening and for tamoxifen chemoprevention.