Prevalence of the variant allele rs61764370 T>G in the 3'UTR of KRAS among Dutch BRCA1, BRCA2 and non-BRCA1/BRCA2 breast cancer families.

Recently, a variant allele in the 3'UTR of the KRAS gene (rs61764370 T>G) was shown to be associated with an increased risk for developing non-small cell lung cancer, as well as ovarian cancer, and was most enriched in ovarian cancer patients from hereditary breast and ovarian cancer families. This functional variant has been shown to disrupt a let-7 miRNA binding site leading to increased expression of KRAS in vitro. In the current study, we have genotyped this KRAS-variant in breast cancer index cases from 268 BRCA1 families, 89 BRCA2 families, 685 non-BRCA1/BRCA2 families, and 797 geographically matched controls. The allele frequency of the KRAS-variant was found to be increased among patients with breast cancer from BRCA1, but not BRCA2 or non-BRCA1/BRCA2 families as compared to controls. As BRCA1 carriers mostly develop ER-negative breast cancers, we also examined the variant allele frequency among indexes from non-BRCA1/BRCA2 families with ER-negative breast cancer. The prevalence of the KRAS-variant was, however, not significantly increased as compared to controls, suggesting that the variant allele not just simply associates with ER-negative breast cancer. Subsequent expansion of the number of BRCA1 carriers with breast cancer by including other family members in addition to the index cases resulted in loss of significance for the association between the variant allele and mutant BRCA1 breast cancer. In this same cohort, the KRAS-variant did not appear to modify breast cancer risk for BRCA1 carriers. Importantly, results from the current study suggest that KRAS-variant frequencies might be increased among BRCA1 carriers, but solid proof requires confirmation in a larger cohort of BRCA1 carriers.

Selection bias influences reported contralateral breast cancer incidence and survival in high risk non-BRCA1/2 patients.

PURPOSE: The results of studies comparing survival in familial and sporadic breast cancer (BC) are inconsistent. A higher incidence of contralateral breast cancer (CBC) has been reported in familial BC. Ascertainment bias may influence both the reported familial CBC and survival. DESIGN: We assessed CBC incidence, distant disease free (DDFS) and overall survival (OS) in 327 BC patients who had > or =3 breast and/or ovarian cancers in the family but no BRCA1/2 gene mutation (non-BRCA1/2). They were matched to 327 sporadic controls for year and age at detection. To correct for ascertainment bias, we analyzed also separately the results (1) Of the 250 non-BRCA1/2 patients with DNA testing performed before diagnosis or within 2 years ('unselected') and (2) Of the 77 with testing > or =2 years after diagnosis (late-tested). RESULTS: Median follow-up of non-BRCA1/2 patients was 6.1 yrs. Ten years CBC incidence was 11% in non-BRCA1/2 versus 6% in sporadic patients (p = 0.002). At multivariate analysis CBC incidence was increased in late-tested non-BRCA1/2 (HR 4.6; p = 0.001) not in 'unselected' (HR 1.8; p = 0.1). Increased CBC occurred in non-BRCA1/2 patients mainly before genetic testing, suggesting ascertainment bias. Tumors were < or =T1 in 62% of non-BRCA1/2 versus 50% of sporadic patients (p = 0.003), node-negative in 55% versus 52% respectively (p = 0.5). After correction for stage and therapy, OS did not differ between 'unselected' non-BRCA1/2 and sporadic patients (HR 0.8; p = 0.3), but was improved in late-tested non-BRCA1/2. CONCLUSION: Overall survival and contralateral breast cancer incidence were similar in 'unselected' non-BRCA1/2- and sporadic patients. Reports of higher CBC incidence and better survival in non-BRCA1/2 patients may substantially be caused by DNA testing selection-bias.

Use of genetic testing and prophylactic mastectomy and oophorectomy in women with breast or ovarian cancer from families with a BRCA1 or BRCA2 mutation.

PURPOSE: To analyze the use of genetic testing, prophylactic mastectomy, and oophorectomy among women with breast and/or ovarian cancer from families with a BRCA1 or BRCA2 mutation. PATIENTS AND METHODS: We examined prospectively the use of BRCA1/BRCA2 testing in all women with a primary breast or ovarian cancer from a consecutive series of 112 high-risk families in which a BRCA1/BRCA2 mutation eventually was identified. The rate of prophylactic bilateral and contralateral mastectomy and prophylactic oophorectomy was analyzed in the women who carried a BRCA1/BRCA2 mutation and who had no metastatic disease at the time of the genetic test disclosure. We examined predictors for genetic test uptake and prophylactic surgery using univariate and multivariate analysis. RESULTS: Overall, 192 of 220 women (87%) with primary tumors underwent genetic testing. Eleven of these 192 tested women (6%) appeared not to carry the family-specific BRCA1/BRCA2 mutation. Genetic testing occurred significantly more frequently at ages younger than 50 years (P =.04) and in persons with multiple primary tumors (P =.02). Among eligible women, 35 of 101 (35%) requested bilateral or contralateral mastectomy, and 47 of 95 (49%) requested oophorectomy. Women aged younger than 50 years and women who developed their first tumor after the initial identification of a BRCA1/BRCA2 mutation in the family were significantly (both P =.01) more likely to opt for prophylactic bilateral or contralateral mastectomy. CONCLUSION: In a clinical setting, we show a high demand for BRCA1/BRCA2 testing and for prophylactic surgery by women with breast and/or ovarian cancer from high-risk families.

Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations.

Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer, but account for only a small fraction of breast cancer susceptibility. To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3,4,5). We show that CHEK2(*)1100delC, a truncating variant that abrogates the kinase activity, has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003), including 13.5% of individuals from families with male breast cancer (P = 0.00015). We estimate that the CHEK2(*)1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway.