The prevalence of mutations in cancer susceptibility genes such as and and other cancer susceptibility genes and their clinical relevance are largely unknown among a large series of unselected breast cancer patients in the Chinese population. A total of 8,085 consecutive unselected Chinese breast cancer patients were enrolled. Germline mutations in 46 cancer susceptibility genes were detected using a 62-gene panel. Pathogenic mutations were identified in 9.2% of patients among the 8,085 unselected breast cancer patients. Of these, 5.3% of patients carried a or mutation (1.8% in and 3.5% in), 2.9% carried other breast cancer susceptibility genes (BOCG) and 1.0% carried another cancer susceptibility genes. Triple-negative breast cancers had the highest prevalence of mutations (11.2%) and other BOCG mutations (3.8%) among the four molecular subgroups, whereas ER/PRHER2 breast cancers had the lowest mutations in (1.8%) and BOCG (1.6%). In addition, mutation carriers had a significant worse disease-free survival [unadjusted hazard ratio (HR) 1.60; 95% confidence interval (CI) 1.10-2.34; = 0.014] and disease-specific survival (unadjusted HR 1.96; 95% CI, 1.03-3.65; = 0.040) than did non-carriers, whereas no significant difference in survival was found between mutation carriers and non-carriers. 9.2% of breast cancer patients carry a pathogenic mutation in cancer susceptibility genes in this large unselected series. Triple-negative breast cancers have the highest prevalence of mutations in and other breast cancer susceptibility genes among the four molecular subgroups, whereas ER/PRHER2 breast cancers had the lowest mutations in these genes. .

In tamoxifen-treated patients, women with the CYP2D6 *10 T/T genotype have a lower 4OHtam level in the serum and a worse clinical outcome.

PURPOSE Recently, a 36-kDa variant of estrogen receptor alpha (ER-alpha66), ER-alpha36, has been identified and cloned. ER-alpha36 predominantly localizes on the plasma membrane and in the cytoplasm and mediates a membrane-initiated "nongenomic" signaling pathway. Here, we investigate the association between ER-alpha36 expression and tamoxifen resistance in patients with breast cancer. PATIENTS AND METHODS ER-alpha36 protein expression in tumors from 896 women (two independent cohorts, 1 and 2) with operable primary breast cancer was assessed using an immunohistochemistry assay. Results In the first cohort of 710 consecutive patients, overexpression of ER-alpha36 was associated with poorer disease-free survival (DFS) and disease-specific survival (DSS) in patients with ER-alpha66-positive tumors who received tamoxifen treatment (chemotherapy plus tamoxifen or tamoxifen alone, n = 307). In contrast, ER-alpha36 was not associated with survival in patients with ER-alpha66-positive tumors who did not receive tamoxifen (chemotherapy alone, n = 129) and in patients with ER-alpha66-negative tumors whether they received tamoxifen (n = 73) or not (n = 149). In the second cohort of 186 patients who only received tamoxifen as adjuvant therapy, overexpression of ER-alpha36 was significantly associated with poorer DFS and DSS in 156 ER-alpha66-positive patients from this cohort, and ER-alpha36 remained an independent unfavorable factor for both DFS and DSS in these 156 patients by a multivariate analysis (DFS: hazard ratio [HR] = 5.47; 95% CI, 1.81 to 16.51; P =. 003; DSS: HR = 13.97; 95% CI, 1.58 to 123.53; P = .018). CONCLUSION Women with ER-alpha66-positive tumors that also express high levels of ER-alpha36 are less likely to benefit from tamoxifen treatment.

The genetic cause for approximately 80% of familial breast cancer patients is unknown. Here, by sequencing the entire exomes of nine early-onset familial breast cancer patients without BRCA1/2 mutations (diagnosed with breast cancer at or before the age of 35) we found that two index cases carried a potentially deleterious mutation in the RECQL gene (RecQ helicase-like; chr12p12). Recent studies suggested that RECQL is involved in DNA double-strand break repair and it plays an important role in the maintenance of genomic stability. Therefore, we further screened the RECQL gene in an additional 439 unrelated familial breast cancer patients. In total, we found three nonsense mutations leading to a truncated protein of RECQL (p.L128X, p.W172X, and p.Q266X), one mutation affecting mRNA splicing (c.395-2A>G), and five missense mutations disrupting the helicase activity of RECQL (p.A195S, p.R215Q, p.R455C, p.M458K, and p.T562I), as evaluated through an in vitro helicase assay. Taken together, 9 out of 448 BRCA-negative familial breast cancer patients carried a pathogenic mutation of the RECQL gene compared with one of the 1,588 controls (P = 9.14×10-6). Our findings suggest that RECQL is a potential breast cancer susceptibility gene and that mutations in this gene contribute to familial breast cancer development.