The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.

OMEN WHO HAVE IN-herited mutations in the BRCA1 or BRCA2 (BRCA1/2) genes have substantially elevated risks of breast cancer and ovarian cancer, with a lifetime risk of breast cancer of 56% to 84%. [1][2][3] The estimated ovarian cancer risks range from 36% to 63% for BRCA1 mutation carriers and 10% to 27% for BRCA2 mutation carriers. [3][4][5][6] Women who are mutation carriers have cancer risk-management options that include risk-reducing salpingooophorectomy, risk-reducing mastectomy, annual cancer screening, and chemoprevention. Due to the lack of effective screening for ovarian cancer, salpingo-oophorectomy is strongly recommended once childbearing is complete.Salpingo-oophorectomy has been demonstrated to decrease the risk of both breast cancer and ovarian cancer in BRCA1/2 mutation carriers. [7][8][9][10][11][12][13][14][15][16] However, estimates for risk and mortality reduction for women with and without For editorial comment see p 1011.

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BackgroundRisk-reducing salpingo-oophorectomy (RRSO) is widely used by carriers of BRCA1 or BRCA2 (BRCA1/2) mutations to reduce their risks of breast and ovarian cancer. To guide women and their clinicians in optimizing cancer prevention strategies, we summarized the magnitude of the risk reductions in women with BRCA1/2 mutations who have undergone RRSO compared with those who have not.MethodsAll reports of RRSO and breast and/or ovarian or fallopian tube cancer in BRCA1/2 mutation carriers published between 1999 and 2007 were obtained from a PubMed search. Hazard ratio (HR) estimates were identified directly from the original articles. Pooled results were computed from nonoverlapping studies by fixed-effects meta-analysis.ResultsTen studies investigated breast or gynecologic cancer outcomes in BRCA1/2 mutation carriers who had undergone RRSO. Breast cancer outcomes were investigated in three nonoverlapping studies of BRCA1/2 mutation carriers, four of BRCA1 mutation carriers, and three of BRCA2 mutation carriers. Gynecologic cancer outcomes were investigated in three nonoverlapping studies of BRCA1/2 mutation carriers and one of BRCA1 mutation carriers. RRSO was associated with a statistically significant reduction in risk of breast cancer in BRCA1/2 mutation carriers (HR = 0.49; 95% confidence interval [CI] = 0.37 to 0.65). Similar risk reductions were observed in BRCA1 mutation carriers (HR = 0.47; 95% CI = 0.35 to 0.64) and in BRCA2 mutation carriers (HR = 0.47; 95% CI = 0.26 to 0.84). RRSO was also associated with a statistically significant reduction in the risk of BRCA1/2-associated ovarian or fallopian tube cancer (HR = 0.21; 95% CI = 0.12 to 0.39). Data were insufficient to obtain separate estimates for ovarian or fallopian tube cancer risk reduction with RRSO in BRCA1 or BRCA2 mutation carriers.ConclusionThe summary estimates presented here indicate that RRSO is strongly associated with reductions in the risk of breast, ovarian, and fallopian tube cancers and should provide guidance to women in planning cancer risk reduction strategies.

Bilateral prophylactic mastectomy reduces the risk of breast cancer in women with BRCA1/2 mutations by approximately 90%.

SUMMARY The discovery of long non-coding RNA (lncRNA) has dramatically altered our understanding of cancer. Here, we describe a comprehensive analysis of lncRNA alterations at transcriptional, genomic, and epigenetic levels in 5,037 human tumor specimens across 13 cancer types from the Cancer Genome Atlas (TCGA). Our results suggest that the expression and dysregulation of lncRNAs are highly cancer-type specific compared to protein-coding genes. Using the integrative data generated by this analysis, we present a clinically guided small interfering RNA screening strategy and a co-expression analysis approach to identify cancer driver lncRNAs and predict their functions. This provides a resource for investigating lncRNAs in cancer and lays the groundwork for the development of new diagnostics and treatments.

A B S T R A C T PurposeEndometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors. Patients and MethodsIndividual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n ϭ 7,246), adenocarcinoma not otherwise specified (n ϭ 4,830), and adenocarcinoma with squamous differentiation (n ϭ 777) as type I tumors and serous (n ϭ 508) and mixed cell (n ϭ 346) as type II tumors. ResultsParity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m 2 increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (P heterogeneity Ͻ .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar. ConclusionThe results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.

TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10 −7 ), reduced estrogen receptor negative (ER-negative) (P=1.0×10 −8 ) and BRCA1 mutation carrier (P=1.1×10 −5 ) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10 −14 ), increased low malignant potential ovarian cancer risk (P=1.3×10 −15 ) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10 −12 ) and BRCA1 mutation carrier (P=1.6×10 −14 ) breast and invasive ovarian (P=1.3×10 −11 ) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splicevariant.