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.

IMPORTANCE Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES Breast and ovarian cancer risks. RESULTS Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22–1.74; P = 2 × 10−6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01–1.78; P = .04), and c. 5261 to c.5563 (BCCR23, RHR = 1.38; 95% CI, 1.22–1.55; P = 6 × 10−9). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56–0.70; P = 9 × 10−17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06–2.78; P = .03), c.772 to c.1806 (BCCR13; RHR = 1.63; 95% CI, 1.10–2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69–3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44–0.60; P = 6 × 10−17). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41–0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

We have undertaken a hospital-based study, to identify possible BRCA1 and BRCA2 founder mutations in the Polish population. The study group consisted of 66 Polish families with cancer who have at least three related females affected with breast or ovarian cancer and who had cancer diagnosed, in at least one of the three affected females, at age <50 years. A total of 26 families had both breast and ovarian cancers, 4 families had ovarian cancers only, and 36 families had breast cancers only. Genomic DNA was prepared from the peripheral blood leukocytes of at least one affected woman from each family. The entire coding region of BRCA1 and BRCA2 was screened for the presence of germline mutations, by use of SSCP followed by direct sequencing of observed variants. Mutations were found in 35 (53%) of the 66 families studied. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all four families with ovarian cancer only, in 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; five of these occurred in two or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Three BRCA1 abnormalities-5382insC, C61G, and 4153delA-accounted for 51%, 20%, and 11% of the identified mutations, respectively.

Importance Cytotoxic CD8+ T lymphocytes (TILs) participate in immune control of ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. Objective To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. Design Prospective survival cohort. Setting Multi-center observational. Participants Over 5,500 patients, including 3,196 high-grade serous ovarian carcinomas (HGSOCs), followed prospectively for over 24,650 person-years. Exposure(s) Following immunohistochemistry, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1–2), moderate (3–19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcome Measure(s) Overall survival time. Results Among the five major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (p-trend=4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near linear functional form. Conclusions and Relevance This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors which drive infiltration will be key to unravelling outcome heterogeneity in this cancer.

Three mutations in BRCA1 (5382insC, C61G and 4153delA) are common in Poland and account for the majority of mutations identified to date in Polish breast and breast-ovarian cancer families. It is not known, however, to what extent these 3 founder mutations account for all of the BRCA mutations distributed throughout the country. This question has important implications for health policy and the design of epidemiologic studies. To establish the relative contributions of founder and nonfounder BRCA mutations, we established the entire spectrum of BRCA1 and BRCA2 mutations in a large set of breast-ovarian cancer families with origins in all regions of Poland. We sequenced the entire coding regions of the BRCA1 and BRCA2 genes in 100 Polish families with 3 or more cases of breast cancer and in 100 families with cases of both breast and ovarian cancer. A mutation in BRCA1 or BRCA2 was detected in 66% of breast cancer families and in 63% of breast-ovarian cancer families. Of 129 mutations, 122 (94.6%) were in BRCA1 and 7 (5.4%) were in BRCA2. Of the 122 families with BRCA1 mutations, 119 (97.5%) had a recurrent mutation (i.e., one that was seen in at least 2 families). In particular, 111 families (91.0%) carried one of the 3 common founder mutations. The mutation spectrum was not different between families with and without ovarian cancer. These findings suggest that a rapid and inexpensive assay directed at identifying the 3 common founder mutations will have a sensitivity of 86% compared to a much more costly and labor-intensive full-sequence analysis of both genes. This rapid test will facilitate large-scale national epidemiologic and clinical studies of hereditary breast cancer, potentially including studies of chemoprevention. Germline mutations in BRCA1 (MIM 113-705) and BRCA2 (MIM 600185) account for familial clustering in the majority of families with both breast and ovarian cancers and in approximately one-half of families with site-specific breast cancer. 1-3 Of the more than 1,000 BRCA mutations reported to the Breast Cancer Information Core (BIC) database, many are unique but there are also numerous examples of founder mutations. Founder mutations have been reported in genetic isolates such as Ashkenazi Jews 4,5 and the Icelandic, 6 Finnish, 7 Dutch 8,9 and French Canadian 10 populations. Founder mutations have also been noted in Slavic countries, including Poland. 11 Three BRCA1 mutations (5382insC, C61G and 4153delA) are common in Poland, 11 but several other BRCA1 and BRCA2 mutations have also been reported in one or a few families. 11-17 Our goal was to describe the frequency of BRCA1 and BRCA2 constitutional mutations in a series of 200 breast cancer and breast-ovarian cancer families representing all regions of