SummaryWhile several lung cancer susceptibility loci have been identified, much of lung cancer heritability remains unexplained. Here, 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated GWAS analysis of lung cancer on 29,266 patients and 56,450 controls. We identified 18 susceptibility loci achieving genome wide significance, including 10 novel loci. The novel loci highlighted the striking heterogeneity in genetic susceptibility across lung cancer histological subtypes, with four loci associated with lung cancer overall and six with lung adenocarcinoma. Gene expression quantitative trait analysis (eQTL) in 1,425 normal lung tissues highlighted RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes, OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

To provide a resource for assessing continental ancestry in a wide variety of genetic studies we identified, validated and characterized a set of 128 ancestry informative markers (AIMs). The markers were chosen for informativeness, genome-wide distribution, and genotype reproducibility on two platforms (TaqMan® assays and Illumina arrays). We analyzed genotyping data from 825 subjects with diverse ancestry, including European, East Asian, Amerindian, African, South Asian, Mexican, and Puerto Rican. A comprehensive set of 128 AIMs and subsets as small as 24 AIMs are shown to be useful tools for ascertaining the origin of subjects from particular continents, and to correct for population stratification in admixed population sample sets. Our findings provide general guidelines for the application of specific AIM subsets as a resource for wide application. We conclude that investigators can use TaqMan assays for the selected AIMs as a simple and cost efficient tool to control for differences in continental ancestry when conducting association studies in ethnically diverse populations.

An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3).Patients and Methods Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competingrisks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. ResultsMost risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] , .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het # .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas. ConclusionThe heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype.

Context.-Previous studies of BRCA1 mutation prevalence have been based on high-risk groups, yielding estimates that do not reflect the experience of the general population of US patients with breast cancer.Objective.-To determine prevalence of known disease-related mutations and other variants in BRCA1 and how it differs by race, age at diagnosis, and family history status in a population-based sample of white and black patients with breast cancer unselected for family history.Design.-Case-control study.Setting.-A 24-county area of central and eastern North Carolina.Participants.-Cases were women aged 20 to 74 years diagnosed as having a first invasive breast cancer between May 1993 and June 1996. Controls were frequency matched to cases by 5-year age range and race. The first 211 cases and 188 controls regardless of race and the subsequent 99 cases and 108 controls of African American ancestry are included in this report.Main Outcome Measure.-Germline variants at any site in the coding sequence, splice junctions, 5Ј untranslated region, or 3Ј untranslated region of the BRCA1 gene were analyzed in cases, and selected variants were analyzed in controls. Screening was performed using multiplex single-strand conformation analysis, with all potential variants confirmed using genomic sequencing.Results.-Three of 211 patients with breast cancer had disease-related variants at BRCA1, all of which were protein-truncating mutations. After adjustment for sampling probabilities, the proportion of patients with breast cancer with diseaserelated variants was 3.3% (95% confidence interval, 0%-7.2%) in white women and 0% in black women. Young age at diagnosis alone did not predict BRCA1 carrier status in this population. In white women, prevalence of inherited mutation was 23% for cases with family history of ovarian cancer, 13% for cases from families with at least 4 cases of breast cancer with or without ovarian cancer, and 33% for cases from families with both breast and ovarian cancer and at least 4 affected relatives. Because these results are based on few families at the highest levels of risk, confidence intervals around these estimates are wide. An additional 5 patients had rare missense mutations or a single amino acid deletion, the biological significance of which is unknown. In black women, a variant in the 3Ј untranslated region was statistically significantly more common in cases than in controls.Conclusions.-These data suggest that in the general US population, widespread screening of BRCA1 is not warranted. In contrast, BRCA1 mutations are sufficiently frequent in families with both breast and ovarian cancer, or at least 4 cases of breast cancer (at any age), that genotyping might be considered. The emerging picture of BRCA1 population genetics involves complex interactions of family history, age, and genetic ancestry, all of which should be taken into account when considering testing or interpreting results.