Genome-wide interaction analysis identified low-frequency variants with sex disparity in lung cancer risk.

Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10-8); rs79942605 (OR = 2.17, P = 2.81×10-8) and rs208908 (OR = 0.70, P = 4.54×10-8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

Association between major discrimination and deficit accumulation in African American cancer survivors: The Detroit Research on Cancer Survivors Study.

BACKGROUND: Discrimination can adversely affect health and accelerate aging, but little is known about these relationships in cancer survivors. This study examines associations of discrimination and aging among self-identified African American survivors. METHODS: A population-based sample of 2232 survivors 20-79 years old at diagnosis were enrolled within 5 years of breast (n = 787), colorectal (n = 227), lung (n = 223), or prostate (n = 995) cancer between 2017 and 2022. Surveys were completed post-active therapy. A deficit accumulation index measured aging-related disease and function (score range, 0-1, where <0.20 is robust, 0.20 to <0.35 is pre-frail, and 0.35+ is frail; 0.06 is a large clinically meaningful difference). The discrimination scale assessed ever experiencing major discrimination and seven types of events (score, 0-7). Linear regression tested the association of discrimination and deficit accumulation, controlling for age, time from diagnosis, cancer type, stage and therapy, and sociodemographic variables. RESULTS: Survivors were an average of 62 years old (SD, 9.6), 63.2% reported ever experiencing major discrimination, with an average of 2.4 (SD, 1.7) types of discrimination events. Only 24.4% had deficit accumulation scores considered robust (mean score, 0.30 [SD, 0.13]). Among those who reported ever experiencing major discrimination, survivors with four to seven types of discrimination events (vs. 0-1) had a large, clinically meaningful increase in adjusted deficits (0.062, p < .001) and this pattern was consistent across cancer types. CONCLUSION: African American cancer survivors have high deficit accumulated index scores, and experiences of major discrimination were positively associated with these deficits. Future studies are needed to understand the intersectionality between aging, discrimination, and cancer survivorship among diverse populations.

Racial and ethnic variation in BRCA1 and BRCA2 genetic test results among individuals referred for genetic counseling at a large urban comprehensive cancer center.

PURPOSE: The prevalence of pathogenic variants in BRCA1 and BRCA2 in populations other than Ashkenazi Jewish (AJ) is not well defined. We describe the racial and ethnic-specific prevalence of BRCA1/2 pathogenic variants and variants of uncertain significance (VUS) among individuals referred for genetic testing in a large urban comprehensive cancer center over a 20-year period. METHODS: The population included 3,537 unrelated individuals who underwent genetic testing from January 1999 to October 2019 at the Karmanos Cancer Institute. We estimated the prevalence of pathogenic variants and VUS and evaluated associations with race and ethnicity for African American (AA), Arab, AJ and Hispanic individuals compared to Non-Hispanic Whites (NHW). We used multivariable models to adjust for other predictors of pathogenic variants. We also reported the most common pathogenic variants by racial and ethnic group. RESULTS: The racial and ethnic breakdown of our population was: NHW (68.9%), AA (20.3%), AJ (2.5%), Arab (2.2%), Hispanic (1.0%), Asian Pacific Islander, Native American/Alaskan Native (4.7%), and < 1% unknown. The overall prevalence of pathogenic variants in BRCA1/2 was 8.9% and the prevalence of VUS was 5.6%. Compared to NHW, there were no racial or ethnic differences in the rate of pathogenic variants. However, AA individuals were more likely to have VUS in BRCA1 (adjusted OR 2.43, 95% CI 1.38-4.28) and AJ were more likely to have VUS in BRCA2 (adjusted OR 3.50, 95% CI 1.61-6.58). CONCLUSION: These results suggest the continued need for genetic testing and variant reclassification for individuals of all racial and ethnic groups.

Physicians' perceptions of breast density notification laws and appropriate patient follow-up.

Breast density notification laws have been adopted in the absence of consistent guidelines for post-notification follow-up. This can lead to inconsistent and potentially deficient management of women's health due to inconsistent physician practices. We examined physicians' knowledge and practices regarding follow-up for patients who receive density notifications. Physicians who referred patients to a Michigan hospital network for screening mammograms were recruited to participate in survey study; 105 (29.8%) responded. The survey assessed physicians' demographics, knowledge, and awareness of breast density and breast cancer risk and of density notification laws, and perceptions of appropriate follow-up behaviors for their patients who received density notifications. Most physicians (75%) knew about the notification law, and they were generally comfortable responding to breast density questions and deciding on follow-up. Most indicated that additional breast imaging (68.0%), followed by assessing breast cancer risk (24.7%) were appropriate follow-up responses. Physicians who performed breast cancer risk assessments, and who were more comfortable with breast density questions and follow-up decision making, were more likely to propose additional imaging. Male physicians were less likely to propose assessing breast cancer risk, and less likely to propose clinical and/or breast self-examinations. Divergence between practice and guidelines when it comes to supplemental breast cancer screening, coupled with density notification language that promotes additional screening in the absence of consistent evidence, remains concerning. Improved understanding of how density notification recipients and their physicians make decisions about supplemental screening is warranted to ensure that breast cancer risk is properly considered.

COPD-dependent effects of genetic variation in key inflammation pathway genes on lung cancer risk.

Genome-wide association studies (GWAS) have identified several loci contributing to lung cancer and COPD risk independently; however, inflammation-related pathways likely harbor additional lung cancer risk-associated variants in biologically relevant immune genes that differ dependent on COPD. We selected single nucleotide polymorphisms (SNPs) proximal to 2,069 genes within 48 immune pathways. We modeled the contribution of these variants to lung cancer risk in a discovery sample of 1,932 lung cancer cases and controls stratified by COPD status and validation sample of 953 cases and controls also stratified by COPD. There were 43 validated SNPs in those with COPD and 60 SNPs in those without COPD associated with lung cancer risk. Furthermore, 29 of 43 and 28 of 60 SNPs demonstrated a statistically significant interaction with COPD in the pooled sample. These variants demonstrated tissue-dependent effects on proximal gene expression, enhanced network connectivity and resided together in specific immune pathways. These results reveal that key inflammatory related genes and pathways, not found in prior GWAS, impact lung cancer risk in a COPD-dependent manner. Genetic variation identified in our study supplements prior lung cancer GWAS and serves as a foundation to further interrogate risk relationships in smoking and COPD populations.

Patterns of cancer family history and genetic counseling eligibility among African Americans with breast, prostate, lung, and colorectal cancers: A Detroit Research on Cancer Survivors cohort study.

BACKGROUND: Family history (FH) remains one of the strongest risk factors for many common cancers and is used to determine cancer genetic counseling (CGC) eligibility, but the understanding of familial cancer patterns in African Americans is limited. METHODS: This study evaluated cancer FH among African Americans with invasive breast cancer, prostate cancer, lung cancer, or colorectal cancer (CRC) in the Detroit Research on Cancer Survivors (ROCS) cohort. Associations between participant cancer type, site-specific FH, and meeting national guidelines for CGC were evaluated via logistic regression. Cancer FH patterns were evaluating via hierarchical clustering. RESULTS: Among 1500 ROCS participants, 71% reported at least 1 first-degree relative or grandparent with cancer. FHs of breast cancer, CRC, lung cancer, and prostate cancer were most common among participants with the same diagnosis (odds ratio [OR] for breast cancer, 1.14; P < .001; OR for CRC, 1.08; P = .003; OR for lung cancer, 1.09; P = .008; OR for prostate cancer, 1.14; P < .001). Nearly half of the participants (47%) met national CGC guidelines, and 24.4% of these participants met CGC criteria on the basis of their cancer FH alone. FH was particularly important in determining CGC eligibility for participants with prostate cancer versus breast cancer (OR for FH vs personal history alone, 2.91; 95% confidence interval, 1.94-4.35; P < .001). In clustering analyses, breast and prostate cancer FH-defined clusters were common across all participants. Clustering of CRC and breast cancer FHs was also observed. CONCLUSIONS: ROCS participants reported high rates of cancer FH. The high rate of eligibility for CGC among ROCS participants supports the need for interventions to increase referrals and uptake of CGC among African Americans.

Racial differences in estrogen receptor staining levels and implications for treatment and survival among estrogen receptor positive, HER2-negative invasive breast cancers.

BACKGROUND: African American women (AAW) die more frequently from estrogen receptor (ER) positive breast cancer than European American women (EAW). We investigated the relationship between race, percent ER staining, treatment, and clinical outcomes. METHODS: Percent ER staining (weakly ER+: 1-10%, moderately ER+: 11-50%, strongly ER+: > 50%) was abstracted from pathology reports for 1573 women with ER+/HER2- invasive breast cancer treated at a single cancer center in Detroit, MI from 2010 to 2017. Clinical outcomes and tumor characteristics were obtained from the Metropolitan Detroit Cancer Surveillance System. Associations of ER levels with demographic and clinical characteristics were evaluated using logistic regression. Overall and breast cancer-specific (BCS) survival were evaluated using Cox proportional hazards models. RESULTS: AAW were more likely to have tumors with lower ER staining levels than EAW (weakly ER+: Odds ratio (OR) 2.19, p = 0.019; moderately ER+: OR 2.80, p = 0.005). Women with weakly compared to strongly ER+ tumors were less likely to receive endocrine therapy (ET) regardless of race (OR 0.79, p < 0.001). Mortality was predicted by both AA race (Overall hazard ratio (HR) = 1.72, p < 0.001; BCS HR 1.45, p = 0.08) and low (1-50%) ER (Overall HR 1.57, p = 0.083; BCS HR 2.11, p = 0.017) adjusting for clinic-pathologic characteristics. ET was associated with improved BCS survival in all women (1-50%: HR 0.11, p < 0.001; > 50%: HR 0.24, p < 0.001). CONCLUSION: The biology of ER+/HER2- tumors varies by race, although this does not appear to account for racial differences in survival. Although ET substantially reduces mortality among women with weakly ER+ tumors, these women are less likely to be treated with ET and have poorer outcomes.

Between-Race Differences in Processes Predicting Physician Communication for African American and European American Recipients of Breast Density Notifications.

BACKGROUND: Breast density notification laws mandate reporting of dense breast to applicable women. The same psychological and systemic barriers that yield between-race differences in mammography use will probably yield between-race differences in women's psychological and behavioral responses to breast density notifications. PURPOSE: We used the theory of planned behavior as a framework to examine between-race differences in the likelihood of following-up with physicians after receiving breast density notifications and to examine differences in African American and Caucasian American women's behavioral decision-making processes. METHODS: A subset of 212 African American and Caucasian American women who participated in an initial and follow-up survey examining responses to breast density notifications were examined for this study. Participants reported background and demographic measures, psychological responses to receiving notifications, and planned behavior measures related to following up with physicians approximately 2 weeks after receiving their mammogram reports. Participants self-reported their behaviors 3 months later. RESULTS: There were no between-race differences in self-reported physician communication; however, there were differences in processes that predicted behavior. For Caucasian American women, behavioral intentions, education, and income predicted behaviors. Instead of intentions, group-based medical suspicion, confusion, breast cancer worry, and breast density anxiety predicted behaviors for African American women. CONCLUSIONS: Behavioral decision-making processes for Caucasian American women were in line with well-validated theoretical predictions. For African American women, race-related medical suspicion, prior breast density awareness, and emotional responses to breast density notifications predicted behavior. The results highlight the need to focus on racially distinct psychological targets when designing interventions to support guideline concordant behavioral decisions among women who receive breast density notifications.

Prognostic modeling of the immune-centric transcriptome reveals interleukin signaling candidates contributing to differential patient outcomes.

Immunotherapy is a promising advancement in the treatment of non-small-cell lung carcinoma (NSCLC), although much of how lung tumors interact with the immune system in the natural course of disease remains unknown. We investigated the impact of the expression of immune-centric genes and pathways in tumors on patient survival to reveal novel candidates for immunotherapeutic research. Tumor transcriptomes and detailed clinical characteristics were obtained from patients with NSCLC who were participants of either the Inflammation, Health and Lung Epidemiology (INHALE) (discovery, N = 280) or The Cancer Genome Atlas (TCGA) Lung (replication, N = 1026) studies. Expressions of 2253 genes derived from 48 major immune pathways were assessed for association with patient prognosis using a multivariable Cox model and pathway effects were assessed with an in-house implementation of the Gene Set Enrichment Analysis (GSEA) algorithm. Prognosis-guided gene and pathway analysis of immune-centric expression in tumors revealed significant survival enrichments across both cohorts. The 'Interleukin Signaling' pathway, containing 430 genes, was found to be statistically and significantly enriched with prognostic signal in both the INHALE (P = 0.008) and TCGA (P = 0.039) datasets. Subsequent leading-edge analysis identified a subset of genes (N = 23) shared between both cohorts, driving the pathway enrichment. Cumulative expression of this leading-edge gene signature was a strong predictor of patient survival [discovery: hazard ratio (HR) = 1.59, P = 3.0 × 10-8; replication: HR = 1.29, P = 7.4 × 10-7]. These data demonstrate the impact of immune-centric expression on patient outcomes in NSCLC. Furthermore, prognostic gene effects were localized to discrete immune pathways, of which Interleukin Signaling had the greatest impact on overall survival and the subset of genes driving these effects have promise for future therapeutic intervention.

The effect of genetic variants on the relationship between statins and breast cancer in postmenopausal women in the Women's Health Initiative observational study.

PURPOSE: Statins have been postulated to have chemopreventive activity against breast cancer. We evaluated whether germline genetic polymorphisms modified the relationship between statins and breast cancer risk using data from the Women's Health Initiative. We evaluated these interactions using both candidate gene and agnostic genome-wide approaches. METHODS: To identify candidate gene-statin interactions, we tested interactions between 22 SNPS in nine candidate genes implicated in the effect of statins on lipid metabolism in 1687 cases and 1687 controls. We then evaluated statin use interaction with the remaining 30,380 SNPs available in this sample from the CGEMS GWAS study. RESULTS: After adjusting for multiple comparisons, no SNP interactions with statin usage and risk of breast cancer were statistically significant in either the candidate genes or genome-wide approaches. CONCLUSIONS: We found no evidence of SNP interactions with statin usage for breast cancer risk in a population of 3374 individuals. These results suggest that genome-wide common genetic variants do not moderate the association between statin usage and breast cancer in the population of women in the Women's Health Initiative.

Whole-exome sequencing reveals genetic variability among lung cancer cases subphenotyped for emphysema.

Lung cancer continues to be a major public health challenge in the United States despite efforts to decrease the prevalence of smoking; outcomes are especially poor for African-American patients compared to other races/ethnicities. Chronic obstructive pulmonary disease (COPD) co-occurs with lung cancer frequently, but not always, suggesting both shared and distinct risk factors for these two diseases. To identify germline genetic variation that distinguishes between lung cancer in the presence and absence of emphysema, we performed whole-exome sequencing on 46 African-American lung cancer cases (23 with and 23 without emphysema frequency matched on age, sex, histology and pack years). Using conditional logistic regression, we found 6305 variants (of 168 150 varying sites) significantly associated with lung cancer subphenotype (P ≤ 0.05). Next, we validated 10 of these variants in an independent set of 612 lung cancer cases (267 with emphysema and 345 without emphysema) from the same population of inference as the sequenced cases. We found one variant that was significantly associated with lung cancer subphenotype in the validation sample. These findings contribute to teasing apart shared genetic factors from independent genetic factors for lung cancer and COPD.

Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.

Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.

Genes associated with histopathologic features of triple negative breast tumors predict molecular subtypes.

Distinct subtypes of triple negative (TN) breast cancer have been identified by tumor expression profiling. However, little is known about the relationship between histopathologic features of TN tumors, which reflect aspects of both tumor behavior and tumor microenvironment, and molecular TN subtypes. The histopathologic features of TN tumors were assessed by central review and 593 TN tumors were subjected to whole genome expression profiling using the Illumina Whole Genome DASL array. TN molecular subtypes were defined based on gene expression data associated with histopathologic features of TN tumors. Gene expression analysis yielded signatures for four TN subtypes (basal-like, androgen receptor positive, immune, and stromal) consistent with previous studies. Expression analysis also identified genes significantly associated with the 12 histological features of TN tumors. Development of signatures using these markers of histopathological features resulted in six distinct TN subtype signatures, including an additional basal-like and stromal signature. The additional basal-like subtype was distinguished by elevated expression of cell motility and glucose metabolism genes and reduced expression of immune signaling genes, whereas the additional stromal subtype was distinguished by elevated expression of immunomodulatory pathway genes. Histopathologic features that reflect heterogeneity in tumor architecture, cell structure, and tumor microenvironment are related to TN subtype. Accounting for histopathologic features in the development of gene expression signatures, six major subtypes of TN breast cancer were identified.

Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.

The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3' untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated.

Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions.

Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10(-07)), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m(2) (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m(2) or higher (OR = 0.89, 95% CI 0.72-1.11, P for interaction = 3.2 × 10(-05)). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.

A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients.

BACKGROUND: Personalized therapy considering clinical and genetic patient characteristics will further improve breast cancer survival. Two widely used treatments, chemotherapy and radiotherapy, can induce oxidative DNA damage and, if not repaired, cell death. Since base excision repair (BER) activity is specific for oxidative DNA damage, we hypothesized that germline genetic variation in this pathway will affect breast cancer-specific survival depending on treatment. METHODS: We assessed in 1,408 postmenopausal breast cancer patients from the German MARIE study whether cancer specific survival after adjuvant chemotherapy, anthracycline chemotherapy, and radiotherapy is modulated by 127 Single Nucleotide Polymorphisms (SNPs) in 21 BER genes. For SNPs with interaction terms showing p<0.1 (likelihood ratio test) using multivariable Cox proportional hazard analyses, replication in 6,392 patients from nine studies of the Breast Cancer Association Consortium (BCAC) was performed. RESULTS: rs878156 in PARP2 showed a differential effect by chemotherapy (p=0.093) and was replicated in BCAC studies (p=0.009; combined analysis p=0.002). Compared to non-carriers, carriers of the variant G allele (minor allele frequency=0.07) showed better survival after chemotherapy (combined allelic hazard ratio (HR)=0.75, 95% 0.53-1.07) and poorer survival when not treated with chemotherapy (HR=1.42, 95% 1.08-1.85). A similar effect modification by rs878156 was observed for anthracycline-based chemotherapy in both MARIE and BCAC, with improved survival in carriers (combined allelic HR=0.73, 95% CI 0.40-1.32). None of the SNPs showed significant differential effects by radiotherapy. CONCLUSIONS: Our data suggest for the first time that a SNP in PARP2, rs878156, may together with other genetic variants modulate cancer specific survival in breast cancer patients depending on chemotherapy. These germline SNPs could contribute towards the design of predictive tests for breast cancer patients.

Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer.

Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.

Cumulative exposure to medical radiation for children requiring surgery for congenital heart disease.

OBJECTIVE: To describe cumulative radiation exposure in a large single-center cohort of children with congenital heart disease (CHD) and identify risk factors for greater exposure. STUDY DESIGN: A detailed medical radiation exposure history was collected retrospectively for patients aged <18 years who underwent surgery for CHD between January 1, 2001, and July 22, 2009. Cumulative per patient exposure was quantified as the effective dose in millisieverts (mSv) and annualized (mSv/year). RESULTS: A total of 4132 patients were subjected to 134,715 radiation examinations at a median follow-up of 4.3 years (range, 0-8.6 years). Exposure clustered around the time of surgery. The median exposure was 14 radiologic tests (the majority of which were plain film radiographs) at an effective dose of 0.96 mSv (the majority of which was from cardiac catheterization), although this distribution had a very wide range. Almost three-quarters (73.7%) were exposed to <3 mSv/year, and 5.3% were exposed to >20 mSv/year. Neonates, children with genetic syndromes, and children requiring surgery for cardiomyopathy, pulmonary valve, single ventricle, or tricuspid valve diseases were more likely to have higher exposure levels, and those requiring surgery for aortic arch anomalies or atrioventricular septal defects were more likely to have lower levels. CONCLUSION: Children with CHD requiring surgery are exposed to numerous medical forms of ionizing radiation. Although the majority of patients receive <3 mSv/year, there are identifiable risk factors for higher exposure levels. This may have important health implications as these patients age.

Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies.

BACKGROUND: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. METHODS: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. RESULTS: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 × 10-8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior. CONCLUSIONS: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies. IMPACT: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer.

Efforts to Grow Genomic Research in Ancestrally Diverse and Admixed Populations.

Recent initiatives by the research community to characterize the genomic and molecular landscapes of tumors in ancestrally diverse and admixed populations, including the publication by Ding and colleagues in this issue of Cancer Research, represent important efforts to improve our understanding of the entire spectrum of cancer genomic variation with potential clinical consequences. Ding and colleagues confirmed a similar prevalence of mutations in established breast cancer driver genes including PIK3CA, TP53, GATA3, MAP3K1, CDH1, CBFB, PTEN, and RUNX1 and recurrent amplifications in breast cancer drivers including MYC, FGFR1, CCND1, and ERBB2 in tumors from Hispanic/Latina women as compared with non-Hispanic White women. Importantly, they also identified Catalogue of Somatic Mutations in Cancer (COSMIC) signature 16 in a significant fraction of tumors from Hispanic/Latina women and a novel recurrent amplification on 17q11.2. This study highlights the potential for inclusion of participants from diverse populations to accelerate discoveries and advance equity in genomic medicine, as well as the need for even larger collaborative initiatives. See related article by Ding et al., p. 2600.