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.

Predictors of nonadherence to breast cancer screening guidelines in a United States urban comprehensive cancer center.

BACKGROUND: This study aimed to identify predictors of nonadherence to breast cancer screening guidelines in an urban screening clinic among high- and average-risk women in the United States. METHODS: We reviewed records of 6090 women who received ≥2 screening mammograms over 2 years at the Karmanos Cancer Institute to examine how breast cancer risk and breast density were associated with guideline-concordant screening. Incongruent screening was defined as receiving supplemental imaging between screening mammograms for average-risk women, and as not receiving recommended supplemental imaging for high-risk women. We used t-tests and chi-square tests to examine bivariate associations with guideline-congruent screening, and probit regression to regress guideline-congruence unto breast cancer risk, breast density, and their interaction, controlling for age and race. RESULTS: Incongruent screening was more likely among high- versus average-risk women (97.7% vs. 0.9%, p < 0.01). Among average-risk women, incongruent screening was more likely among those with dense versus nondense breasts (2.0% vs. 0.1%, p < 0.01). Among high-risk women, incongruent screening was more likely among those with nondense versus dense breasts (99.5% vs. 95.2%, p < 0.01). The significant main effects of density and high-risk on increased incongruent screening were qualified by a density by high-risk interaction, showing a weaker association between risk and incongruent screening among women with dense breasts (simple slope = 3.71, p < 0.01) versus nondense breasts (simple slope = 5.79, p < 0.01). Age and race were not associated with incongruent screening. CONCLUSIONS: Lack of adherence to evidence-based screening guidelines has led to underutilization of supplementary imaging for high-risk women and potential overutilization for women with dense breasts without other risk factors.

The role of area-level socioeconomic disadvantage in racial disparities in cancer incidence in metropolitan Detroit.

BACKGROUND: Neighborhood deprivation is associated with both race and cancer incidence, but there is a need to better understand the effect of structural inequities on racial cancer disparities. The goal of this analysis was to evaluate the relationship between a comprehensive measure of neighborhood-level social disadvantage and cancer incidence within the racially diverse population of metropolitan Detroit. METHODS: We estimated breast, colorectal, lung, and prostate cancer incidence rates using Metropolitan Detroit Cancer Surveillance System and US decennial census data. Neighborhood socioeconomic disadvantage was measured by the Area Deprivation Index (ADI) using Census Bureau's American Community Survey data at the Public Use Microdata Areas (PUMA) level. Associations between ADI at time of diagnosis and cancer incidence were estimated using Poisson mixed-effects models adjusting for age and sex. Attenuation of race-incidence associations by ADI was quantified using the "mediation" package in R. RESULTS: ADI was inversely associated with incidence of breast cancer for both non-Hispanic White (NHW) and non-Hispanic Black (NHB) women (NHW: per-quartile RR = 0.92, 95% CI 0.88-0.96; NHB: per-quartile RR = 0.94, 95% CI 0.91-0.98) and with prostate cancer incidence only for NHW men (per-quartile RR = 0.94, 95% CI 0.90-0.97). ADI was positively associated with incidence of lung cancer for NHWs and NHBs (NHW: per-quartile RR = 1.12, 95% CI 1.04-1.21; NHB: per-quartile RR = 1.37, 95% CI 1.25-1.51) and incidence of colorectal cancer (CRC) only among NHBs (per-quartile RR = 1.11, 95% CI 1.02-1.21). ADI significantly attenuated the relationship between race and hormone receptor positive, HER2-negative breast cancer (proportion attenuated = 8.5%, 95% CI 4.1-16.6%) and CRC cancer (proportion attenuated = 7.3%, 95% CI 3.7 to 12.8%), and there was a significant interaction between race and ADI for lung (interaction RR = 1.22, p < 0.0001) and prostate cancer (interaction RR = 1.09, p = 0.00092). CONCLUSIONS: Area-level socioeconomic disadvantage is associated with risk of common cancers in a racially diverse population and plays a role in racial differences in cancer incidence.

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.

Area-level Socioeconomic Disadvantage and Cancer Survival in Metropolitan Detroit.

BACKGROUND: Racial segregation is linked to poorer neighborhood quality and adverse health conditions among minorities, including worse cancer outcomes. We evaluated relationships between race, neighborhood social disadvantage, and cancer survival. METHODS: We calculated overall and cancer-specific survival for 11,367 non-Hispanic Black (NHB) and 29,481 non-Hispanic White (NHW) individuals with breast, colorectal, lung, or prostate cancer using data from the Metropolitan Detroit Cancer Surveillance System. The area deprivation index (ADI) was used to measure social disadvantage at the census block group level, where higher ADI is associated with poorer neighborhood factors. Associations between ADI and survival were estimated using Cox proportional hazards mixed-effects models accounting for geographic grouping and adjusting for demographic and clinical factors. RESULTS: Increasing ADI quintile was associated with increased overall mortality for all four cancer sites in multivariable-adjusted models. Stratified by race, these associations remained among breast (NHW: HR = 1.16, P < 0.0001; NHB: HR = 1.20, P < 0.0001), colorectal (NHW: HR = 1.11, P < 0.0001; NHB: HR = 1.09, P = 0.00378), prostate (NHW: HR = 1.18, P < 0.0001; NHB: HR = 1.18, P < 0.0001), and lung cancers (NHW: HR = 1.06, P < 0.0001; NHB: HR = 1.07, P = 0.00177). Cancer-specific mortality estimates were similar to overall mortality. Adjustment for ADI substantially attenuated the effects of race on mortality for breast [overall proportion attenuated (OPA) = 47%, P < 0.0001; cancer-specific proportion attenuated (CSPA) = 37%, P < 0.0001] prostate cancer (OPA = 51%, P < 0.0001; CSPA = 56%, P < 0.0001), and colorectal cancer (OPA = 69%, P = 0.032; CSPA = 36%, P = 0.018). CONCLUSIONS: Area-level socioeconomic disadvantage is related to cancer mortality in a racially diverse population, impacting racial differences in cancer mortality. IMPACT: Understanding the role of neighborhood quality in cancer survivorship could improve community-based intervention practices.

Moderators of the effects of perceived racism and discrimination on cancer-related health behaviors among two samples of African Americans.

BACKGROUND: Assumptions regarding within-race variation in the associations between measures of discrimination racism and health-related behaviors among African Americans have been largely unexplored. METHODS: We conducted secondary analyses of two studies to examine support for a model which describes several theoretical moderators of the effects of discrimination and racism on health behaviors. The first study examined the effects of group-based behavioral information and racial identity on the association between perceived racism and requests for at home colorectal cancer screening tests among a sample of 205 geographically diverse African Americans who participated in an online experiment from 2019 to 2020. RESULTS: Group-based behavioral information attenuated the association between perceived racism and requests for at-home screening kit. In the absence of group-based behavioral information, perceived racism was positively associated with screening kit requests for African Americans with weaker racial identity and negatively associated with requests for African Americans with stronger racial identity. The second study examined the influence of personal and group-based perceived discrimination, and behavior-relevant affective information related to a breast cancer risk notification, on 89 Michigan dwelling African American women's self-reported physician communication from 2015 to 2016. Results showed that perceived group-based discrimination was positively associated with physician communication in the absence of negative affective information, and perceived personal discrimination was negatively associated with physician communication as positive affective information increased. CONCLUSIONS: Together, these results support our theoretical model highlighting variation in the effects of discrimination and racism on health behaviors among African Americans, and indicates group-relevant behavioral information, racial identity, behavior relevant affective information, and target of discrimination as moderators of the effect. Implications for conceptualizing the effects of racism and discrimination and for examining racially targeted interventions are discussed.

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.

Uptake of genetic counseling and testing in a clinic-based population of women with breast cancer.

BACKGROUND: The study was conducted to evaluate racial differences in referral and uptake of genetic counseling (GC) in a clinic-based population of women with breast cancer. METHODS: Medical records of 150 breast cancer patients at the Karmanos Cancer Institute were reviewed to determine eligibility for GC according to National Comprehensive Cancer Network guidelines, GC referral rates, and appointment completion rates. Logistic regression was used to assess the relationship between demographic and clinical factors and GC eligibility and referral. RESULTS: The mean age at diagnosis was 57.1 (SD 12.6) and 66% of the women were Black. There were 91 women (60.7%) eligible for GC and of those, 54 (61.4%) were referred. After multivariable analyses, factors associated with reduced eligibility were older age at diagnosis (OR = 0.91, 95% CI [0.87,0.95]) and Black race (OR = 0.37, 95% CI [0.15, 0.96]). After additional multivariable analysis, eligibility was associated with an increased likelihood of referral (OR = 5.97, 95% CI [2.29, 15.56]), however, Medicare versus private insurance was associated with a lower likelihood for referral (OR = 0.32, 95% CI [0.12-0.80]. Of those referred, 49 (76.6%) completed an appointment, and 47 had genetic testing. Women with Medicare were also less likely to complete an appointment. Race had no impact on referral or appointment completion. CONCLUSIONS: There were no racial differences in GC referral or appointment completion in a clinic-based sample of women with breast cancer. Further interventions are needed to promote increased referral and appointment completion for women with breast cancer who are eligible for GC.

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.

Racial and ethnic variation in multigene panel testing in a cohort of BRCA1/2-negative individuals who had genetic testing in a large urban comprehensive cancer center.

BACKGROUND: There is sparse clinical information on the racial and ethnic distribution of results of multigene panel testing among individuals at high risk for hereditary cancer. METHODS: We evaluated the results of multigene panel testing across eight clinical sites across the state of Michigan for individuals seen for genetic counseling from May 13, 2013 to October 31, 2019 at the Karmanos Cancer Institute's cancer genetics clinic. We estimated the prevalence of pathogenic variants and variants of uncertain significance (VUS) from genes other than BRCA1/2 among individuals of non-Hispanic White (NHW), Black or African American (AA), Ashkenazi Jewish (AJ), Arab, Hispanic, and other ancestry. RESULTS: The racial and ethnic distribution of 2419 individuals who had panel testing included 68.8% NHW, 22.1% AA, 2.3% Arab, 2.2% AJ, 1.0% Hispanic, and 3.6% other. Of these, 11.2% had pathogenic variants and 17.5% had VUS. After multivariable analyses, compared to NHW, AA were less likely to have pathogenic variants (OR 95% CI, 0.38, 0.24-0.59, p < 0.001). Both AA and Arabs were more likely to have VUS (OR 95% CI, 1.53, 1.18-1.98, p = 0.001 and OR 95% CI, 2.28, 1.17-4.43, p = 0.015, respectively). There were no significant differences for other groups. The most common pathogenic variants were CHEK2 (n = 65), MUTYH (n = 45), ATM (n = 28), and MSH2 (n = 22); the most common pathogenic variants by race and ethnicity were CHEK2 (NHW), MSH2 and MUTYH (AA), MSH2 (Arab), MSH6 and CHEK2 (AJ), and MLH1 (Hispanic); the most common pathogenic variants by primary cancer site were CHEK2 (breast), MSH2 (colon), BRIP1 and MUTYH (ovarian), and MSH2 and MSH6 (endometrial). CONCLUSIONS: Understanding the racial and ethnic distribution of pathogenic variants in multi-gene panels has the potential to lead to better identification of individuals at risk for hereditary cancer.

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.

Heritable Susceptibility to Breast Cancer among African-American Women in the Detroit Research on Cancer Survivors Study.

BACKGROUND: African-American women have high rates of breast cancer associated with hereditary features. However, no studies have reported the prevalence of inherited variation across all genes known to be breast cancer risk factors among African-American patients with breast cancer not selected for high-risk characteristics. METHODS: We evaluated 182 African-American women diagnosed with invasive breast cancer in metropolitan Detroit via targeted capture and multiplex sequencing of 13 well-established breast cancer risk genes and five suggested breast cancer risk genes. RESULTS: We identified 24 pathogenic variants in 23 women [12.6%; 95% confidence interval (CI), 8.2%-18.4%] and five genes (BRCA2, BRCA1, ATM, RAD50, CDH1). BRCA1 and BRCA2 accounted for 58.3% of all pathogenic variants. An additional six pathogenic variants were found in suggested breast cancer risk genes (MSH6, MUTYH, NF1, BRIP1). CONCLUSIONS: The prevalence of germline pathogenic variants is relatively high among African-American patients with breast cancer unselected for high-risk characteristics across a broad spectrum of genes. IMPACT: This study helps to define the genomic landscape of breast cancer susceptibility in African-American women who could benefit from enhanced surveillance and screening.

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.

CLCA2 expression is associated with survival among African American women with triple negative breast cancer.

PURPOSE: Black/African American (AA) women are twice as likely to be diagnosed with triple negative breast cancer (TNBC) compared to whites, an aggressive breast cancer subtype associated with poor prognosis. There are no routinely used targeted clinical therapies for TNBC; thus there is a clear need to identify prognostic markers and potential therapeutic targets. METHODS: We evaluated expression of 27,016 genes in 155 treatment-naïve TN tumors from AA women in Detroit. Associations with survival were evaluated using Cox proportional hazards models adjusting for stage and age at diagnosis, and p-values were corrected using a false discovery rate. Our validation sample consisted of 494 TN tumors using four publically available data sets. Meta-analyses were performed using summary statistics from the four validation results. RESULTS: In the Detroit AA cohort, CLCA2 [Hazard ratio (HR) = 1.56, 95% confidence interval (CI) 1.31-1.86, nominal p = 5.1x10-7, FDR p = 0.014], SPIC [HR = 1.47, 95%CI 1.26-1.73, nominal p = 1.8x10-6, FDR p = 0.022], and MIR4311 [HR = 1.57, 95% CI 1.31-1.92, nominal p = 2.5x10-5, FDR p = 0.022] expression were associated with overall survival. Further adjustment for treatment and breast cancer specific survival analysis did not substantially alter effect estimates. CLCA2 was also associated with increased risk of death in the validation cohorts [HR = 1.14, 95% CI 1.05-1.24, p = 0.038, p-heterogeneity = 0.88]. CONCLUSIONS: We identified CLCA2 as a potential prognostic marker for TNBC in AA women.

Using Whole Breast Ultrasound Tomography to Improve Breast Cancer Risk Assessment: A Novel Risk Factor Based on the Quantitative Tissue Property of Sound Speed.

Mammographic percent density (MPD) is an independent risk factor for developing breast cancer, but its inclusion in clinical risk models provides only modest improvements in individualized risk prediction, and MPD is not typically assessed in younger women because of ionizing radiation concerns. Previous studies have shown that tissue sound speed, derived from whole breast ultrasound tomography (UST), a non-ionizing modality, is a potential surrogate marker of breast density, but prior to this study, sound speed has not been directly linked to breast cancer risk. To that end, we explored the relation of sound speed and MPD with breast cancer risk in a case-control study, including 61 cases with recent breast cancer diagnoses and a comparison group of 165 women, frequency matched to cases on age, race, and menopausal status, and with a recent negative mammogram and no personal history of breast cancer. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the relation of quartiles of MPD and sound speed with breast cancer risk adjusted for matching factors. Elevated MPD was associated with increased breast cancer risk, although the trend did not reach statistical significance (OR per quartile = 1.27, 95% CI: 0.95, 1.70; ptrend = 0.10). In contrast, elevated sound speed was significantly associated with breast cancer risk in a dose-response fashion (OR per quartile = 1.83, 95% CI: 1.32, 2.54; ptrend = 0.0003). The OR trend for sound speed was statistically significantly different from that observed for MPD (p = 0.005). These findings suggest that whole breast sound speed may be more strongly associated with breast cancer risk than MPD and offer future opportunities for refining the magnitude and precision of risk associations in larger, population-based studies, including women younger than usual screening ages.

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.

Profiling the Mutational Landscape in Known Driver Genes and Novel Genes in African American Non-Small Cell Lung Cancer Patients.

PURPOSE: Identifying novel driver genes and mutations in African American non-small cell lung cancer (NSCLC) cases can inform targeted therapy and improve outcomes for this traditionally underrepresented population. EXPERIMENTAL DESIGN: Tumor DNA, RNA, and germline DNA were collected from African American NSCLC patients who participated in research conducted at the Karmanos Cancer Institute (KCI) in Detroit, Michigan. Known mutations were ascertained through the Sequenom LungCarta panel of 214 mutations in 26 genes, RET/ROS1 fusions, amplification of FGFR1, and expression of ALK. Paired tumor and normal DNA was whole-exome sequenced for a subset of cases without known driver mutations. RESULTS: Of the 193 tumors tested, 77 known driver mutations were identified in 66 patients (34.2%). Sixty-seven of the 127 patients without a known driver mutation were sequenced. In 54 of these patients, 50 nonsynonymous mutations were predicted to have damaging effects among the 26 panel genes, 47 of which are not found in The Cancer Genome Atlas NSCLC white or African American samples. Analyzing the whole-exome sequence data using MutSig2CV identified a total of 88 genes significantly mutated at FDR q < 0.1. Only 5 of these genes were previously reported as oncogenic. CONCLUSIONS: These findings suggest that broader mutation profiling including both known and novel driver genes in African Americans with NSCLC will identify additional mutations that may be useful in treatment decision-making.

Obesity-induced MBD2_v2 expression promotes tumor-initiating triple-negative breast cancer stem cells.

Obesity is a risk factor for triple-negative breast cancer (TNBC) incidence and poor outcomes, but the underlying molecular biology remains unknown. We previously identified in TNBC cell cultures that expression of epigenetic reader methyl-CpG-binding domain protein 2 (MBD2), specifically the alternative mRNA splicing variant MBD variant 2 (MBD2_v2), is dependent on reactive oxygen species (ROS) and is crucial for maintenance and expansion of cancer stem cell-like cells (CSCs). Because obesity is coupled with inflammation and ROS, we hypothesized that obesity can fuel an increase in MBD2_v2 expression to promote the tumor-initiating CSC phenotype in TNBC cells in vivo. Analysis of TNBC patient datasets revealed associations between high tumor MBD2_v2 expression and high relapse rates and high body mass index (BMI). Stable gene knockdown/overexpression methods were applied to TNBC cell lines to elucidate that MBD2_v2 expression is governed by ROS-dependent expression of serine- and arginine-rich splicing factor 2 (SRSF2). We employed a diet-induced obesity (DIO) mouse model that mimics human obesity to investigate whether obesity causes increased MBD2_v2 expression and increased tumor initiation capacity in inoculated TNBC cell lines. MBD2_v2 and SRSF2 levels were increased in TNBC cell line-derived tumors that formed more frequently in DIO mice relative to tumors in lean control mice. Stable MBD2_v2 overexpression increased the CSC fraction in culture and increased TNBC cell line tumor initiation capacity in vivo. SRSF2 knockdown resulted in decreased MBD2_v2 expression, decreased CSCs in TNBC cell cultures, and hindered tumor formation in vivo. This report describes evidence to support the conclusion that MBD2_v2 expression is induced by obesity and drives TNBC cell tumorigenicity, and thus provides molecular insights into support of the epidemiological evidence that obesity is a risk factor for TNBC. The majority of TNBC patients are obese and rising obesity rates threaten to further increase the burden of obesity-linked cancers, which reinforces the relevance of this report.