Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants that Confer Risk for Breast Cancer.

Breast cancer includes several subtypes with distinct characteristic biological, pathological, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate development of improved prevention and treatment approaches. Here, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case GWAS (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared to luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to 2-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among breast cancer patients. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC.

The interrelationship between obesity and race in breast cancer prognosis: a prospective cohort study.

BACKGROUND: Obesity is associated with an increased breast cancer risk in postmenopausal women and may contribute to worse outcomes. Black women experience higher obesity and breast cancer mortality rates than non-Black women. We examined associations between race, obesity, and clinical tumor stage with breast cancer prognosis. METHODS: We conducted a prospective cohort study in 1,110 breast cancer patients, using univariable and multivariable Cox regression analyses to evaluate the effects of obesity, race/ethnicity, and clinical tumor stage on progression-free and overall survival (PFS and OS). RESULTS: 22% of participants were Black, 64% were Hispanic White, and 14% were non-Hispanic White or another race. 39% of participants were obese (body mass index [BMI] ≥ 30 kg/m2). In univariable analyses, tumor stage III-IV was associated with worse PFS and OS compared to tumor stage 0-II (hazard ratio [HR] = 4.68, 95% confidence interval [CI] = 3.52-6.22 for PFS and HR = 5.92, 95% CI = 4.00-8.77 for OS). Multivariable analysis revealed an association between Black race and worse PFS in obese (HR = 2.19, 95% CI = 1.06-4.51) and non-obese (HR = 2.11, 95% CI = 1.05-4.21) women with tumors staged 0-II. Obesity alone was not associated with worse PFS or OS. CONCLUSIONS: Results suggest a complex interrelationship between obesity and race in breast cancer prognosis. The association between the Black race and worse PFS in tumor stages 0-II underscores the importance of early intervention in this group. Future studies are warranted to evaluate whether alternative measures of body composition and biomarkers are better prognostic indicators than BMI among Black breast cancer survivors.

Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia.

BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.

The Interrelationship between Obesity and Race in Breast Cancer Prognosis: A Prospective Cohort Study.

Purpose: Obesity is associated with an increased breast cancer risk in postmenopausal women and may contribute to worse outcomes. Black women experience higher obesity and breast cancer mortality rates than non-Black women. We examined associations between race, obesity, and clinical tumor stage with breast cancer prognosis. Methods: We conducted a prospective cohort study in 1,110 breast cancer patients, using univariable and multivariable Cox regression analyses to evaluate the effects of obesity, race/ethnicity, and clinical tumor stage on progression-free and overall survival (PFS and OS). Results: 22% of participants were Black, 64% were Hispanic White, and 14% were non-Hispanic White or another race. 39% of participants were obese (body mass index [BMI] ≥ 30 kg/m2). In univariable analyses, tumor stage III-IV was associated with worse PFS and OS compared to tumor stage 0-II (hazard ratio [HR] = 4.68, 95% confidence interval [CI] = 3.52-6.22 for PFS and HR = 5.92, 95% CI = 4.00-8.77 for OS). Multivariable analysis revealed an association between Black race and worse PFS in obese (HR = 2.19, 95% CI = 1.06-4.51) and non-obese (HR = 2.11, 95% CI = 1.05-4.21) women with tumors staged 0-II. Obesity alone was not associated with worse PFS or OS. Conclusion: Results suggest a complex interrelationship between obesity and race in breast cancer prognosis. The association between Black race and worse PFS in tumor stages 0-II underscores the importance of early intervention in this group. Future studies are warranted to evaluate whether alternative measures of body composition and biomarkers are better prognostic indicators than BMI among Black breast cancer survivors.

Smoking and Radiation-induced Skin Injury: Analysis of a Multiracial, Multiethnic Prospective Clinical Trial.

INTRODUCTION: Smoking during breast radiotherapy (RT) may be associated with radiation-induced skin injury (RISI). We aimed to determine if a urinary biomarker of tobacco smoke exposure is associated with increased rates of RISI during and after breast RT. PATIENTS AND METHODS: Women with Stage 0-IIIA breast cancer treated with breast-conserving surgery or mastectomy followed by RT to the breast or chest wall with or without regional nodal irradiation were prospectively enrolled on a multicenter study assessing acute/late RISI. 980 patients with urinary cotinine (UCot) measurements (baseline and end-RT) were categorized into three groups. Acute and late RISI was assessed using the ONS Acute Skin Reaction scale and the LENT-SOMA Criteria. RESULTS: Late Grade 2+ and Grade 3+ RISI occurred in 18.2% and 1.9% of patients, respectively-primarily fibrosis, pain, edema, and hyperpigmentation. Grade 2+ late RISI was associated with UCot group (P= 006). Multivariable analysis identified UCot-based light smoker/secondhand smoke exposure (HR 1.79, P= .10) and smoking (HR 1.60, p = .06) as non-significantly associated with an increased risk of late RISI. Hypofractionated breast RT was associated with decreased risk of late RISI (HR 0.51, P=.03). UCot was not associated with acute RISI, multivariable analysis identified race, obesity, RT site/fractionation, and bra size to be associated with acute RISI. CONCLUSIONS: Tobacco exposure during breast RT may be associated with an increased risk of late RISI without an effect on acute toxicity. Smoking cessation should be encouraged prior to radiotherapy to minimize these and other ill effects of smoking.

A Recurrent ADPRHL1 Germline Mutation Activates PARP1 and Confers Prostate Cancer Risk in African American Families.

African American (AA) families have the highest risk of prostate cancer. However, the genetic factors contributing to prostate cancer susceptibility in AA families remain poorly understood. We performed whole-exome sequencing of one affected and one unaffected brother in an AA family with hereditary prostate cancer. The novel non-synonymous variants discovered only in the affected individuals were further analyzed in all affected and unaffected men in 20 AA-PC families. Here, we report one rare recurrent ADPRHL1 germline mutation (c.A233T; p.D78V) in four of the 20 families affected by prostate cancer. The mutation co-segregates with prostate cancer in two families and presents in two affected men in the other two families, but was absent in 170 unrelated healthy AA men. Functional characterization of the mutation in benign prostate cells showed aberrant promotion of cell proliferation, whereas expression of the wild-type ADPRHL1 in prostate cancer cells suppressed cell proliferation and oncogenesis. Mechanistically, the ADPRHL1 mutant activates PARP1, leading to an increased H2O2 or cisplatin-induced DNA damage response for prostate cancer cell survival. Indeed, the PARP1 inhibitor, olaparib, suppresses prostate cancer cell survival induced by mutant ADPRHL1. Given that the expression levels of ADPRHL1 are significantly high in normal prostate tissues and reduce stepwise as Gleason scores increase in tumors, our findings provide genetic, biochemical, and clinicopathological evidence that ADPRHL1 is a tumor suppressor in prostate tissue. A loss of function mutation in ADPRHL1 induces prostate tumorigenesis and confers prostate cancer susceptibility in high-risk AA families. IMPLICATIONS: This study highlights a potential strategy for ADPRHL1 mutation detection in prostate cancer-risk assessment and a potential therapeutic application for individuals with prostate cancer in AA families.

Polygenic risk scores for prediction of breast cancer risk in women of African ancestry: a cross-ancestry approach.

Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for the prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and 10 184 controls from four genome-wide association study (GWAS) consortia and a GWAS study in Ghana. We randomly divided samples into training and validation sets. We built PRSs using individual-level AA data by a forward stepwise logistic regression and then developed joint PRSs that combined (1) the PRSs built in the AA training dataset and (2) a 313-variant PRS previously developed in women of European ancestry. PRSs were evaluated in the AA validation set. For overall breast cancer, the odds ratio per standard deviation of the joint PRS in the validation set was 1.34 [95% confidence interval (CI): 1.27-1.42] with the area under receiver operating characteristic curve (AUC) of 0.581. Compared with women with average risk (40th-60th PRS percentile), women in the top decile of the PRS had a 1.98-fold increased risk (95% CI: 1.63-2.39). For PRSs of ER-positive and ER-negative breast cancer, the AUCs were 0.608 and 0.576, respectively. Compared with existing methods, the proposed joint PRSs can improve prediction of breast cancer risk in AA women.

Differences in somatic TP53 mutation type in breast tumors by race and receptor status.

PURPOSE: Somatic driver mutations in TP53 are associated with triple-negative breast cancer (TNBC) and poorer outcomes. Breast cancers in women of African ancestry (AA) are more likely to be TNBC and have somatic TP53 mutations than cancers in non-Hispanic White (NHW) women. Missense driver mutations in TP53 have varied functional impact including loss-of-function (LOF) or gain-of-function (GOF) activity, and dominant negative (DNE) effects. We aimed to determine if there were differences in somatic TP53 mutation types by patient ancestry or TNBC status. METHODS: We identified breast cancer datasets with somatic TP53 mutation data, ancestry, age, and hormone receptor status. Mutations were classified for functional impact using published data and type of mutation. We assessed differences using Fisher's exact test. RESULTS: From 96 breast cancer studies, we identified 2964 women with somatic TP53 mutations: 715 (24.1%) Asian, 258 (8.7%) AA, 1931 (65.2%) NHW, and 60 (2%) Latina. The distribution of TP53 mutation type was similar by ancestry. However, 35.8% of tumors from NHW individuals had GOF mutations compared to 29% from AA individuals (p = 0.04). Mutations with DNE activity were positively associated with TNBC (OR 1.37, p = 0.03) and estrogen receptor (ER) negative status (OR 1.38; p = 0.005). CONCLUSIONS: Somatic TP53 mutation types did not differ by ancestry overall, but GOF mutations were more common in NHW women than AA women. ER-negative and TNBC tumors are less likely to have DNE+ TP53 mutations which could reflect biological processes. Larger cohorts and functional studies are needed to further elucidate these findings.

Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

BACKGROUND: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. MATERIALS AND METHODS: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. RESULTS: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. CONCLUSION: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women.

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P < 0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes (KCNK2, C5orf56, SCAMP2, and SIN3A) and the other index SNPs are located close to GSTM4, AMPD2, CASTOR2, and RP11-168G16.2. Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants.

Phase 1 trial of nelfinavir added to standard cisplatin chemotherapy with concurrent pelvic radiation for locally advanced cervical cancer.

BACKGROUND: Nelfinavir (NFV), an HIV-1 protease inhibitor, has been shown to sensitize cancer cells to chemoradiation (CRT). The objectives of this phase 1 trial were to evaluate safety and identify the recommended phase 2 dose of NFV added to concurrent CRT for locally advanced cervical cancer. METHODS: Two dose levels of NFV were evaluated: 875 mg orally twice daily (dose level 1 [DL1]) and 1250 mg twice daily (DL2). NFV was initiated 7 days before CRT and continued through CRT completion. Toxicity, radiographic responses, and pathologic responses were evaluated. Serial tumor biopsies (baseline, after NFV monotherapy, on NFV + CRT, and posttreatment) were evaluated by immunohistochemistry, NanoString, and reverse-phase-protein-array analyses. RESULTS: NFV sensitized cervical cancer cells to radiation, increasing apoptosis and tumor suppression in vivo. Patients (n = 13) with International Federation of Gynecology and Obstetrics stage IIA through IVA squamous cell cervical carcinoma were enrolled, including 7 patients at DL1 and 6 patients at DL2. At DL1, expansion to 6 patients was required after a patient developed a dose-limiting toxicity, whereas no dose-limiting toxicities occurred at DL2. Therefore, DL2 was established as the recommended phase 2 dose. All patients at DL2 completed CRT, and 1 of 6 experienced grade 3 or 4 anemia, nausea, and diarrhea. One recurrence was noted at DL2, with disease outside the radiation field. Ten of 11 evaluable patients remained without evidence of disease at a median follow-up of 50 months. NFV significantly decreased phosphorylated Akt levels in tumors. Cell cycle and cancer pathways also were reduced by NFV and CRT. CONCLUSIONS: NFV with CRT is well tolerated. The response rate is promising compared with historic controls in this patient population and warrants further investigation.

Evaluating Polygenic Risk Scores for Breast Cancer in Women of African Ancestry.

BACKGROUND: Polygenic risk scores (PRSs) have been demonstrated to identify women of European, Asian, and Latino ancestry at elevated risk of developing breast cancer (BC). We evaluated the performance of existing PRSs trained in European ancestry populations among women of African ancestry. METHODS: We assembled genotype data for women of African ancestry, including 9241 case subjects and 10 193 control subjects. We evaluated associations of 179- and 313-variant PRSs with overall and subtype-specific BC risk. PRS discriminatory accuracy was assessed using area under the receiver operating characteristic curve. We also evaluated a recalibrated PRS, replacing the index variant with variants in each region that better captured risk in women of African ancestry and estimated lifetime absolute risk of BC in African Americans by PRS category. RESULTS: For overall BC, the odds ratio per SD of the 313-variant PRS (PRS313) was 1.27 (95% confidence interval [CI] = 1.23 to 1.31), with an area under the receiver operating characteristic curve of 0.571 (95% CI = 0.562 to 0.579). Compared with women with average risk (40th-60th PRS percentile), women in the top decile of PRS313 had a 1.54-fold increased risk (95% CI = 1.38-fold to 1.72-fold). By age 85 years, the absolute risk of overall BC was 19.6% for African American women in the top 1% of PRS313 and 6.7% for those in the lowest 1%. The recalibrated PRS did not improve BC risk prediction. CONCLUSION: The PRSs stratify BC risk in women of African ancestry, with attenuated performance compared with that reported in European, Asian, and Latina populations. Future work is needed to improve BC risk stratification for women of African ancestry.

African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer.

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.

Disparities in Head and Neck Cancer: A Case for Chemoprevention with Vitamin D.

Blacks experience disproportionate head and neck cancer (HNC) recurrence and mortality compared to Whites. Overall, vitamin D status is inversely associated to HNC pointing to a potential protective linkage. Although hypovitaminosis D in Blacks is well documented it has not been investigated in Black HNC patients. Thus, we conducted a prospective pilot study accessing vitamin D status in newly diagnosed HNC patients stratified by race and conducted in vitro studies to investigate mechanisms associated with potential cancer inhibitory effects of vitamin D. Outcome measures included circulating levels of vitamin D, related nutrients, and risk factor characterization as well as dietary and supplemental estimates. Vitamin D-based in vitro assays utilized proteome and microRNA (miR) profiling. Nineteen patients were enrolled, mean circulating vitamin D levels were significantly reduced in Black compared to White HNC patients, 27.3 and 20.0 ng/mL, respectively. Whites also supplemented vitamin D more frequently than Blacks who had non-significantly higher vitamin D from dietary sources. Vitamin D treatment of HNC cell lines revealed five significantly altered miRs regulating genes targeting multiple pathways in cancer based on enrichment analysis (i.e., negative regulation of cell proliferation, angiogenesis, chemokine, MAPK, and WNT signaling). Vitamin D further altered proteins involved in cancer progression, metastasis and survival supporting a potential role for vitamin D in targeted cancer prevention.

A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry.

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.

Association Between Polymorphisms in DNA Damage Repair Genes and Radiation Therapy-Induced Early Adverse Skin Reactions in a Breast Cancer Population: A Polygenic Risk Score Approach.

PURPOSE: Genetic variations in DNA damage repair (DDR) genes may influence radiation therapy (RT)-induced acute normal tissue toxicity in patients with breast cancer. Identifying an individual or multiple single-nucleotide polymorphisms (SNPs) associated with RT-induced early adverse skin reactions (EASR) is critical for precision medicine in radiation oncology. METHODS AND MATERIALS: At the completion of RT, EASR was assessed using the Oncology Nursing Society scale (0-6) in 416 patients with breast cancer, and Oncology Nursing Society score ≥4 was considered RT-induced EASR. PLINK set-based tests and subsequent individual SNP association analyses were conducted to identify genes and SNPs associated with EASR among the 53 DDR genes and 1968 SNPs. A weighted polygenic risk score (PRS) model was constructed to ascertain the association between the joint effect of risk alleles and EASR. RESULTS: The study population consisted of 264 Hispanic whites, 86 blacks or African Americans, 55 non-Hispanic whites, and 11 others. A total of 115 patients (27.6%) developed EASR. Five genes (ATM, CHEK1, ERCC2, RAD51C, and TGFB1) were significantly associated with RT-induced EASR. Nine SNPs within these 5 genes were further identified: ATM rs61915066, CHEK1 rs11220184, RAD51C rs302877, rs405684, TBFB1 rs4803455, rs2241714, and ERCC2 rs60152947, rs10404465, rs1799786. In a multivariable-adjusted PRS model, patients in a higher quartile of PRS were more likely to develop EASR compared with patients in the lowest quartile (ORq2 vs.q1 = 1.94, 95% CI, 0.86-4.39; ORq3 vs.q1 = 3.46, 95% CI, 1.57-7.63; ORq4 vs.q1 = 8.64, 95% CI, 3.92-19.02; and Ptrend < .0001). CONCLUSIONS: We newly identified the associations between 9 SNPs in ATM, CHEK1, RAD51C, TGFB1, and ERCC2 and RT-induced EASR. PRS modeling showed its potential in identifying populations at risk. Multiple SNPs in DDR genes may jointly contribute to interindividual variation in RT-induced EASR. Validation in an independent external cohort is required to determine the clinical significance of these predictive biomarkers.

A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry.

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

Genome-wide enriched pathway analysis of acute post-radiotherapy pain in breast cancer patients: a prospective cohort study.

BACKGROUND: Adjuvant radiotherapy (RT) can increase the risk of developing pain; however, the molecular mechanisms of RT-related pain remain unclear. The current study aimed to identify susceptibility loci and enriched pathways for clinically relevant acute post-RT pain, defined as having moderate to severe pain (pain score ≥ 4) at the completion of RT. METHODS: We conducted a genome-wide association study (GWAS) with 1,344,832 single-nucleotide polymorphisms (SNPs), a gene-based analysis using PLINK set-based tests of 19,621 genes, and a functional enrichment analysis of a gene list of 875 genes with p < 0.05 using NIH DAVID functional annotation module with KEGG pathways and GO terms (n = 380) among 1112 breast cancer patients. RESULTS: About 29% of patients reported acute post-RT pain. None of SNPs nor genes reached genome-wide significant level. Four SNPs showed suggestive associations with post-RT pain; rs16970540 in RFFL or near the LIG3 gene (p = 1.7 × 10-6), rs4584690, and rs7335912 in ABCC4/MPR4 gene (p = 5.5 × 10-6 and p = 7.8 × 10-6, respectively), and rs73633565 in EGFL6 gene (p = 8.1 × 10-6). Gene-based analysis suggested the potential involvement of neurotransmitters, olfactory receptors, and cytochrome P450 in post-RT pain, whereas functional analysis showed glucuronidation (FDR-adjusted p value = 9.46 × 10-7) and olfactory receptor activities (FDR-adjusted p value = 0.032) as the most significantly enriched biological features. CONCLUSIONS: This is the first GWAS suggesting that post-RT pain is a complex polygenic trait influenced by many biological processes and functions such as glucuronidation and olfactory receptor activities. If validated in larger populations, the results can provide biological targets for pain management to improve cancer patients' quality of life. Additionally, these genes can be further tested as predictive biomarkers for personalized pain management.