Association of rare, recurrent nonsynonymous variants in the germline of prostate cancer patients of African ancestry.

BACKGROUND: Although men of African ancestry (AA) have the highest mortality rate from prostate cancer (PCa), relatively little is known about the germline variants that are associated with PCa risk in AA men. The goal of this study is to systematically evaluate rare, recurrent nonsynonymous variants across the exome for their association with PCa in AA men. METHODS: Whole exome sequencing (WES) of germline DNA in two AA PCa patient cohorts of Johns Hopkins Hospital (N = 960) and Wayne State University (N = 747) was performed. All nonsynonymous variants present in both case cohorts, with a carrier rate between 0.5% and 1%, were identified. Their carrier rates were compared with rates from 8128 African/African American (AFR) control subjects from The Genome Aggregation Database (gnomAD) using Fisher's exact test. Significant variants, defined as false discovery rate (FDR) adjusted p-value ≤ 0.05, were further evaluated in AA PCa cases (N = 132) and controls (N = 1184) from the UK Biobank (UKB). RESULTS: Two variants reached a pre-specified statistical significance level. The first was p.R14Q in GPRC5C (found in 0.47% of PCa cases and 0.01% of population controls); odds ratio (OR) for PCa was 37.46 (95% confidence interval CI 4.68-299.72), pexact = 7.01E-06, FDR-adjusted p-value = 0.05. The second was p.R511Q in IGF1R (found in 0.53% of PCa cases and 0.01% of population controls); OR for PCa was 21.54 (95%CI 4.65-99.76), pexact = 5.51E-06, FDR-adjusted p-value = 0.05. The mean percentage of African ancestry was similar between variant carriers and noncarriers of each variant, p > 0.05. In the UKB AA men, GPRC5C R14Q was 0.76% and 0.08% in cases and controls, respectively, OR for PCa was 9.00 (95%CI 0.56-145.23), pexact = 0.19. However, IGF1R R511Q was not found in cases or controls. CONCLUSIONS: This WES study identified two rare, recurrent nonsynonymous PCa risk-associated variants in AA. Confirmation in additional large populations of AA PCa cases and controls is required.

Association of sickle cell trait with adverse pregnancy outcomes in a population-based cohort.

INTRODUCTION: Sickle cell trait (SCT) is common in African descendants. Its association with several adverse pregnancy outcomes (APOs) has been reported but remains inconsistent. The objectives of this study are to test associations of SCT with APOs in non-Hispanic Black women, including (1) validate the associations of SCT with previously reported APOs, (2) test novel associations of SCT with broad spectrum of APOs, and (3) estimate the attributable risk of SCT for implicated APOs. MATERIAL AND METHODS: This is a retrospective analysis of a prospectively designed population-based cohort. Women/participants were self-reported non-Hispanic Black women from the UK Biobank (UKB). SCT status was determined based on heterozygous Glu6Val in the HBB gene. Several APOs were studied, including four previously reported SCT-associated APOs (preeclampsia, bacteriuria, pregnancy loss, and preterm delivery), and broad conditions related to pregnancy, childbirth, and the puerperium. APOs were curated by experts' peer review and consensus processes. Associations of SCT with APOs were tested by estimating its relative risk and 95% confidence interval (95% CI), adjusting for number of live births and age at first birth. Attributable risk proportion (ARP) and population attributable risk proportion (PARP) of SCT to APOs were estimated. RESULTS: Among the 4057 self-reported non-Hispanic Black women with pregnancy records in the UKB, 581 (14.32%) were SCT carriers. For four previously reported SCT-associated APOs, two were confirmed at a nominal P < 0.05; relative risk (RR) was 2.39 (95% CI 1.09-5.23) for preeclampsia, and 4.85 (95% CI 1.77-13.27) for bacteriuria. SCT contributed substantially to these two APOs among SCT carriers, with attributable risk proportion estimated at 61.00% and 68.96% for preeclampsia and bacteriuria, respectively. SCT also contributed substantially to these two APOs in the population (self-reported Black UK women), with population attributable risk proportion estimated at 18.30% and 24.14% for preeclampsia and bacteriuria, respectively. In addition, novel associations were found for seven other APOs (nominal P < 0.05). CONCLUSIONS: SCT is significantly associated with APOs in this study and contributes substantially to APOs among self-reported Black women in the UK. Confirmation of these findings in independent study populations is required.

Calibration of polygenic risk scores is required prior to clinical implementation: results of three common cancers in UKB.

BACKGROUND: SNP-based polygenic risk scores have recently been adopted in the clinic for risk assessment of some common diseases. Their validity is supported by a consistent trend between their percentile rank and disease risk in populations. However, for clinical use at the individual level, the reliability of score values is necessary considering they are directly used to calculate remaining lifetime risk. OBJECTIVES: We assessed the reliability of polygenic score values to estimate prostate cancer (PCa), breast cancer (BCa) and colorectal cancer (CRC) risk in three incident cohorts from the UK Biobank (n>500 000). METHODS: Cancer-specific Genetic Risk Score (GRS), a well-established population-standardised polygenic risk score, was calculated. RESULTS: A systematic bias was found between estimated risks (GRS values) and observed risks; ß (95% CI) was 0.67 (0.58-0.76), 0.74 (0.65-0.84) and 0.82 (0.75-0.89), respectively, for PCa, BCa and CRC, all significantly lower than 1.00 (perfect calibration), p<0.001. After applying a correction factor derived from a training data set, the ß for corrected GRS values in an independent testing data set were 1.09 (1.05-1.13), 1.00 (0.88-1.12) and 1.08 (0.96-1.21), respectively, for PCa, BCa and CRC. CONCLUSION: Assessing the calibration of polygenic risk scores is necessary and feasible to ensure their reliability prior to clinical implementation.

Association of germline rare pathogenic mutations in guideline-recommended genes with prostate cancer progression: A meta-analysis.

BACKGROUND: Germline mutations in several genes, mainly DNA repair genes, have been associated with prostate cancer (PCa) progression. However, primarily due to the rarity of mutations, statistical evidence for these associations is not consistently established. The objective of this study is to synthesize evidence from multiple studies using a meta-analysis. METHODS: Genes analyzed were chosen based on National Comprehensive Cancer Network guidelines recommendations (10 genes) and a commonly reported gene (NBN). PCa progression in this analysis was defined as either having metastases or PCa-specific mortality. We searched PubMed for papers published before April 26, 2021, using selected keywords. Pooled odds ratio (OR) was estimated in all races and Caucasians-only using both fixed- and random-effect models. RESULTS: The search identified 1028 papers and an additional five from a manual review of references. After a manual process that excluded noneligible studies, 11 papers remained, including a total of 3944 progressors and 20,054 nonprogressors. Combining results from these eligible studies, mutation carrier rates were significantly higher in progressors than nonprogressors for NBN, BRCA2, ATM (under both fixed- and random-effect models), for CHEK2 (under fixed-effect model only), and for PALB2 (under random-effect model only), p < 0.05. Pooled OR (95% confidence interval) was 6.38 (2.25-18.05), 3.41 (2.31; 5.03), 1.93 (1.17-3.20), and 1.53 (1.00-2.33) for NBN, BRCA2, ATM, and CHEK2, respectively, under fixed-effect model and 2.63 (1.12-6.13) for PALB2 under random-effect model. No significant association was found for the six remaining genes. Certainty of evidence was low for many genes due primarily to the limited number of eligible studies and mutation carriers. CONCLUSIONS: Statistical evidence for five genes was obtained in this first meta-analysis of germline mutations and PCa progression. While these results may help urologists and genetic counselors interpret germline testing results for PCa progression, more original studies are needed.

Cystic fibrosis F508del carriers and cancer risk: Results from the UK Biobank.

Cystic fibrosis (CF) carriers carrying one defective copy of a CFTR germline mutation are common in the general population. A recent study reported associations of CF carriers with risk for cancers of digestive organs and pancreatic cancer. In the current study, we assessed associations of CFTR F508del carriers with the risk for 54 types of cancers in the UK Biobank, a large population-based study. In Caucasians, compared to the carrier rate of 3.15% (12 357/392274) in noncancer subjects, the rate was significantly higher in cancer patients overall (2621/79619 = 3.29%), especially in patients with colorectal cancer (247/6667 = 3.70%), cancers of gallbladder and biliary tract (21/351 = 5.98%), thyroid cancer (30/665 = 4.51%) and unspecified non-Hodgkin's lymphoma (74/1805 = 4.10%), all P ≤ .05. In contrast, the carrier rate in patients with cancers of lung and bronchus was significantly lower (89/3463 = 2.57%), P = .05. The association of CFTR F508del carriers with these types of cancer remained significant after adjusting for respective cancer-specific risk factors. For pancreatic cancer, although a higher carrier rate (38/1004 = 3.78%) was found in patients with this cancer, the difference was not statistically significant (P = .26). This null association was unlikely due to lack of statistical power; the large sample size of our study had >80% power, at a significance level of .05, to detect an association of >1.5-fold increased risk. In conclusion, the identified associations of CFTR F508del carriers with multiple types of cancer may have potential biological and clinical implications if confirmed in independent study populations.

Observed evidence for guideline-recommended genes in predicting prostate cancer risk from a large population-based cohort.

BACKGROUND: Germline testing for prostate cancer (PCa) is now recommended by the National Comprehensive Cancer Network. While multi-gene testing has been proposed, evidence for their association with PCa risk is not well established. METHODS: We tested associations of pathogenic/likely pathogenic mutations in 10 guideline-recommended genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, MLH1, MSH2, MSH6, PMS2, and HOXB13) with PCa risk in the UK Biobank, a population-based cohort. Mutations were annotated based on prostate-specific transcripts using the American College of Medical Genetics and Genomics standards. Associations were tested in 4399 PCa cases and 85,403 unaffected male controls using logistic regression adjusting for age and genetic background. p < .005 was considered significant based on Bonferroni correction. RESULTS: Among the 10 tested genes, significantly higher mutation carrier rates in PCa cases versus controls were found for four genes at p < .005; HOXB13, BRCA2, ATM, and CHEK2, with odds ratios (95% confidence interval) estimated at 4.96 (3.62-6.69), 3.23 (2.23-4.56), 2.95 (2.01-4.22), 1.94 (1.43-2.58), respectively. No significant association was found between mutation carrier status and age at PCa diagnosis or family history of PCa. Despite the large sample size of this study, statistical power remains limited, especially for genes where pathogenic mutation carrier rates are extremely rare (<0.03%). CONCLUSION: Observed evidence for PCa risk was found for four of the 10 guideline-recommended genes in this large population-based study. Mutations in these four genes can be interpreted with confidence in genetic counseling for PCa risk assessment. Evidence for the remaining six genes needs to be further evaluated in larger studies.

Association of prostate cancer polygenic risk score with number and laterality of tumor cores in active surveillance patients.

BACKGROUND: Prostate cancer (PCa) is characterized by its tendency to be multifocal. However, few studies have investigated the endogenous factors that explain the multifocal disease. The primary objective of the current study is to test whether inherited PCa risk is associated with multifocal tumors in PCa patients. METHODS: Subjects in this study were PCa patients of European ancestry undergoing active surveillance at Johns Hopkins Hospital (N = 805) and NorthShore University HealthSystem (N = 432). The inherited risk was measured by genetic risk score (GRS), an odds ratio-weighted and population-standardized polygenic risk score based on known risk-associated single nucleotide polymorphisms. PCa multifocality was indirectly measured by the number and laterality of positive tumor cores from a 12-core systematic biopsy. RESULTS: In the combined cohort, 35.7% and 66.3% of patients had ≥2 tumor cores at the initial diagnostic biopsy and on at least one subsequent surveillance biopsy, respectively. For tumor laterality, 7.8% and 47.8% of patients had bilateral tumor cores at diagnostic and surveillance biopsies, respectively. We found, for the first time, that patients with higher numbers of positive cores at diagnostic and surveillance biopsies, respectively, had significantly higher mean GRS values; p = .01 and p = 5.94E-04. Additionally, patients with bilateral tumors at diagnostic and surveillance biopsies, respectively, had significantly higher mean GRS values than those with unilateral tumors; p = .04 and p = .01. In contrast, no association was found between GRS and maximum core length of tumor or tumor grade at diagnostic/surveillance biopsies (all p > .05). Finally, we observed a modest trend that patients with higher GRS quartiles had a higher risk for tumor upgrading on surveillance biopsies. The trend, however, was not statistically significant (p > .05). CONCLUSIONS: The associations of GRS with two measurements of PCa multifocality (core numbers and laterality) provide novel and consistent evidence for the link between inherited PCa risk and multifocal tumors.

Assessing the clinical utility of genetic risk scores for targeted cancer screening.

BACKGROUND: Genome-wide association studies have identified thousands of disease-associated single nucleotide polymorphisms (SNPs). A subset of these SNPs may be additively combined to generate genetic risk scores (GRSs) that confer risk for a specific disease. Although the clinical validity of GRSs to predict risk of specific diseases has been well established, there is still a great need to determine their clinical utility by applying GRSs in primary care for cancer risk assessment and targeted intervention. METHODS: This clinical study involved 281 primary care patients without a personal history of breast, prostate or colorectal cancer who were 40-70 years old. DNA was obtained from a pre-existing biobank at NorthShore University HealthSystem. GRSs for colorectal cancer and breast or prostate cancer were calculated and shared with participants through their primary care provider. Additional data was gathered using questionnaires as well as electronic medical record information. A t-test or Chi-square test was applied for comparison of demographic and key clinical variables among different groups. RESULTS: The median age of the 281 participants was 58 years and the majority were female (66.6%). One hundred one (36.9%) participants received 2 low risk scores, 99 (35.2%) received 1 low risk and 1 average risk score, 37 (13.2%) received 1 low risk and 1 high risk score, 23 (8.2%) received 2 average risk scores, 21 (7.5%) received 1 average risk and 1 high risk score, and no one received 2 high risk scores. Before receiving GRSs, younger patients and women reported significantly more worry about risk of developing cancer. After receiving GRSs, those who received at least one high GRS reported significantly more worry about developing cancer. There were no significant differences found between gender, age, or GRS with regards to participants' reported optimism about their future health neither before nor after receiving GRS results. CONCLUSIONS: Genetic risk scores that quantify an individual's risk of developing breast, prostate and colorectal cancers as compared with a race-defined population average risk have potential clinical utility as a tool for risk stratification and to guide cancer screening in a primary care setting.

Polygenic risk score is a predictor of adenomatous polyps at screening colonoscopy.

BACKGROUND: Single nucleotide polymorphism (SNP)-based polygenic risk scoring is predictive of colorectal cancer (CRC) risk. However, few studies have investigated the association of genetic risk score (GRS) with detection of adenomatous polyps at screening colonoscopy. METHODS: We randomly selected 1769 Caucasian subjects who underwent screening colonoscopy from the Genomic Health Initiative (GHI), a biobank of NorthShore University HealthSystem. Outcomes from initial screening colonoscopy were recorded. Twenty-two CRC risk-associated SNPs were obtained from the Affymetrix™ SNP array and used to calculate an odds ratio (OR)-weighted and population-standardized GRS. Subjects with GRS of < 0.5, 0.5-1.5, and > 1.5 were categorized as low, average and elevated risk. RESULTS: Among 1,769 subjects, 520 (29%) had 1 or more adenomatous polyps. GRS was significantly higher in subjects with adenomatous polyps than those without; mean (95% confidence interval) was 1.02 (1.00-1.05) and 0.97 (0.95-0.99), respectively, p < 0.001. The association remained significant after adjusting for age, gender, body mass index, and family history, p < 0.001. The detection rate of adenomatous polyps was 10.8%, 29.0% and 39.7% in subjects with low, average and elevated GRS, respectively, p-trend < 0.001. Higher GRS was also associated with early age diagnosis of adenomatous polyps, p < 0.001. In contrast, positive family history was not associated with risk and age of adenomatous polyps. CONCLUSIONS: GRS was significantly associated with adenomatous polyps in subjects undergoing screening colonoscopy. This result may help in stratifying average risk patients and facilitating personalized colonoscopy screening strategies.

Broad- and narrow-sense validity performance of three polygenic risk score methods for prostate cancer risk assessment.

BACKGROUND: Several polygenic risk score (PRS) methods are available for measuring the cumulative effect of multiple risk-associated single nucleotide polymorphisms (SNPs). Their performance in predicting risk at the individual level has not been well studied. METHODS: We compared the performance of three PRS methods for prostate cancer risk assessment in a clinical trial cohort, including genetic risk score (GRS), pruning and thresholding (P + T), and linkage disequilibrium prediction (LDpred). Performance was evaluated for score deciles (broad-sense validity) and score values (narrow-sense validity). RESULTS: A training process was required to identify the best P + T model (397 SNPs) and LDpred model (3 011 362 SNPs). In contrast, GRS was directly calculated based on 110 established risk-associated SNPs. For broad-sense validity in the testing population, higher deciles were significantly associated with higher observed risk; Ptrend was 7.40 × 10-11 , 7.64 × 10-13 , and 7.51 × 10-10 for GRS, P + T, and LDpred, respectively. For narrow-sense validity, the calibration slope (1 is best) was 1.03, 0.77, and 0.87, and mean bias score (0 is best) was 0.09, 0.21, and 0.10 for GRS, P + T, and LDpred, respectively. CONCLUSIONS: The performance of GRS was better than P + T and LDpred. Fewer and well-established SNPs of GRS also make it more feasible and interpretable for genetic testing at the individual level.

Validation of a prostate cancer polygenic risk score.

BACKGROUND: Genome-wide association studies have identified over 100 single-nucleotide polymorphisms (SNPs) associated with prostate cancer (PrCa), and polygenic risk scores (PRS) based on their combined genotypes have been developed for risk stratification. We aimed to assess the contribution of PRS to PrCa risk in a large multisite study. METHODS: The sample included 1972 PrCa cases and 1919 unaffected controls. Next-generation sequencing was used to assess pathogenic variants in 14 PrCa-susceptibility genes and 72 validated PrCa-associated SNPs. We constructed a population-standardized PRS and tested its association with PrCa using logistic regression adjusted for age and family history of PrCa. RESULTS: The mean age of PrCa cases at diagnosis and age of controls at testing/last clinic visit was 59.5 ± 7.2 and 57.2 ± 13.0 years, respectively. Among 1740 cases with pathology data, 57.4% had Gleason score ≤ 6, while 42.6% had Gleason score ≥ 8. In addition, 39.6% cases and 20.1% controls had a family history of PrCa. The PRS was significantly higher in cases than controls (mean ± SD: 1.42 ± 1.11 vs 1.02 ± 0.76; P < .0001). Compared with men in the 1st quartile of age-adjusted PRS, those in the 2nd, 3rd, and 4th quartile were 1.58 (95% confidence interval [CI]: 1.31-1.90), 2.36 (95% CI: 1.96-2.84), and 3.98 (95% CI: 3.29-4.82) times as likely to have PrCa (all P < .0001). Adjustment for family history yielded similar results. PRS predictive performance was consistent with prior literature (area under the receiver operating curve = 0.64; 95% CI: 0.62-0.66). CONCLUSIONS: These data suggest that a 72-SNP PRS is predictive of PrCa, supporting its potential use in clinical risk assessment.

Germline HOXB13 G84E mutation carriers and risk to twenty common types of cancer: results from the UK Biobank.

Germline HOXB13 G84E mutation has been consistently associated with prostate cancer (PCa) risk, but its association with other cancers is controversial. We systematically tested its association with the 20 most common cancer types in subjects from the UK Biobank. The G84E mutation was found in 1,545 (0.34%) of 460,224 participants of European ancestry. While mutation status did not associate with cancer risk in females, it was significantly associated with increased risk in males; odds ratio (OR) (95% confidence interval) for overall cancer diagnosis was 2.19 (1.89-2.52), P = 2.5E-19. The association remained after excluding PCa; OR = 1.4 (1.16-1.68), P = 0.003, suggesting association with other cancers. Indeed, suggestive novel associations were found for two other cancer types; rectosigmoid cancer, OR = 2.25 (1.05-4.15), P = 0.05 and non-melanoma skin cancer (NMSC), OR = 1.40 (1.12-1.74), P = 0.01. For NMSC, the association was found only in basal cell carcinoma, OR = 1.37 (1.07-1.74), P = 0.03. These findings have potential clinical utility for genetic counselling regarding HOXB13.

Concept and benchmarks for assessing narrow-sense validity of genetic risk score values.

BACKGROUND: While higher genetic risk score (GRS) has been statistically associated with increased disease risk (broad-sense validity), the concept and tools for assessing the validity of reported GRS values from tests (narrow-sense validity) are underdeveloped. METHODS: We propose two benchmarks for assessing the narrow-sense validity of GRS. The baseline benchmark requires that the mean GRS value in a general population approximates 1.0. The calibration benchmark assesses the agreement between observed risks and estimated risks (GRS values). We assessed benchmark performance for three prostate cancer (PCa) GRS tests, derived from three SNP panels with increasing stringency of selection criteria, in a PCa chemoprevention trial where 714 of 3225 men were diagnosed with PCa during the 4-year follow-up. RESULTS: GRS from Panels 1, 2, and 3 were all statistically associated with PCa risk; P = 5.58 × 10-3 , P = 1 × 10-3 , and P = 1.5 × 10-13 , respectively (broad-sense validity). For narrow-sense validity, the mean GRS value among men without PCa was 1.33, 1.09, and 0.98 for Panels 1, 2, and 3, respectively (baseline benchmark). For assessing the calibration benchmark, observed risks were calculated for seven groups of men with GRS values <0.3, 0.3-0.79, 0.8-1.19, 1.2-1.49, 1.5-1.99, 2-2.99, and ≥3. The calibration slope (higher is better) was 0.15, 0.12, and 0.60, and the bias score (lower is better) between the observed risks and GRS values was 0.08, 0.08, and 0.02 for Panels 1, 2, and 3, respectively. CONCLUSION: Performance differed considerably among GRS tests. We recommend that all GRS tests be evaluated using the two benchmarks before clinical implementation for individual risk assessment.

Genetic risk score modifies the effect of APOE on risk and age onset of Alzheimer's disease.

Single nucleotide polymorphism (SNP)-based genetic risk score (GRS) and APOE genotype are both important in risk prediction of Alzheimer's disease (AD); however, the interaction between GRS and APOE has not been extensively investigated. Our objective was to determine whether GRS modifies the APOE effect on AD risk and age at onset (AAO). The study included 774 AD cases and 767 controls of European descent. Population standardized GRS was calculated based on 17 previously implicated AD risk-associated SNPs. Association was analyzed using logistic regression, Cox proportional hazards model and Kaplan-Meier curve. We found that GRS was significantly associated with AD risk and the association was stronger among APOE ε4 carriers. Compared to ε4 non-carriers, the Odds Ratio (OR) for AD was 8.09 (95% Confidence Interval [CI]: 4.98-13.63) for ε4 carriers with high-GRS (≥1.5). In contrast, the OR was 2.55 (95% CI: 1.46-4.49) for ε4 carriers with low-GRS (<0.6). In conclusion, these results suggest SNP-based GRS may supplement APOE for better assessment of inherited risk and age of onset of AD.

Genetic variants in Barrett's esophagus and esophageal adenocarcinoma: a literature review.

Surveillance of Barrett's esophagus (BE) is a clinical challenge; metaplasia of the distal esophagus increases a patient's risk of esophageal adenocarcinoma (EAC) significantly but the actual percentage of patients who progress is low. The current screening recommendations require frequent endoscopy and biopsy, which has inherent risk, high cost, and operator variation. Identifying BE patients genetically who are at high risk of progressing could deemphasize the role of endoscopic screening and create an opportunity for early therapeutic intervention. Genetic alterations in germline DNA have been identified in other disease processes and allow for early intervention or surveillance well before disease develops. The genetic component of BE remains mostly unknown and only a few genome-wide association studies exist on this topic. This review summarizes the current literature available that examines genetic alterations in BE and EAC with a particular emphasis on clinical implications.

A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer.

BACKGROUND: Germline mutations in CHEK2 have been associated with prostate cancer (PCa) risk. Our objective is to examine whether germline pathogenic CHEK2 mutations can differentiate risk of lethal from indolent PCa. METHODS: A case-case study of 703 lethal PCa patients and 1455 patients with low-risk localized PCa of European, African, and Chinese origin was performed. Germline DNA samples from these patients were sequenced for CHEK2. Mutation carrier rates and their association with lethal PCa were analyzed using the Fisher exact test and Kaplan-Meier survival analysis. RESULTS: In the entire study population, 40 (1.85%) patients were identified as carrying one of 15 different germline CHEK2 pathogenic or likely pathogenic mutations. CHEK2 mutations were detected in 16 (2.28%) of 703 lethal PCa patients compared with 24 (1.65%) of 1455 low-risk PCa patients (P = 0.31). No association was found between CHEK2 mutation status and early-diagnosis or PCa-specific survival time. However, the most common mutation in CHEK2, c.1100delC (p.T367 fs), had a significantly higher carrier rate (1.28%) in lethal PCa patients than low-risk PCa patients of European American origin (0.16%), P = 0.0038. The estimated Odds Ratio of this mutation for lethal PCa was 7.86. The carrier rate in lethal PCa was also significantly higher than that (0.46%) in 32 461 non-Finnish European subjects from the Exome Aggregation Consortium (ExAC) (P = 0.01). CONCLUSIONS: While overall CHEK2 mutations were not significantly more common in men with lethal compared to low-risk PCa, the specific CHEK2 mutation, c.1100delC, appears to contribute to an increased risk of lethal PCa in European American men.

Germline mutations in PPFIBP2 are associated with lethal prostate cancer.

BACKGROUND: Few genes have germline mutations which predispose men to more aggressive prostate cancer (PCa). This study evaluated the contribution of germline loss of function (LOF) variants in PPFIBP2 to risk of lethal PCa. METHODS: A case-case study of 1414 PCa patients with lethal PCa and low-risk localized PCa was performed. Germline DNA samples from these patients were sequenced for PPFIBP2. Mutation carrier rates and association with lethal PCa were analyzed using the Fisher exact test, logistic regression, and Kaplan-Meier survival analysis. RESULTS: In the entire study population, eight patients, all of European ancestry, were identified as carrying PPFIBP2 pathogenic or likely pathogenic mutations. Seven (1.52%) of 462 lethal PCa patients were carriers compared with only one (0.12%) carrier in 810 low-risk PCa patients, P = 0.0029. The estimated Odds Ratio (OR) of carrying PPFIBP2 mutation for lethal PCa was 13.8 in European American population. The PPFIBP2 loss-of-function mutation carrier rate in lethal PCa cases was also higher than in 33 370 non-Finnish European individuals from the Exome Aggregation Consortium (ExAC) (carrier rate of 0.17%, P = 1.92 × 10-5 ) and in 498 men with localized PCa from The Cancer Genome Atlas cohort (TCGA) cohort (carrier rate of 0%, P = 0.0058). Survival analysis in European American lethal cases revealed PPFIBP2 mutation status as an independent predictor of shorter survival after adjusting for age at diagnosis, PSA at diagnosis, and genetic background (hazard ratio = 2.62, P = 0.034). CONCLUSIONS: While larger studies are needed, germline mutations in a novel gene, PPFIBP2, differentiated risk for lethal PCa from low-risk cases and were associated with shorter survival times after diagnosis.

Genetic variants in five novel loci including CFB and CD40 predispose to chronic hepatitis B.

UNLABELLED: Hepatitis B virus affects more than 2 billion people worldwide, 350 million of which have developed chronic hepatitis B (CHB). The genetic factors that confer CHB risk are still largely unknown. We sought to identify genetic variants for CHB susceptibility in the Chinese population. We undertook a genome-wide association study (GWAS) in 2,514 CHB cases and 1,130 normal controls from eastern China. We replicated 33 of the most promising signals and eight previously reported CHB risk loci through a two-stage validation totaling 6,600 CHB cases and 8,127 controls in four independent populations, of which two populations were recruited from eastern China, one from northern China and one from southern China. The joint analyses of 9,114 CHB cases and 9,257 controls revealed significant association of CHB risk with five novel loci. Four loci are located in the human leukocyte antigen (HLA) region at 6p21.3, including two nonsynonymous variants (rs12614 [R32W] in complement factor B [CFB], Pmeta =1.28 × 10(-34) ; and rs422951 [T320A] in NOTCH4, Pmeta = 5.33 × 10(-16) ); one synonymous variant (rs378352 in HLA-DOA corresponding to HLA-DOA*010101, Pmeta = 1.04 × 10(-23) ); and one noncoding variant (rs2853953 near HLA-C, Pmeta = 5.06 × 10(-20) ). Another locus is located at 20q13.1 (rs1883832 in the Kozak sequence of CD40, Pmeta = 2.95 × 10(-15) ). Additionally, we validated seven of eight previously reported CHB susceptibility loci (rs3130542 at HLA-C, rs1419881 at TCF19, rs652888 at EHMT2, rs2856718 at HLA-DQB1, rs7453920 at HLA-DQB2, rs3077 at HLA-DPA1, and rs9277535 at HLA-DPA2, which are all located in the HLA region, 9.84 × 10(-71) ≤ Pmeta ≤ 9.92 × 10(-7) ). CONCLUSION: Our GWAS identified five novel susceptibility loci for CHB. These findings improve the understanding of CHB etiology and may provide new targets for prevention and treatment of this disease.

MiR-608 rs4919510 is associated with prognosis of hepatocellular carcinoma.

Single nucleotide polymorphisms (SNPs) within microRNAs (miRNAs) are considered potential markers for risk and prognosis of various cancers. In the current study, we aimed to determine whether miR-608 rs4919510 affected hepatocellular carcinoma (HCC) prognosis. We genotyped rs4919510 using DNA from blood samples of 362 HCC patients receiving surgical resection of HCC tumor. Associations between rs4919510 and overall survival (OS) and demographic characteristics and clinical features were estimated using the Cox proportional hazards model. Results showed that HCC patients who carried the rs4919510 CC genotype had a significantly longer OS compared to those who carried the GG genotype (P = 0.013, hazard ratio [HR] = 0.600, 95 % confidence interval [CI] 0.402-0.897) and the CG + GG genotype (P = 0.033, HR = 0.681, 95 % CI 0.479-0.970) in univariate analysis. Similar results were obtained in multivariate analysis. Further stratification analysis indicated that rs4919510 was significantly associated with OS in patients who were satisfied with one of the following criteria: male gender, HbsAg-positive, α-fetoprotein (AFP)-positive, tumor size >5 cm, cirrhosis, solitary tumor, I + II pTNM stage, or no tumor capsule. Finally, a significantly higher frequency of rs4919510 CC genotype was observed in patients with cirrhosis (22.9 %, 55/240) than those without cirrhosis (14.0 %, 17/121) (P = 0.047). In conclusion, our results illustrated the potential role of miR-608 rs4919510 as a prognostic marker for HCC patients undergoing surgical resection of the tumor.

miR-492G>C polymorphism (rs2289030) is associated with overall survival of hepatocellular carcinoma patients.

Single-nucleotide polymorphisms (SNPs) of microRNAs (miRNAs) are considered potential markers of cancer risk and prognosis in various cancers. In the current study, the primary aim is to determine whether the miR-492G>C polymorphism (rs2289030) altered hepatocellular carcinoma (HCC) prognosis. The SNP rs2289030 of miR-492 was genotyped using DNA from blood samples of 362 HCC patients that had undergone surgical resection of a HCC tumor. The associations between overall survival and demographic characteristics, clinical features, and the SNP rs2289030 were estimated using the Cox proportional hazards model. Results showed that patients who carried the CG genotype (P = 0.015, hazard ratio [HR] = 0.704, 95 % confidence interval [CI] 0.530-0.934) and CG+GG genotype (P = 0.011, HR = 0.703, 95 % CI 0.536-0.924) had significantly decreased risk of death compared to those with the CC genotype. Similar results were found in the multivariate analysis adjusted by tumor size and venous invasion. Further stratification analysis indicated that the effect of rs2289030 had more prominence in patients ≤50 years old and that reported ever using alcohol, male gender, a family history of HCC, being HbsAg or alpha fetoprotein (AFP) positive, differentiation I + II, presence of venous invasion or cirrhosis, multiple tumors, and pTNM stage I + II. Results from this study illustrate the potential use of miR-492 rs2289030 as a prognostic marker for HCC patients that have undergone a surgical resection of the tumor.