BACKGROUND:The HOXB13 c.G251G>A:p.G84E (rs138213197) variant is associated with an increased risk of prostate cancer (PrCa); however, its link to aggressive PrCa remains controversial. Limited data from large, population-based cohorts are available to inform genetic counseling and clarify the PrCa risk associated with this variant. PATIENTS AND METHODS:We identified individuals heterozygous for HOXB13 p.G84E or homozygous wild-type among 592,158 male participants in single nucleotide polymorphism genotyping data from the Veterans Health Administration (VA) Million Veteran Program (MVP). Individuals with PrCa were identified, and Cox proportional hazards models were used to estimate age-specific risk of developing PrCa. In a subset of patients who underwent their first prostate biopsy within the VA health system, a multivariable logistic regression model-adjusting for known PrCa risk factors-was used to assess PrCa risk. RESULTS:Of the MVP participants, 1,660 (0.3%) were heterozygous for HOXB13 p.G84E. Heterozygosity was significantly associated with risk of any PrCa (hazard ratio [HR], 3.17 [95% CI, 2.90-3.46]; P<2.0E-16), metastatic PrCa (HR, 2.99 [95% CI, 2.32-3.84]; P<2.0E-16), and PrCa-specific mortality (HR, 2.63 [95% CI, 1.66-4.19]; P=4.4E-05). In the subset of MVP participants who underwent prostate biopsy within the VA health system (n=36,321), a multivariable logistic regression model controlling for known PrCa risk factors showed that HOXB13 p.G84E heterozygotes had a higher risk of PrCa diagnosis (odds ratio, 2.60 [95% CI, 1.94-3.52]; P<.001). HOXB13 p.G84E heterozygotes were diagnosed with PrCa at a slightly younger age but had similar Gleason score distributions and comparable rates of de novo, any, and castration-resistant metastatic disease. CONCLUSIONS:In the largest cohort of men with the HOXB13 p.G84E variant studied to date, we demonstrate a moderately increased lifetime risk of PrCa. However, the PrCa that develops is not more aggressive, although it may occur at younger ages. Further research is warranted to determine whether early PrCa screening in HOXB13 p.G84E heterozygotes improves outcomes.

PURPOSE Considerable genetic heterogeneity is currently thought to underlie hereditary prostate cancer (HPC). Most families meeting criteria for HPC cannot be attributed to currently known pathogenic variants. METHODS To discover pathogenic variants predisposing to prostate cancer, we conducted a familial case-control association study using both genome-wide single-allele and identity-by-descent analytic approaches. Sequence of high-risk haplotype carriers was used for variant detection. Candidate pathogenic variants were tested for association with prostate cancer across independent biobanks for replication of observations. RESULTS Pathogenic variants within WNT9B were associated with familial prostate cancer and observations replicated within four of four independent biobanks. WNT9B E152K carried 2.5-fold risk and reached genome-wide significance under meta-analysis, collectively encompassing a half million patients. WNT9B Q47R was also associated with prostate cancer with genome-wide significance among Finns, for which identity-by-descent analyses confirmed a founder effect. WNT9B shares an unexpected commonality with the previously established prostate cancer risk genes HOXB13 and HNF1B : they are each required for embryonic prostate development. With this recognition, we further evaluated two additional genes known to cause Mendelian genitourinary developmental defects, KMT2D and DHCR7 . These too were nominally associated with prostate cancer under meta-analyses. CONCLUSION WNT9B and additional genes that are required for early genitourinary development are also involved in the later development of prostate cancer.

PURPOSELong-standing clinical predictors of cancer survival have included histopathologic type, stage, and grade. We hypothesized that the principal categories of tumor somatic mutations might also portend survival. We investigated this hypothesis using the Pan-Cancer Atlas, encompassing clinical, genomic, and outcome data of 10,652 patients and 32 cancer types.METHODSWe evaluated the prognostic capability of cancer type, stage, grade and the burden of each major mutation category on overall and disease-specific survival. Mutation categories included short substitution and insertion-deletion mutations (SMs), copy number alterations (CNAs), and gene fusions.RESULTSSM count and CNA fraction proved to be strong independent predictors of survival (joint P = 5.3e-95) that remained highly significant when adjusted for the traditional factors. Importantly, the relationship between mutation burden and survival proved to be nonlinear (P = 9.5e-56); survival improved at both low- and high-burden extremes. In clinically predictive modeling, SM count together with CNA fraction meaningfully distinguished survival even among patients sharing a given cancer type, stage, or grade.CONCLUSIONBurden of somatic mutation is a key index of survival of analogous clinical utility to these traditional factors.

Supplementary Table 2 from A Multistage Association Study Identifies a Breast Cancer Genetic Locus at <i>NCOA7</i>

Supplementary Table 1 from A Multistage Association Study Identifies a Breast Cancer Genetic Locus at <i>NCOA7</i>

Supplementary Figure 1 from A Multistage Association Study Identifies a Breast Cancer Genetic Locus at NCOA7

Supplementary Table 1 from Haplotype Analysis of CYP11A1 Identifies Promoter Variants Associated with Breast Cancer Risk

PDF file, 36K, Number of risk allele carriers.

Supplementary Table 2 from Haplotype Analysis of <i>CYP11A1</i> Identifies Promoter Variants Associated with Breast Cancer Risk

Supplementary Table 1 from A Multistage Association Study Identifies a Breast Cancer Genetic Locus at NCOA7

Supplementary Material from Blood Vitamin D Levels in Relation to Genetic Estimation of African Ancestry

The G84E germline mutation of HOXB13 predisposes to prostate cancer and is clinically tested for familial cancer care. We investigated the HOXB locus to define a potentially broader contribution to prostate cancer heritability. We sought HOXB locus germline variants altering prostate cancer risk in three European-ancestry case–control study populations (combined 7812 cases and 5047 controls): the International Consortium for Prostate Cancer Genetics Study; the Nashville Familial Prostate Cancer Study; and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Multiple rare genetic variants had concordant and strong risk effects in these study populations and exceeded genome-wide significance. Independent risk signals were best detected by sentinel variants rs559612720 within SKAP1 (OR = 8.1, P = 2E−9) and rs138213197 (G84E) within HOXB13 (OR = 5.6, P = 2E−11), separated by 567 kb. Half of carriers inherited both risk alleles, while others inherited either alone. Under mutual adjustment, the variants separately carried 3.6- and 3.1-fold risk, respectively, while joint inheritance carried 11.3-fold risk. These risks were further accentuated among men meeting criteria for hereditary prostate cancer, and further still for those with early-onset or aggressive disease. Among hereditary prostate cancer cases diagnosed under age 60 and with aggressive disease, joint inheritance carried a risk of OR = 27.7 relative to controls, P = 2E−8. The HOXB sentinel variant pair more fully captured genetic risk for prostate cancer within the study populations than either variant alone.

Genome-wide association studies bring into focus specific genetic variants of particular interest for which validation is often sought in large numbers of study subjects. Practical alternative methods are limiting for the application of genotyping few variants in many samples. A common scenario is the need to genotype a study population at a specific high-value single nucleotide polymorphism (SNP) or insertion-deletion (indel). Not all such variants, however, will be amenable to assay by a given approach. We have adapted a single-nucleotide primer extension (SNuPE) method that may be tailored to genotype a required variant, and implemented it as a useful general laboratory protocol. We demonstrate reliable application for production-scale genotyping, successfully converting 87% of SNPs and indels for assay with an estimated error rate of 0.003. Our implementation of the SNuPE genotyping assay is a viable addition to existing alternative methods; it is readily customizable, scalable, and uses standard reagents and a laboratory plate reader.

The 8q24 genomic locus is tied to the origin of numerous cancers. We investigate its contribution to hereditary prostate cancer (HPC) in independent study populations of the Nashville Familial Prostate Cancer Study and International Consortium for Prostate Cancer Genetics (combined: 2,836 HPC cases, 2,206 controls of European ancestry). Here we report 433 variants concordantly associated with HPC in both study populations, accounting for 9% of heritability and modifying age of diagnosis as well as aggressiveness; 183 reach genome-wide significance. The variants comprehensively distinguish independent risk-altering haplotypes overlapping the 648 kb locus (three protective, and four risk (peak odds ratios: 1.5, 4, 5, and 22)). Sequence of the near-Mendelian haplotype reveals eleven causal mutation candidates. We introduce a linkage disequilibrium-based algorithm discerning eight independent sentinel variants, carrying considerable risk prediction ability (AUC = 0.625) for a single locus. These findings elucidate 8q24 locus structure and correlates for clinical prediction of prostate cancer risk.

sentinel selects sentinel SNPs from the genetic variants in indepvars. These are SNPs that best detect independent risk-altering signals. In a multivariable multiplicative logistic regression model that regresses depvar against the sentinel variants, each variant is significantly associated with depvar and the absolute value of the correlation coefficient of each pair of variants is low.

Second generation p-values preserve the simplicity that has made p-values popular while resolving critical flaws that promote misinterpretation of data, distraction by trivial effects, and unreproducible assessments of data. The second-generation p-value (SGPV) is an extension that formally accounts for scientific relevance by using a composite null hypothesis that captures null and scientifically trivial effects. Because the majority of spurious findings are small effects that are technically nonnull but practically indistinguishable from the null, the second-generation approach greatly reduces the likelihood of a false discovery. SGPVs promote transparency, rigor and reproducibility of scientific results by a priori identifying which candidate hypotheses are practically meaningful and by providing a more reliable statistical summary of when the data are compatible with the candidate hypotheses or null hypotheses, or when the data are inconclusive. We illustrate the importance of these advances using a dataset of 247,000 single-nucleotide polymorphisms, i.e., genetic markers that are potentially associated with prostate cancer.

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BACKGROUND: Women with atypical hyperplasia (AH) on breast biopsy have a substantially increased risk of breast cancer (BC). Here the BC risk for the extent and subtype of AH is reported for 2 separate cohorts. METHODS: All samples containing AH were included from 2 cohorts of women with benign breast disease (Mayo Clinic and Nashville). Histology review quantified the number of foci of atypical ductal hyperplasia (ADM) and atypical lobular hyperplasia (ALH). The BC risk was stratified for the number of AH foci within AH subtypes. RESULTS: The study included 708 Mayo AH subjects and 466 Nashville AH subjects. In the Mayo cohort, an increasing number of foci of AH was associated with a significant increase in the risk of BC both for ADM (relative risks of 2.61, 5.21, and 6.36 for 1, 2, and >= 3 foci, respectively; P for linear trend =.006) and for ALH (relative risks of 2.56, 3.50, and 6.79 for 1, 2, and >= 3 foci, respectively; P for linear trend =.0013. In the Nashville cohort, the relative risks of BC for ADH were 2.70, 5.17, and 15.06 for 1, 2,, and >= 3 foci, respectively (fl for linear trend <.001), for ALH, the relative risks also increased but riot significantly (2.61, 3.48, and 4.02, respectively; P =148). When the Mayo and Nashville samples were combined the risk increased significantly for 1 2 and >= 3 foci: the relative risks were 2.65, 5.19, and 8.94, respectively, for ADH (P <;.001) and 2.58, 3.49, and 4.97, respectively, for ALH (P 4413. CONCLUSIONS: in 2 independent cohort studies of benign breast disease, the extent of atypia stratified the long-term BC risk for ADH and ALH. (C) 2016 American Cancer Society.

Elevated concentrations of inflammatory mediators are characteristic of autoimmune disease accompanied by chronic or recurrent inflammation. We examined the hypothesis that mediators of inflammation known to be elevated in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are associated with genetic polymorphism previously identified in studies of inflammatory disease. Serum interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) concentrations in patients with SLE (n = 117) or RA (n = 164) and in inflammatory disease-free control subjects (n = 172) were measured by multiplex ELISA. Candidate genes were chosen from studies of autoimmune and inflammatory disease. Genotypes were determined for 345 SNP markers in 75 genes. Association between serum analytes and single alleles was tested by linear regression. Polymorphisms in several genes were associated with IL-6 levels (including IL10, TYK2, and CD40L in SLE and DRB1, NOD2, and CSF1 in RA) or with TNFα levels (including TNFSF4 and CSF2 in SLE and PTPN2, DRB1, and NOD2 in RA). Some associations were shared between disease and control groups or between IL-6 and TNFα within a group. In conclusion, variation in genes implicated in disease pathology is associated with serum IL-6 or TNFα concentration. Some genetic associations are more apparent in healthy controls than in SLE or RA, suggesting dysregulation of the principal mediators of chronic inflammation in disease. Susceptibility genes may affect inflammatory response with variable effect on disease etiology.