Profiling the Somatic Mutational Landscape of Breast Tumors from Hispanic/Latina Women Reveals Conserved and Unique Characteristics.

Somatic mutational profiling is increasingly being used to identify potential targets for breast cancer. However, limited tumor-sequencing data from Hispanic/Latinas (H/L) are available to guide treatment. To address this gap, we performed whole-exome sequencing (WES) and RNA sequencing on 146 tumors and WES of matched germline DNA from 140 H/L women in California. Tumor intrinsic subtype, somatic mutations, copy-number alterations, and expression profiles of the tumors were characterized and compared with data from tumors of non-Hispanic White (White) women in The Cancer Genome Atlas (TCGA). Eight genes were significantly mutated in the H/L tumors including PIK3CA, TP53, GATA3, MAP3K1, CDH1, CBFB, PTEN, and RUNX1; the prevalence of mutations in these genes was similar to that observed in White women in TCGA. Four previously reported Catalogue of Somatic Mutations in Cancer (COSMIC) mutation signatures (1, 2, 3, 13) were found in the H/L dataset, along with signature 16 that has not been previously reported in other breast cancer datasets. Recurrent amplifications were observed in breast cancer drivers including MYC, FGFR1, CCND1, and ERBB2, as well as a recurrent amplification in 17q11.2 associated with high KIAA0100 gene expression that has been implicated in breast cancer aggressiveness. In conclusion, this study identified a higher prevalence of COSMIC signature 16 and a recurrent copy-number amplification affecting expression of KIAA0100 in breast tumors from H/L compared with White women. These results highlight the necessity of studying underrepresented populations. SIGNIFICANCE: Comprehensive characterization of genomic and transcriptomic alterations in breast tumors from Hispanic/Latina patients reveals distinct genetic alterations and signatures, demonstrating the importance of inclusive studies to ensure equitable care for patients. See related commentary by Schmit et al., p. 2443.

Bi-directional Mendelian randomization of epithelial ovarian cancer and schizophrenia and uni-directional Mendelian randomization of schizophrenia on circulating 1- or 2-glycerophosphocholine metabolites.

Most women with epithelial ovarian cancer (EOC) present with late-stage disease. As a result, globally, EOC is responsible for >150,000 deaths a year. Thus, a better understanding of risk factors for developing EOC is crucial for earlier screening and detection to improve survival. To that effort, there have been suggestions that there is an association of schizophrenia and cancer, possibly because metabolic changes are a hallmark of both cancer and schizophrenia (SZ). Perturbed choline metabolism has been documented in both diseases. Our objective was to use Mendelian randomization to evaluate whether SZ increased risk for developing EOC or the converse, and, whether SZ impacted 1- or 2-glycerophosphocholine (1- or 2-GPC) metabolites. We found that SZ conferred a weak but increased risk for EOC, but not the reverse (no evidence that EOC caused SZ). SZ was also causally associated with lower levels of two 1- or 2-GPC species and with suggestively lower levels in an additional three 1- or 2-GPCs. We postulate that perturbed choline metabolism in SZ may mimic or contribute to a "cholinic" phenotype, as observed in EOC cells.

The Precautionary Principle for Shift-Work Research and Decision-Making.

Shift work (working outside of 6:00 AM to 6:00 PM) is a fixture of our 24-hour economy, with approximately 18 per cent of workers in the USA engaging in shift work, many overnight. Since shift work has been linked to an increased risk for an array of serious maladies, including cardiometabolic disorders and cancer, and is done disproportionately by the poor and by minorities, shift work is a highly prevalent economic and occupational health disparity. Here we draw primarily on the state of science around shift work and breast cancer to argue that shift work represents a public health threat serious enough to warrant a precautionary stance. We use the precautionary principle to advance our case and view it as a moral compass for shift work research, empowering public health to cast shift work within the domain of health disparities deserving action despite scientific uncertainty. With the precautionary principle, we call for a deliberative decision-making process and formation of a broad shift work research collaboration to protect the health of many millions who work at night.

Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.

BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR). METHODS: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

Nightshift work, chronotype, and genome-wide DNA methylation in blood.

Molecular mechanisms underlying the negative health effects of shift work are poorly understood, which remains a barrier to developing intervention strategies to protect the long-term health of shift workers. We evaluated genome-wide differences in DNA methylation (measured in blood) between 111 actively employed female nightshift and 86 actively employed female dayshift workers from the Seattle metropolitan area. We also explored the effect of chronotype (i.e., measure of preference for activity earlier or later in the day) on DNA methylation among 110 of the female nightshift workers and an additional group of 131 male nightshift workers. Methylation data were generated using the Illumina Infinium HumanMethylation450 BeadChip (450K) Array. After applying the latest methylation data processing methods, we compared methylation levels at 361,210 CpG loci between the groups using linear regression models adjusted for potential confounders and applied the false-discovery rate (FDR) ≤ 0.05 to account for multiple comparisons. No statistically significant associations at the genome-wide level were observed with shift work or chronotype, though based on raw P values and absolute effect sizes, there were suggestive associations in genes that have been previously linked with cancer (e.g., BACH2, JRK, RPS6KA2) and type-2 diabetes (e.g., KCNQ1). Given that our study was underpowered to detect moderate effects, examining these suggestive results in well-powered independent studies or in pooled data sets may improve our understanding of the pathways underlying the negative health effects of shift work and the influence of personal factors such as chronotype. Such an approach may help identify potential interventions that can be used to protect the long-term health of shift workers.

Otologic manifestations of Fanconi anemia and other inherited bone marrow failure syndromes.

BACKGROUND: The inherited bone marrow failure syndromes (IBMFSs) are diverse disorders with syndrome-specific features; their otologic and audiologic manifestations have not been well described. Our objective was to characterize these in patients with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS), and to determine the association between physical findings and hearing loss. METHODS: Patients with an IBMFS underwent comprehensive clinical and laboratory evaluations and testing for syndrome-specific gene mutations. Hearing loss was measured by pure tone audiometry and otologic abnormalities by otomicroscopy. RESULTS: Patients included 33 with FA, 37 with DC, 32 with DBA, and nine with SDS. Hearing loss was most frequent in patients with FA (45%) and DBA (14%). The most common type of hearing loss in FA was conductive (65%). Absent or hypoplastic radius, noted in 21% of the patients with FA, was associated with hearing loss in all cases. Otomicroscopy was abnormal in 66% of patients with FA. Characteristic ear abnormalities included small tympanic membrane (66%), malformed malleus (57%), aberrant tympanic bony island (48%), narrow external auditory canal (EAC) (32%), and abnormal course of chorda tympani (34%). Ear malformations were almost always associated with hearing loss. Hearing loss was rare in patients with DC and SDS. CONCLUSIONS: FA is the major IBMFS with associated hearing loss, which is most commonly conductive. Radial hypoplasia or aplasia and characteristic congenital ear malformations are associated with hearing loss in patients with FA. Recognition of these syndrome-specific abnormalities should lead to earlier management of hearing loss.

Prospectively Identified Incident Testicular Cancer Risk in a Familial Testicular Cancer Cohort.

BACKGROUND: Human testicular germ cell tumors (TGCT) have a strong genetic component and a high familial relative risk. However, linkage analyses have not identified a rare, highly penetrant familial TGCT (FTGCT) susceptibility locus. Currently, multiple low-penetrance genes are hypothesized to underlie the familial multiple-case phenotype. The observation that two is the most common number of affected individuals per family presents an impediment to FTGCT gene discovery. Clinically, the prospective TGCT risk in the multiple-case family context is unknown. METHODS: We performed a prospective analysis of TGCT incidence in a cohort of multiple-affected-person families and sporadic-bilateral-case families; 1,260 men from 140 families (10,207 person-years of follow-up) met our inclusion criteria. Age-, gender-, and calendar time-specific standardized incidence ratios (SIR) for TGCT relative to the general population were calculated using SEER*Stat. RESULTS: Eight incident TGCTs occurred during prospective FTGCT cohort follow-up (versus 0.67 expected; SIR = 11.9; 95% CI, 5.1-23.4; excess absolute risk = 7.2/10,000). We demonstrate that the incidence rate of TGCT is greater among bloodline male relatives from multiple-case testicular cancer families than that expected in the general population, a pattern characteristic of adult-onset Mendelian cancer susceptibility disorders. Two of these incident TGCTs occurred in relatives of sporadic-bilateral cases (0.15 expected; SIR = 13.4; 95% CI, 1.6-48.6). CONCLUSIONS: Our data are the first to indicate that despite relatively low numbers of affected individuals per family, members of both multiple-affected-person FTGCT families and sporadic-bilateral TGCT families comprise high-risk groups for incident testicular cancer. IMPACT: Men at high TGCT risk might benefit from tailored risk stratification and surveillance strategies.