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Hypobaric hypoxia exerts a significant evolutionary pressure on highlanders who have resided at high altitude for thousands of years. This evolutionary pressure has resulted in signatures of natural selection within native highlanders’ genomes, some of which associate with adaptive physiological traits. Our recent analyses examined the overlap of a priori functional candidate genes and genes identified in the composite of multiple signals test of selection in 40 Andean genomes. We identified ICAM1, which encodes the intercellular adhesion molecule 1 protein, as one of the top 10 candidate genes of positive selection in this highland population. We utilized LDproxy and CADD score analysis to prioritize variants of functional relevance in this gene. The single-nucleotide variant (SNV) rs1799969, located in exon 4, exhibited the highest CADD score of 22.0. We genotyped rs1799969 in a larger cohort of 255 Andean highlanders and found that 68% of Andeans have at least one copy of the SNV, compared to 6% and 20% in worldwide and American populations, respectively, from the 1000 Genomes data set. Given the soluble form of ICAM1 is elevated in patients with COPD, atherosclerosis, coronary heart disease, and other cardiometabolic phenotypes, and rs1799969 is associated with less soluble ICAM1 in larger, worldwide cohorts, we tested the hypothesis that putatively adaptive copies of ICAM1 would be associated with blood pressure in the high-altitude Andean cohort. We found that more copies of the putatively adaptive haplotype containing rs1799969 is associated with lower systolic blood pressure (p-value = 0.012 for 0 vs 2 alleles, 0.028 for 0 vs 1 allele; effect size = 7.1mmHg for males, 13.5mmHg for females; NS diastolic blood pressure), whereby the effect size of the number of adaptive gene copies on systolic blood pressure is comparable to commonly prescribed medications and orders of magnitude larger than previous genetic association studies of blood pressure (~1.5mmHg for rare variants, ~0.5mmHg for common variants). Because ICAM1 is activated by hypoxia, it is plausible that rs1799969 may play a protective physiological role in the context of chronic hypoxia in Andean highlanders. Hypertension is one of the strongest modifiable risk factors for cardiometabolic disease, and this may be especially relevant in hypobaric hypoxia, where chronic activation of sympathetic activity can increase blood pressure. Additionally, elevated blood pressure is a known causative agent for diseases that are exacerbated at high altitude, such as pre-eclampsia. However, studies of hypertension in native highland populations have mixed results, often reporting conflicting associations depending on the population being studied, warranting further investigations into hypertension prevalence in various highland populations and genetic factors that may impact blood pressure. Supported by NIH 1R01HL145470 to TSS This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Purpose:Little is known about the genetic alterations characteristic of small bowel adenocarcinoma (SBA). Our purpose was to identify targetable alterations and develop experimental models of this disease.Experimental Design: Whole-exome sequencing (WES) was completed on 17 SBA patient samples and targeted-exome sequencing (TES) on 27 samples to confirm relevant driver mutations. Two SBA models with ERBB2 kinase activating mutations were tested for sensitivity to anti-ERBB2 agents in vivo and in vitro. Biochemical changes were measured by reverse-phase protein arrays.Results:WES identified somatic mutations in 4 canonical pathways (WNT, ERBB2, STAT3, and chromatin remodeling), which were validated in the TES cohort. Although APC mutations were present in only 23% of samples, additional WNT-related alterations were seen in 12%. ERBB2 mutations and amplifications were present in 23% of samples. Patients with alterations in the ERBB2 signaling cascade (64%) demonstrated worse clinical outcomes (median survival 70.3 months vs. 109 months; log-rank HR = 2.4, P = 0.03). Two ERBB2-mutated (V842I and Y803H) cell lines were generated from SBA patient samples. Both demonstrated high sensitivity to ERBB2 inhibitor dacomitinib (IC50 < 2.5 nmol/L). In xenografts derived from these samples, treatment with dacomitinib reduced tumor growth by 39% and 59%, respectively, whereas it had no effect in an SBA wild-type ERBB2 model.Conclusions:The in vitro and in vivo models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating ERBB2 mutations in patients with SBA that harbor these alterations.

Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.93, 95% CI = 0.76–1.13, P = 0.46) or aggressive (aggregate OR = 1.14, 95% CI = 0.92–1.41, P = 0.22) prostate cancer risk. CHIP was weakly associated with genetic risk of overall prostate cancer, measured using a polygenic risk score (OR = 1.05 per unit increase, 95% CI = 1.01–1.10, P = 0.01). CHIP was not significantly associated with carrying pathogenic/likely pathogenic/deleterious variants in DNA repair genes, which have previously been found to be associated with aggressive prostate cancer. While findings from this study suggest that CHIP is likely not a risk factor for prostate cancer, it will be important to investigate other types of CH in association with prostate cancer risk.

Causes of racial disparities in ovarian cancer survival are likely multifactorial, including socio-environmental, structural, and biological factors. Mutational signatures reflect endogenous and exogenous exposures, which may differ by race and ethnicity. This study aims to characterize mutational signatures and their associated etiologies among Black high-grade serous ovarian cancer (HGSC) cases, and to compare the occurrence and distribution of signatures with White TCGA cases. Mutational profiling with whole exome sequencing in matched blood and tumor formalin-fixed paraffin-embedded specimens was performed in 271 HGSC cases identifying as Black or African American and participating in the African American Cancer Epidemiology Study (AACES) or the North Carolina Ovarian Cancer Study (NCOCS). After filtering, we identified 28,601 high-confidence coding mutations in 256 samples that passed quality control assessments. The median number of mutations per sample was 67, similar to that in TCGA at 66. Mutation frequencies of the major genes identified in TCGA were nearly identical in Black AACES/NCOCS cases; mutations in TP53 were present in 96% and 89%, respectively, and mutation frequencies in BRCA1/2, CSMD3, NF1, CDK12, FAT3, GABRA6, and RB1 differed by only 0-2%. We performed mutational signature analysis using SigProfiler and refitting to the Catalogue of Somatic Mutations in Cancer (COSMIC) previously published single base-pair substitution (SBS) signatures reflecting mutational processes resulting from known endogenous and exogenous exposures. SBS signatures are defined by 96 mutation features including the single nucleotide variant class (e.g., C>A, C>G, C>T, T>A, T>C, and T>G) and the identity of the 5’/3’ flanking bases. We observed much higher frequencies of the mismatch repair deficiency, homologous recombination deficiency, ultraviolet light, and treatment exposure signatures in Black AACES/NCOCS cases (26%, 22%, 9%, and 8%, respectively) than in White TCGA cases (3%, 10%, 3%, and 2%, respectively). The frequencies of the remaining signatures with known etiologies (clock-like, reactive oxygen species, base excision repair, mutagen exposure, DNA polymerase epsilon, and tobacco signatures) differed by less than 5% between Black and White cases. Many mismatch repair deficiency signatures identified in Black AACES/NCOCS cases are dominated by C>T or T>C mutations and may represent an artifact from formalin fixation. While we observed that the somatic mutation frequencies in major genes associated with HGSC were similar in Black and White cases, the frequencies of some known mutational signatures were considerably higher in Black HGSC. In particular, despite similar frequencies of BRCA1/2 mutations, the homologous recombination deficiency signature was considerably more common in Black than White HGSC. Citation Format: Katherine A. Lawson-Michod, David Nix, Lindsay Collin, Natalie Davidson, Ariel Hippen, Chad Huff, Aaron Atkinson, Lucas A. Salas, Lauren Peres, Casey Greene, Joellen Schildkraut, Jeffrey Marks, Jennifer A. Doherty. High-grade serous ovarian cancer somatic mutational signatures in Black and White individuals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3506.

Introduction: Neuroblastoma (NBL) is the most common type of extracranial pediatric solid tumor. NBL exhibits a wide spectrum of phenotypes, from low-risk cases that spontaneously regress to high-risk cases with 50% mortality, and it is responsible for 12% to 15% of deaths due to childhood cancer. While genome-wide association studies have identified a handful of risk loci, the germline genetic origins of sporadic NBL remain largely unknown. Notably, NBL is one of several childhood cancers that tend to co-occur with specific birth defects, which could point to novel genetic origins. For example, the risk of neuroblastoma is increased 3- to 7-fold among children with certain congenital heart defects (CHD). It is hypothesized that this co-occurrence arises from pleiotropic defects in the neural crest cells that are progenitors of both NBL and some heart structures. Based on these lines of evidence, we hypothesize that novel germline risk loci for NBL can be identified through pleiotropic analyses of CHD and NBL cohorts. Therefore, in this study we seek to identify germline risk loci for neuroblastoma by jointly analyzing CHD and NBL data sets with a primary focus on de novo variants. Methods: Using whole genome sequencing data from the Gabriella Miller Kids First Data Resource Center, we will identify NBL and CHD associated loci by testing for high rates of de novo variants (DNV) in each cohort separately and in the two cohorts combined. The testing strategy compares the rate of DNV to the expected locus-specific mutation rate. In our primary analyses, we will focus on genes known to be associated with CHD in order to reduce the multiple testing penalty for that family of loci. A broader analysis will explore coding and regulatory loci genome wide to identify loci associated jointly with NBL and CHD. Results: We acquired whole genome sequencing data of parent-offspring trios for NBL (n=609) and CHD (n=711) from the Gabriella Miller Kids First Data Resource Center. The probands in the NBL cohort was 54% male and 81% Non-Hispanic White, with a median age at diagnosis of 16 months. The probands in the CHD cohort was 59% male and 60% Non-Hispanic White. The most common CHD phenotypes were ventricular septal defect (46%), tetralogy of Fallot (32%), hypoplastic left heart syndrome (28%), atrial septal defect (25%), and right aortic arch (25%). Analyses to identify DNV are ongoing. Conclusion: The identification of germline risk loci associated with NBL will help to inform the developmental origins of this important childhood cancer and may inform novel risk stratification protocols and therapies. This study also aims to help explain the NBL-CHD co-occurrence, and that could shed light on the development of other neural crest cell derived cancers. Citation Format: Alexander Renwick, Yao Yu, Chad Huff, Philip J. Lupo. De novo variants associated with neuroblastoma and congenital heart defects: evidence of pleiotropic effect from 1311 WGS trios [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2506.

The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.The ORs associated for high-grade serous ovarian cancer were 3.01 forWe have found strong evidence that carriers of

ObjectivesA polygenic hazard score (PHS1)—weighted sum of 54 single-nucleotide polymorphism genotypes—was previously associated with age at prostate cancer (PCa) diagnosis and improved PCa screening accuracy in Europeans. Performance in more diverse populations is unknown. We evaluated PHS association with PCa in multi-ethnic populations.DesignPHS1 was adapted for compatibility with genotype data from the OncoArray project (PHS2) and tested for association with age at PCa diagnosis, at aggressive PCa diagnosis, and at PCa death.SettingMultiple international institutions.ParticipantsMen with available OncoArray data from the PRACTICAL consortium who were not included in PHS1 development/validation.Main Outcomes and MeasuresPHS2 was tested via Cox proportional hazards models for age at PCa diagnosis, age at aggressive PCa diagnosis (any of: Gleason score ≥7, stage T3-T4, PSA≥10 ng/mL, nodal/distant metastasis), and age at PCa-specific death.Results80,491 men of various self-reported race/ethnicities were included (30,575 controls, 49,916 PCa cases; genetic ancestry groups: 71,856 European, 6,253 African, 2,382 Asian). Median age at last follow-up was 70 years (IQR 63-76); 3,983 PCa deaths, 5,806 other deaths, 70,702 still alive. PHS2 had 46 polymorphisms: 24 directly genotyped and 22 acceptable proxies (r2 ≥0.94). PHS2 was associated with age at PCa diagnosis in the multi-ethnic dataset (z=54, p-16) and in each genetic ancestry group: European (z=56, p-16), Asian (z=47, p-16), African (z=29, p-16). PHS2 was also associated with age at aggressive PCa diagnosis in each genetic ancestry group (p-16) and with age of PCa death in the full dataset (p-16). Comparing the 80th and 20th percentiles of genetic risk, men with high PHS had hazard ratios of 5.3 [95% CI: 5.0-5.7], 5.9 [5.5-6.3], and 5.7 [4.6-7.0] for PCa, aggressive PCa, and PCa-specific death, respectively. Within European, Asian, and African ancestries, analogous hazard ratios for PCa were 5.5 [5.2-5.9], 4.5 [3.2-6.3], and 2.5 [2.1-3.1], respectively.ConclusionsPHS2 is strongly associated with age at PCa diagnosis in a multi-ethnic dataset. PHS2 stratifies men of European, Asian, and African ancestry by genetic risk for any, aggressive, and fatal PCa.Summary boxesWhat is already known on this topicGenetic risk stratification can identify men with greater predisposition for developing prostate cancer, but these risk models may worsen health disparities, as most have only been validated for men of European ancestryA polygenic hazard score was previously associated with age at prostate cancer diagnosis and improved PCa screening accuracy in EuropeansPerformance of the polygenic hazard score in multi-ethnic populations is unknownWhat this study addsIn a dataset from 80,491 men of various self-reported race/ethnicities, the polygenic hazard score was associated with age at prostate cancer diagnosis, aggressive prostate cancer diagnosis, and prostate cancer death.PHS stratifies men of European, Asian, and African ancestry by genetic risk for any, aggressive, and fatal prostate cancer.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.

What is the topic of this review? Tibetans have genetic adaptations that are hypothesized to underlie the distinct set of traits they exhibit at altitude. What advances does it highlight? Several adaptive signatures in the same genomic regions have been identified among Tibetan populations resident throughout the Qinghai-Tibetan Plateau. Many highland Tibetans exhibit a haemoglobin concentration within the range expected at sea level, and this trait is associated with putatively adaptive regions harbouring the hypoxia-inducible factor pathway genes EGLN1, EPAS1 and PPARA. Precise functional variants at adaptive loci and relationships to physiological traits, beyond haemoglobin concentration, are currently being examined in this population. Some native Tibetan, Andean and Ethiopian populations have lived at altitudes ranging from 3000 to >4000 m above sea level for hundreds of generations and exhibit distinct combinations of traits at altitude. It was long hypothesized that genetic factors contribute to adaptive differences in these populations, and recent advances in genomics provide evidence that some of the strongest signatures of positive selection in humans are those identified in Tibetans. Many of the top adaptive genomic regions highlighted thus far harbour genes related to hypoxia sensing and response. Putatively adaptive copies of three hypoxia-inducible factor pathway genes, EPAS1, EGLN1 and PPARA, are associated with sea-level range, rather than elevated, haemoglobin concentration observed in many Tibetans at high altitude, and recent studies provide insight into some of the precise adaptive variants, timing of adaptive events and functional roles. While several studies in highland Tibetans have converged on a few hypoxia-inducible factor pathway genes, additional candidates have been reported in independent studies of Tibetans located throughout the Qinghai-Tibetan Plateau. Various aspects of adaptive significance have yet to be identified, integrated, and fully explored. Given the rapid technological advances and interdisciplinary efforts in genomics, physiology and molecular biology, careful examination of Tibetans and comparisons with other distinctively adapted highland populations will provide valuable insight into evolutionary processes and models for both basic and clinical research.

Global DNA methylation, possibly influenced by lifestyle and environmental factors, has been suggested to play an active role in carcinogenesis. However, its role in melanoma has rarely been explored. The aims of this study were to evaluate the relationship between melanoma risk and levels of 5-methylcytosine (5-mC), a marker for global DNA methylation, in blood leukocyte DNA, and to determine whether this 5-mC level is influenced by pigmentation and sun exposure. This case-control study included 540 melanoma cases and 540 healthy controls. Overall, melanoma cases had significantly lower levels of 5-mC% than healthy controls (median: 3.24 vs. 3.91, p 0.001). The significant difference between two groups did not differ by pigmentation or sun exposure. Among healthy controls, however, those who had fair skin color (p = 0.041) or light or no tanning after prolonged sun exposure (p = 0.031) or used a sunlamp (p = 0.028) had lower levels of 5-mC% than their counterparts. In addition, those with an intermediate or high phenotypic index, an indicator of cutaneous cancer susceptibility, had 2.58-fold greater likelihood of having a low level of 5-mC% [odds ratio (OR): 2.58; 95% confidence interval (CI): 1.72, 3.96] than those with a low phenotypic index. Lower levels of 5-mC% were associated with a 1.25-fold greater risk of melanoma (OR: 1.25; 95% CI: 1.08, 1.37). A significant dose-response relationship was observed in quartile analysis (p = 0.001). Our results suggest that global hypomethylation in blood leukocyte DNA is associated with increased risk of melanoma and that the level of methylation is influenced by pigmentation and sun exposure.

As a consequence of the accumulation of insertion events over evolutionary time, mobile elements now comprise nearly half of the human genome. The Alu, L1, and SVA mobile element families are still duplicating, generating variation between individual genomes. Mobile element insertions (MEI) have been identified as causes for genetic diseases, including hemophilia, neurofibromatosis, and various cancers. Here we present a comprehensive map of 7,380 MEI polymorphisms from the 1000 Genomes Project whole-genome sequencing data of 185 samples in three major populations detected with two detection methods. This catalog enables us to systematically study mutation rates, population segregation, genomic distribution, and functional properties of MEI polymorphisms and to compare MEI to SNP variation from the same individuals. Population allele frequencies of MEI and SNPs are described, broadly, by the same neutral ancestral processes despite vastly different mutation mechanisms and rates, except in coding regions where MEI are virtually absent, presumably due to strong negative selection. A direct comparison of MEI and SNP diversity levels suggests a differential mobile element insertion rate among populations., Author Summary We embarked on this study to explore the 1000 Genomes Project (1000GP) pilot dataset as a substrate for Mobile Element Insertion (MEI) discovery and analysis. MEI is already well known as a significant component of genetic variation in the human population. However the full extent and effects of MEI can only be assessed by accurate detection in large whole-genome sequencing efforts such as the 1000GP. In this study we identified 7,380 distinct genomic locations of variant MEI and carried out rigorous validation experiments that confirmed the high accuracy of the detected events. We were able to measure the frequency of each variant in three continental population groups and found that inherited MEI variants propagate through populations in much the same way as single nucleotide polymorphisms, except that MEI are more strongly suppressed in protein coding parts of the genome. We also found evidence that the MEI mutation rate has not been constant over human population history, rather that different populations appear to have different characteristic MEI mutation rates.