Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases

Zeng, Chenjie; Bastarache, Lisa; Tao, Ran; Venner, Eric; Hebbring, Scott J.; Andujar, Justin; Bland, Sarah; Crosslin, David R.; Pratap, Siddharth; Cooley, Ayorinde; Pacheco, Jennifer A.; Christensen, Kurt D.; Perez, Emma; Zawatsky, Carrie L. Blout; Witkowski, Leora; Zouk, Hana; Weng, Chunhua; Leppig, Kathleen A.; Sleiman, Patrick; Hákonarson, Hákon; Williams, Marc S.; Luo, Yuan; Jarvik, Gail P.; Green, Robert C; Chung, Wendy K.; Gharavi, Ali G.; Lennon, Niall J.; Rehm, Heidi L.; Gibbs, Richard A.; Peterson, Josh F.; Roden, Dan M.; Wiesner, Georgia L.; Denny, Joshua C.

doi:10.1001/jamaoncol.2022.0373

Cited by 26 publications

(30 citation statements)

References 78 publications

(123 reference statements)

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“…By systematically reviewing published papers on the association of germline genes with bladder cancer risk and validating reported candidate genes in a large population‐based cohort, we confirmed the association for three genes at the study‐wise significance level ( p < 0.0056), including CHEK2 , ATM and BRCA2 . All the three genes are known to be involved in hereditary breast cancer risk 10 . In addition, we found suggestive evidence of association for two genes at a nominal p < 0.05, including MLH1 and MSH2 .…”

Section: Discussionsupporting

confidence: 55%

“…In addition, we found suggestive evidence of association for two genes at a nominal p < 0.05, including MLH1 and MSH2 . Both of these genes are known to cause Lynch syndrome 10 . These key findings provide needed statistical evidence for previously reported bladder cancer‐associated genes and offer guidance for bladder cancer risk assessment in the general population and clinic.…”

Section: Discussionmentioning

confidence: 55%

“…The rarity of pathogenic mutations in genes further limits the statistical power and can lead to inconsistent findings among studies. For example, in the largest study to date, evaluating 23 hereditary cancer genes among 214 020 subjects from three cohorts (including UKB), 10 Zeng and colleagues reported that pathogenic mutation in The importance of establishing gene-disease associations is emphasized by ClinGen, a National Institutes of Health (NIH)-funded resource dedicated to building a central resource that defines the clinical relevance of genes and variants for use in precision medicine and research. 22 ClinGen recommends an evidence-based framework for evaluating the clinical validity of gene-disease associations, including evidence from case-control studies.…”

Section: Discussionmentioning

confidence: 99%

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Systematic review of reported association studies of monogenic genes and bladder cancer risk and confirmation analysis in a large population cohort

et al. 2022

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Objectives: To evaluate which of previously reported monogenic genes are associated with increased bladder cancer risk, we reviewed published papers on associations of genes and bladder cancer risk and performed a confirmation study of these genes in a large population-based cohort. Subjects and methods:A systematic review of published papers prior to June 2022 was performed first to identify all genes where germline mutations were associated with bladder cancer risk. The associations of these candidate genes with bladder cancer risk were then tested among 1695 bladder cancer cases and 186 271 controls in the UK Biobank (UKB). The robust SKAT-O, a gene-based analysis that properly controls for type I error rates due to unbalanced case-control ratio, was used for association tests adjusting for age at recruitment, gender, smoking status, and genetic background.Results: The systematic review identified nine genes that were significantly associated with bladder cancer risk in at least one study (p < 0.05), including MUTYH, MSH2, MSH6, MLH1, ATM, BRCA2, ERCC5, TGFB1 and CHEK2. When pathogenic/ likely pathogenic mutations were aggregated within each gene, the association was confirmed for three genes in the UKB at p < 0.0056 (Bonferroni correction for nine tests), including CHEK2, ATM and BRCA2, all also known to be associated with hereditary breast cancer. Suggestive evidence of association was found for two other genes, including MLH1 (p = 0.006) and MSH2 (p = 0.007), both known to be associated with Lynch syndrome. Among these five genes, the bladder cancer risks range Abrar Mian and Jun Wei contributed equally to this work.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

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Systematic review of reported association studies of monogenic genes and bladder cancer risk and confirmation analysis in a large population cohort

et al. 2022

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“…In this study, we comprehensively evaluated the susceptibility between genetic variants on human exome and 20 primary cancer types in approximately 420,000 UKB participants of European ancestry. To our knowledge, this is the first exome-wide pan-cancer study including almost the whole UKB population, which could improve the statistical power compared with some previous studies using the early-phase UKB 200k population 34,35 . Trans-omics analyses were performed to evaluate the functional evidence of identified signals, including genomics, transcriptomics, and proteomics.…”

Section: Discussionmentioning

confidence: 98%

Exome-wide association studies discover germline mutation patterns and identify high-risk populations in human cancers

Shen

Jiang

Wang

et al. 2022

Preprint

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Genome-wide association studies have discovered numerous common variants associated with human cancers. However, the contribution of exome-wide rare variants to cancers remains largely unexplored, especially for the protein-coding variants. The UK Biobank provides detailed cancer follow-up information linked to whole-exome sequencing (WES) for approximately 450,000 participants, offering an unprecedented opportunity to evaluate the effect of exome variation on pan-cancer. Here, we performed exome-wide association studies (ExWAS) based on single variant levels and gene levels to detect their associations across 20 primary cancer types in the discovery set (WES-300k, N = 284,456) and replication set (WES-150k, N = 143,478), separately. The ExWAS detected 143 independent variants at variant-level and 49 genes at gene-level, while nine variants and eight genes were shared across cancers. In the cross-trait meta-analysis, we identified 239 additional independent pleiotropic variants, mapping to the genes which were functional through trans-omics analyses in transcriptomics and proteomics. Further, we developed exome-wide risk scores (ERS) to identify high-risk populations based on rare variants with minor allele frequency (MAF) < 0.05. The ERS had satisfactory performance in cancer risk stratification, especially for the extremely high-risk persons (top 5% ERS) that were frequently risk allele carriers. The ERS (median C-index (IQR): 0.655 (0.636-0.667)) outperforms the traditional polygenic risk score (PRS) (median C-index (IQR): 0.585 (0.572-0.614)) for discrimination in the replication set. Our findings offer further insight into the genetic architecture of human exomes for cancer susceptibility.

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“…In heterogeneous population cohorts, as opposed to disease-specific cohorts, low penetrance estimates for TTNtv carriers may also be the result of applying a too-narrow disease phenotype to define cases. As we begin to sequence more broadly in populations, our understanding of genetic disease is changing– classic disease definitions may not completely capture population level clinical manifestations related to genetic variation at a locus(12). Relevant diagnoses may also be different depending on when in the disease course a person is assessed and first treated.…”

Section: Introductionmentioning

confidence: 99%

TTN truncating variants in hiPSI exons show high penetrance for cardiomyopathy in carriers with atrial fibrillation

Barrett

Cirulli

Bolze

et al. 2022

Preprint

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Background: Truncating variants in TTN (TTNtvs) represent the largest known genetic cause of dilated cardiomyopathies (DCM). At the population level, even when limited to TTNtvs in cardiac-specific exons (hiPSI TTNtvs) penetrance estimates for DCM are low. Recent work shows that individuals harboring TTNtvs have a high prevalence of other cardiac conditions aside from heart failure, in particular, atrial fibrillation (Afib). Objectives: Pinpoint the genetic footprint TTN-related diagnoses aside from DCM, such as Afib, and determine if vetting additional significantly-associated phenotypes better stratifies cardiomyopathy risk across TTN carriers. Methods: We leverage longitudinal EHR and exome sequencing data from two cohorts to determine the penetrance of TTNtvs using multiple gene expression models against Afib, CM, and other cardiac diagnoses. Results: Controlling for CM and Afib, related cardio phenotypes retain only nominal association with TTNtvs. An unbiased sliding window analysis of TTNtvs across the locus confirms the association is specific to hiPSI exons for both CM and Afib, with no meaningful associations in lowPSI exons nor improvements from LOFTEE designations. We find 34% of hiPSI TTNtv carriers with early Afib have a CM diagnosis - a 5-fold increase in risk over non-carriers with early Afib and 47-fold increase over population controls. Conclusion: CM and Afib are often coincident in hiPSI TTNtv carriers, which represent varying and progressive manifestations of structurally-based heart failure. We provide statistical support for a hiPSI variant interpretation model for TTNtvs and evidence for the first population-level screening method with clinical utility for cardiomyopathies, especially in relation to an Afib finding.

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Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases

Cited by 26 publications

References 78 publications

Systematic review of reported association studies of monogenic genes and bladder cancer risk and confirmation analysis in a large population cohort

Systematic review of reported association studies of monogenic genes and bladder cancer risk and confirmation analysis in a large population cohort

Exome-wide association studies discover germline mutation patterns and identify high-risk populations in human cancers

TTN truncating variants in hiPSI exons show high penetrance for cardiomyopathy in carriers with atrial fibrillation

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