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Inherited functional regulatory risk variants for common human cancers [MPRA]

ABSTRACT: Single nucleotide variants (SNVs) in regulatory DNA are linked to inherited cancer risk. Massively parallel reporter assays (MPRA) of 5,031 SNVs linked to 14 neoplasms comprising >90% of human malignancies were performed in pertinent diploid cell types then integrated with matching chromatin accessibility, looping, and eQTL data to identify 411 regulatory SNVs and their putative target eGenes. The latter highlighted specific protein networks in lifetime cancer risk, including mitochondrial translation, proliferation, signaling, adhesion, and immunity. This cancer SNV compendium underscores the importance of studying pathogenic variants in disease-relevant cells and implicates specific dysregulated gene networks in cancer predisposition. It also indicates that inherited cancer risk can impact the same gene via orthogonal genetic mechanisms of dysregulated expression as well as protein coding sequence alteration and demonstrates that a subset of germline-encoded risk genes also enable tumor growth of established cancers.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE183301 | GEO | 2024/08/22

REPOSITORIES: GEO

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Project description:Germline BRCA2 loss-of function (LOF) variants identified by clinical genetic testing predispose to breast, ovarian, prostate and pancreatic cancer. However, variants of uncertain significance (VUS) (n>5000) limit the clinical use of testing results. Thus, there is an urgent need for functional characterization and clinical classification of all BRCA2 variants. Here we report on comprehensive saturation genome editing-based functional characterization of 99% of all possible single nucleotide variants (SNVs) in the BRCA2 DNA Binding Domain hotspot for pathogenic missense variants that is encoded by exons 15 to 26. The assay was based on deep sequence analysis of HAP1 haploid cells endogenously targeted using a CRISPR/cas9 knockin approach. A total of 6959 SNVs were characterized for effects on cell survival. The assay was validated relative to nonsense and synonymous variants, ClinVar pathogenic/likely pathogenic and benign/likely benign variants and homology directed repair cell based DNA repair assay results, all of which showed >94% sensitivity and specificity. Variants were assigned posterior probabilities of pathogenicity using a VarCall two component Bayesian mixture model and were further grouped according to ACMG strength of evidence under the PS3/BS3 rule resulting in Benign Strong (n=5430), Benign Moderate (n=190), Benign Supporting (n=61), VUS (122), Pathogenic Strong (n=1021), Pathogenic Moderate (n=88), and Pathogenic Supporting (n=47). Breast cancer case-control association studies showed that pooled SNVs encoding functionally pathogenic missense variants were associated with increased risks of breast (odds ratio (OR)3.81, 95%CI: 2.88-5.07) and ovarian cancer (OR 5.93, 95%CI: 4.12-8.52). The functional data were also combined with other sources of information in the ClinGen BRCA1/2 VCEP ACMG/AMP-classification model. A total of 785 SNVs, including 261 missense SNVs, were classified as pathogenic or likely pathogenic, while 5566 SNVs, including 3786 missense SNVs, were classified as benign or likely benign. These classified variants can now be used for risk assessment and clinical care of variant carriers.

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Inherited functional regulatory risk variants for common human cancers [MPRA]

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