Functional analysis of rare variants in mismatch repair proteins augments results from computation-based predictive methods

The cancer-predisposing Lynch Syndrome (LS) arises from germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1, MSH2, MSH6, and PMS2. A major challenge for clinical diagnosis of LS is the frequent identification of variants of uncertain significance (VUS) in these genes, as it is...

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Bibliographic Details
Published in:Cancer biology & therapy 2017-07, Vol.18 (7), p.519-533
Main Authors: Arora, Sanjeevani, Huwe, Peter J., Sikder, Rahmat, Shah, Manali, Browne, Amanda J., Lesh, Randy, Nicolas, Emmanuelle, Deshpande, Sanat, Hall, Michael J., Dunbrack, Roland L., Golemis, Erica A.
Format: Article
Language:English
Subjects:
Alleles
Amino Acid Substitution
Biomarkers, Tumor
Cell Survival - genetics
Colon cancer
colorectal cancer predisposition
Colorectal Neoplasms, Hereditary Nonpolyposis - genetics
DNA Damage
DNA Mismatch Repair
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Female
Gene Expression
Genetic Variation
Humans
mismatch repair
Models, Molecular
Molecular Conformation
Protein Binding
rare variant
Research Paper
RNA, Messenger - genetics
RNA, Messenger - metabolism
Structure-Activity Relationship
variants of uncertain significance
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Summary:The cancer-predisposing Lynch Syndrome (LS) arises from germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1, MSH2, MSH6, and PMS2. A major challenge for clinical diagnosis of LS is the frequent identification of variants of uncertain significance (VUS) in these genes, as it is often difficult to determine variant pathogenicity, particularly for missense variants. Generic programs such as SIFT and PolyPhen-2, and MMR gene-specific programs such as PON-MMR and MAPP-MMR, are often used to predict deleterious or neutral effects of VUS in MMR genes. We evaluated the performance of multiple predictive programs in the context of functional biologic data for 15 VUS in MLH1, MSH2, and PMS2. Using cell line models, we characterized VUS predicted to range from neutral to pathogenic on mRNA and protein expression, basal cellular viability, viability following treatment with a panel of DNA-damaging agents, and functionality in DNA damage response (DDR) signaling, benchmarking to wild-type MMR proteins. Our results suggest that the MMR gene-specific classifiers do not always align with the experimental phenotypes related to DDR. Our study highlights the importance of complementary experimental and computational assessment to develop future predictors for the assessment of VUS.
ISSN:1538-4047
1555-8576
DOI:10.1080/15384047.2017.1326439