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

References

• Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993; 75:1027-38; PMID:8252616; https://doi.org/10.1016/0092-8674(93)90546-3
   PubMed Web of Science ®Google Scholar
• Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, Peltomäki P, Sistonen P, Aaltonen LA, Nyström-Lahti M, et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993; 75:1215-25; PMID:8261515; https://doi.org/10.1016/0092-8674(93)90330-S
   PubMed Web of Science ®Google Scholar
• Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895-2015. Nat Rev Cancer 2015; 15:181-94; PMID:25673086; https://doi.org/10.1038/nrc3878
   PubMed Web of Science ®Google Scholar
• Andersen SD, Liberti SE, Lutzen A, Drost M, Bernstein I, Nilbert M, Dominguez M, Nyström M, Hansen TV, Christoffersen JW, et al. Functional characterization of MLH1 missense variants identified in Lynch syndrome patients. Hum Mutat 2012; 33:1647-55; PMID:22753075; https://doi.org/10.1002/humu.22153
   PubMed Web of Science ®Google Scholar
• Kadyrov FA, Dzantiev L, Constantin N, Modrich P. Endonucleolytic function of MutLalpha in human mismatch repair. Cell 2006; 126:297-308; PMID:16873062; https://doi.org/10.1016/j.cell.2006.05.039
   PubMed Web of Science ®Google Scholar
• Modrich P. Mechanisms in eukaryotic mismatch repair. J Biol Chem 2006; 281:30305-9; PMID:16905530; https://doi.org/10.1074/jbc.R600022200
   PubMed Web of Science ®Google Scholar
• Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol 2006; 7:335-46; PMID:16612326; https://doi.org/10.1038/nrm1907
   PubMed Web of Science ®Google Scholar
• Provenzale D, Gupta S, Ahnen DJ, Bray T, Cannon JA, Cooper G, David DS, Early DS, Erwin D, Ford JM, et al. Genetic/Familial High-Risk Assessment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2016; 14:1010-30; PMID:27496117; https://doi.org/10.6004/jnccn.2016.0108
   PubMed Web of Science ®Google Scholar
• Sijmons RH, Greenblatt MS, Genuardi M. Gene variants of unknown clinical significance in Lynch syndrome. An introduction for clinicians. Fam Cancer 2013; 12:181-7; PMID:23525798; https://doi.org/10.1007/s10689-013-9629-8
   PubMed Web of Science ®Google Scholar
• Eshleman JR, Markowitz SD. Mismatch repair defects in human carcinogenesis. Hum Mol Genet 1996; 5(Spec No):1489-94; PMID:8875255; https://doi.org/10.1093/hmg/5.Supplement_1.1489
   PubMed Web of Science ®Google Scholar
• Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013; 39:1-10; PMID:23890059; https://doi.org/10.1016/j.immuni.2013.07.012
   PubMed Web of Science ®Google Scholar
• Thompson BA, Greenblatt MS, Vallee MP, Herkert JC, Tessereau C, Young EL, Adzhubey IA, Li B, Bell R, Feng B, et al. Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions. Hum Mutat 2013; 34:255-65; PMID:22949387; https://doi.org/10.1002/humu.22214
   PubMed Web of Science ®Google Scholar
• Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 2003; 31:3812-4; PMID:12824425; https://doi.org/10.1093/nar/gkg509
   PubMed Web of Science ®Google Scholar
• Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7:248-9; PMID:20354512; https://doi.org/10.1038/nmeth0410-248
   PubMed Web of Science ®Google Scholar
• Reva B, Antipin Y, Sander C. Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res 2011; 39:e118; PMID:21727090; https://doi.org/10.1093/nar/gkr407
   PubMed Web of Science ®Google Scholar
• Niroula A, Vihinen M. Variation Interpretation Predictors: Principles, Types, Performance, and Choice. Hum Mutat 2016; 37:579-97; PMID:26987456; https://doi.org/10.1002/humu.22987
   PubMed Web of Science ®Google Scholar
• Grimm DG, Azencott CA, Aicheler F, Gieraths U, MacArthur DG, Samocha KE, Cooper DN, Stenson PD, Daly MJ, Smoller JW, et al. The evaluation of tools used to predict the impact of missense variants is hindered by two types of circularity. Hum Mutat 2015; 36:513-23; PMID:25684150; https://doi.org/10.1002/humu.22768
   PubMed Web of Science ®Google Scholar
• Chao EC, Velasquez JL, Witherspoon MS, Rozek LS, Peel D, Ng P, Gruber SB, Watson P, Rennert G, Anton-Culver H, et al. Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Hum Mutat 2008; 29:852-60; PMID:18383312; https://doi.org/10.1002/humu.20735
   PubMed Web of Science ®Google Scholar
• Terui H, Akagi K, Kawame H, Yura K. CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein. J Biomed Sci 2013; 20:25; PMID:23621914; https://doi.org/10.1186/1423-0127-20-25
   PubMed Web of Science ®Google Scholar
• Niroula A, Vihinen M. Classification of Amino Acid Substitutions in Mismatch Repair Proteins Using PON-MMR2. Hum Mutat 2015; 36:1128-34; PMID:26333163; https://doi.org/10.1002/humu.22900
   PubMed Web of Science ®Google Scholar
• Lin DP, Wang Y, Scherer SJ, Clark AB, Yang K, Avdievich E, Jin B, Werling U, Parris T, Kurihara N, et al. An Msh2 point mutation uncouples DNA mismatch repair and apoptosis. Cancer Res 2004; 64:517-22; PMID:14744764; https://doi.org/10.1158/0008-5472.CAN-03-2957
   PubMed Web of Science ®Google Scholar
• Drotschmann K, Topping RP, Clodfelter JE, Salsbury FR. Mutations in the nucleotide-binding domain of MutS homologs uncouple cell death from cell survival. DNA Repair (Amst) 2004; 3:729-42; PMID:15177182; https://doi.org/10.1016/j.dnarep.2004.02.011
   PubMed Web of Science ®Google Scholar
• Arora S, Yan H, Cho I, Fan HY, Luo B, Gai X, Bodian DL, Vockley JG, Zhou Y, Handorf EA, et al. Genetic Variants That Predispose to DNA Double-Strand Breaks in Lymphocytes From a Subset of Patients With Familial Colorectal Carcinomas. Gastroenterology 2015; 149:1872-83 e9; PMID:26344056; https://doi.org/10.1053/j.gastro.2015.08.052
   PubMed Web of Science ®Google Scholar
• Nicolas E, Arora S, Zhou Y, Serebriiskii IG, Andrake MD, Handorf ED, Bodian DL, Vockley JG, Dunbrack RL, Ross EA, et al. Systematic evaluation of underlying defects in DNA repair as an approach to case-only assessment of familial prostate cancer. Oncotarget 2015; 6:39614-33; PMID:26485759; https://doi.org/10.18632/oncotarget.5554
   PubMed Web of Science ®Google Scholar
• Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 2015; 31:2745-7; PMID:25851949; https://doi.org/10.1093/bioinformatics/btv195
   PubMed Web of Science ®Google Scholar
• Wei Q, Xu Q, Dunbrack RL, Jr. Prediction of phenotypes of missense mutations in human proteins from biological assemblies. Proteins 2013; 81:199-213; PMID:22965855; https://doi.org/10.1002/prot.24176
   PubMed Web of Science ®Google Scholar
• Schymkowitz J, Borg J, Stricher F, Nys R, Rousseau F, Serrano L. The FoldX web server: an online force field. Nucleic Acids Res 2005; 33:W382-8; PMID:15980494; https://doi.org/10.1093/nar/gki387
   PubMed Web of Science ®Google Scholar
• Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009; 37:e67; PMID:19339519; https://doi.org/10.1093/nar/gkp215
   PubMed Web of Science ®Google Scholar
• Halvorsen M, Martin JS, Broadaway S, Laederach A. Disease-associated mutations that alter the RNA structural ensemble. PLoS Genet 2010; 6:e1001074; PMID:20808897; https://doi.org/10.1371/journal.pgen.1001074
   PubMed Web of Science ®Google Scholar
• Zuker M. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 2003; 31:3406-15; PMID:12824337; https://doi.org/10.1093/nar/gkg595
   PubMed Web of Science ®Google Scholar
• Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS. Structure of the human MutSalpha DNA lesion recognition complex. Mol Cell 2007; 26:579-92; PMID:17531815; https://doi.org/10.1016/j.molcel.2007.04.018
   PubMed Web of Science ®Google Scholar
• Krieger E, Koraimann G, Vriend G. Increasing the precision of comparative models with YASARA NOVA–a self-parameterizing force field. Proteins 2002; 47:393-402; PMID:11948792; https://doi.org/10.1002/prot.10104
   PubMed Web of Science ®Google Scholar
• Soding J, Biegert A, Lupas AN. The HHpred interactive server for protein homology detection and structure prediction. Nucleic Acids Res 2005; 33:W244-8; PMID:15980461; https://doi.org/10.1093/nar/gki408
   PubMed Web of Science ®Google Scholar
• Perevoztchikova SA, Romanova EA, Oretskaya TS, Friedhoff P, Kubareva EA. Modern aspects of the structural and functional organization of the DNA mismatch repair system. Acta Naturae 2013; 5:17-34; PMID:24303200
   PubMed Web of Science ®Google Scholar
• Krivov GG, Shapovalov MV, Dunbrack RL, Jr. Improved prediction of protein side-chain conformations with SCWRL4. Proteins 2009; 77:778-95; PMID:19603484; https://doi.org/10.1002/prot.22488
   PubMed Web of Science ®Google Scholar
• Guarne A, Junop MS, Yang W. Structure and function of the N-terminal 40 kDa fragment of human PMS2: a monomeric GHL ATPase. EMBO J 2001; 20:5521-31; PMID:11574484; https://doi.org/10.1093/emboj/20.19.5521
   PubMed Web of Science ®Google Scholar
• Wu H, Zeng H, Lam R, Tempel W, Kerr ID, Min J. Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome. Acta Crystallogr F Struct Biol Commun 2015; 71:981-5; PMID:26249686; https://doi.org/10.1107/S2053230X15010183
   PubMed Web of Science ®Google Scholar
• Graham FL, Smiley J, Russell WC, Nairn R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol 1977; 36:59-74; PMID:886304; https://doi.org/10.1099/0022-1317-36-1-59
   PubMed Web of Science ®Google Scholar
• Heinen CD, Juel Rasmussen L. Determining the functional significance of mismatch repair gene missense variants using biochemical and cellular assays. Hered Cancer Clin Pract 2012; 10:9; PMID:22824075; https://doi.org/10.1186/1897-4287-10-9
   PubMed Web of Science ®Google Scholar
• Cyr JL, Heinen CD. Hereditary cancer-associated missense mutations in hMSH6 uncouple ATP hydrolysis from DNA mismatch binding. J Biol Chem 2008; 283:31641-8; PMID:18790734; https://doi.org/10.1074/jbc.M806018200
   PubMed Web of Science ®Google Scholar
• Cyr JL, Brown GD, Stroop J, Heinen CD. The predicted truncation from a cancer-associated variant of the MSH2 initiation codon alters activity of the MSH2-MSH6 mismatch repair complex. Mol Carcinog 2012; 51:647-58; PMID:21837758; https://doi.org/10.1002/mc.20838
   PubMed Web of Science ®Google Scholar
• Trojan J, Zeuzem S, Randolph A, Hemmerle C, Brieger A, Raedle J, Plotz G, Jiricny J, Marra G. Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. Gastroenterology 2002; 122:211-9; PMID:11781295; https://doi.org/10.1053/gast.2002.30296
   PubMed Web of Science ®Google Scholar
• Brieger A, Trojan J, Raedle J, Plotz G, Zeuzem S. Transient mismatch repair gene transfection for functional analysis of genetic hMLH1 and hMSH2 variants. Gut 2002; 51:677-84; PMID:12377806; https://doi.org/10.1136/gut.51.5.677
   PubMed Web of Science ®Google Scholar
• Perera S, Bapat B. The MLH1 variants p.Arg265Cys and p.Lys618Ala affect protein stability while p.Leu749Gln affects heterodimer formation. Hum Mutat 2008; 29:332; PMID:18205192; https://doi.org/10.1002/humu.9523
   PubMed Web of Science ®Google Scholar
• Mastrocola AS, Heinen CD. Lynch syndrome-associated mutations in MSH2 alter DNA repair and checkpoint response functions in vivo. Hum Mutat 2010; 31:E1699-708; PMID:20672385; https://doi.org/10.1002/humu.21333
   PubMed Web of Science ®Google Scholar
• Blasi MF, Ventura I, Aquilina G, Degan P, Bertario L, Bassi C, Radice P, Bignami M. A human cell-based assay to evaluate the effects of alterations in the MLH1 mismatch repair gene. Cancer Res 2006; 66:9036-44; PMID:16982745; https://doi.org/10.1158/0008-5472.CAN-06-1896
   PubMed Web of Science ®Google Scholar
• Watanabe Y, Haugen-Strano A, Umar A, Yamada K, Hemmi H, Kikuchi Y, Takano S, Shibata Y, Barrett JC, Kunkel TA, et al. Complementation of an hMSH2 defect in human colorectal carcinoma cells by human chromosome 2 transfer. Mol Carcinog 2000; 29:37-49; PMID:11020245; https://doi.org/10.1002/1098-2744(200009)29:1%3c37::AID-MC5%3e3.0.CO;2-210.1002/1098-2744(200009)29:1%3c37::AID-MC5%3e3.3.CO;2-U
   PubMed Web of Science ®Google Scholar
• Imesch P, Goerens A, Fink D, Fedier A. MLH1-deficient HCT116 colon tumor cells exhibit resistance to the cytostatic and cytotoxic effect of the poly(A) polymerase inhibitor cordycepin (3′-deoxyadenosine) in vitro. Oncol Lett 2012; 3:441-4; PMID:22740928; https://doi.org/10.3892/ol.2011.504
   PubMed Web of Science ®Google Scholar
• Ma AH, Xia L, Littman SJ, Swinler S, Lader G, Polinkovsky A, Olechnowicz J, Kasturi L, Lutterbaugh J, Modrich P, et al. Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability. Oncogene 2000; 19:2249-56; PMID:10822375; https://doi.org/10.1038/sj.onc.1203568
   PubMed Web of Science ®Google Scholar
• Glaab WE, Risinger JI, Umar A, Barrett JC, Kunkel TA, Tindall KR. Cellular resistance and hypermutability in mismatch repair-deficient human cancer cell lines following treatment with methyl methanesulfonate. Mutat Res 1998; 398:197-207; PMID:9626980; https://doi.org/10.1016/S0027-5107(98)00004-9
   PubMed Web of Science ®Google Scholar
• Li LS, Morales JC, Veigl M, Sedwick D, Greer S, Meyers M, Wagner M, Fishel R, Boothman DA. DNA mismatch repair (MMR)-dependent 5-fluorouracil cytotoxicity and the potential for new therapeutic targets. Br J Pharmacol 2009; 158:679-92; PMID:19775280; https://doi.org/10.1111/j.1476-5381.2009.00423.x
   PubMed Web of Science ®Google Scholar
• Cersosimo RJ. Management of advanced colorectal cancer, Part 1. Am J Health Syst Pharm 2013; 70:395-406; PMID:23413162; https://doi.org/10.2146/ajhp11053210.2146/ajhp110532b
   PubMed Web of Science ®Google Scholar
• Pabla N, Ma Z, McIlhatton MA, Fishel R, Dong Z. hMSH2 recruits ATR to DNA damage sites for activation during DNA damage-induced apoptosis. J Biol Chem 2011; 286:10411-8; PMID:21285353; https://doi.org/10.1074/jbc.M110.210989
   PubMed Web of Science ®Google Scholar
• Meyers M, Hwang A, Wagner MW, Bruening AJ, Veigl ML, Sedwick WD, Boothman DA. A role for DNA mismatch repair in sensing and responding to fluoropyrimidine damage. Oncogene 2003; 22:7376-88; PMID:14576845; https://doi.org/10.1038/sj.onc.1206941
   PubMed Web of Science ®Google Scholar
• Luo Y, Lin FT, Lin WC. ATM-mediated stabilization of hMutL DNA mismatch repair proteins augments p53 activation during DNA damage. Mol Cell Biol 2004; 24:6430-44; PMID:15226443; https://doi.org/10.1128/MCB.24.14.6430-6444.2004
   PubMed Web of Science ®Google Scholar
• Marechal A, Zou L. DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol 2013; 5:a012716; PMID:24003211; https://doi.org/10.1101/cshperspect.a012716
   PubMed Web of Science ®Google Scholar
• Weber AM, Ryan AJ. ATM and ATR as therapeutic targets in cancer. Pharmacol Ther 2015; 149:124-38; PMID:25512053; https://doi.org/10.1016/j.pharmthera.2014.12.001
   PubMed Web of Science ®Google Scholar
• Stojic L, Mojas N, Cejka P, Di Pietro M, Ferrari S, Marra G, Jiricny J. Mismatch repair-dependent G2 checkpoint induced by low doses of SN1 type methylating agents requires the ATR kinase. Genes Dev 2004; 18:1331-44; PMID:15175264; https://doi.org/10.1101/gad.294404
   PubMed Web of Science ®Google Scholar
• Plys AJ, Rogacheva MV, Greene EC, Alani E. The unstructured linker arms of Mlh1-Pms1 are important for interactions with DNA during mismatch repair. J Mol Biol 2012; 422:192-203; PMID:22659005; https://doi.org/10.1016/j.jmb.2012.05.030
   PubMed Web of Science ®Google Scholar
• Hamid FM, Makeyev EV. Emerging functions of alternative splicing coupled with nonsense-mediated decay. Biochem Soc Trans 2014; 42:1168-73; PMID:25110020; https://doi.org/10.1042/BST20140066
   PubMed Web of Science ®Google Scholar
• Klaff P, Riesner D, Steger G. RNA structure and the regulation of gene expression. Plant Mol Biol 1996; 32:89-106; PMID:8980476; https://doi.org/10.1007/BF00039379
   PubMed Web of Science ®Google Scholar
• Rasmussen LJ, Heinen CD, Royer-Pokora B, Drost M, Tavtigian S, Hofstra RM, de Wind N. Pathological assessment of mismatch repair gene variants in Lynch syndrome: past, present, and future. Hum Mutat 2012; 33:1617-25; PMID:22833534; https://doi.org/10.1002/humu.22168
   PubMed Web of Science ®Google Scholar
• Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capellá G, den Dunnen JT, et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet 2014; 46:107-15; PMID:24362816; https://doi.org/10.1038/ng.2854
   PubMed Web of Science ®Google Scholar
• Wei Q, Dunbrack RL, Jr. The role of balanced training and testing data sets for binary classifiers in bioinformatics. PLoS One 2013; 8:e67863; PMID:23874456; https://doi.org/10.1371/journal.pone.0067863
   PubMed Web of Science ®Google Scholar
• Al-Sukhni W, Aronson M, Gallinger S. Hereditary colorectal cancer syndromes: familial adenomatous polyposis and lynch syndrome. Surg Clin North Am 2008; 88:819-44, vii; PMID:18672142; https://doi.org/10.1016/j.suc.2008.04.012
   PubMed Web of Science ®Google Scholar
• Giannini G, Ristori E, Cerignoli F, Rinaldi C, Zani M, Viel A, Ottini L, Crescenzi M, Martinotti S, Bignami M, et al. Human MRE11 is inactivated in mismatch repair-deficient cancers. EMBO Rep 2002; 3:248-54; PMID:11850399; https://doi.org/10.1093/embo-reports/kvf044
   PubMed Web of Science ®Google Scholar
• Takemura H, Rao VA, Sordet O, Furuta T, Miao ZH, Meng L, Zhang H, Pommier Y. Defective Mre11-dependent activation of Chk2 by ataxia telangiectasia mutated in colorectal carcinoma cells in response to replication-dependent DNA double strand breaks. J Biol Chem 2006; 281:30814-23; PMID:16905549; https://doi.org/10.1074/jbc.M603747200
   PubMed Web of Science ®Google Scholar
• Bali V, Bebok Z. Decoding mechanisms by which silent codon changes influence protein biogenesis and function. Int J Biochem Cell Biol 2015; 64:58-74; PMID:25817479; https://doi.org/10.1016/j.biocel.2015.03.011
   PubMed Web of Science ®Google Scholar
• Hunt RC, Simhadri VL, Iandoli M, Sauna ZE, Kimchi-Sarfaty C. Exposing synonymous mutations. Trends Genet 2014; 30:308-21; PMID:24954581; https://doi.org/10.1016/j.tig.2014.04.006
   PubMed Web of Science ®Google Scholar