Significance of rare variants in genes involved in the pathogenesis of Lynch syndrome

Liccardo,Raffaella; Lambiase,Matilde; Nolano,Antonio; De Rosa,Marina; Izzo,Paola; Duraturo,Francesca

doi:10.3892/ijmm.2022.5137

Significance of rare variants in genes involved in the pathogenesis of Lynch syndrome

Authors:
- Raffaella Liccardo
- Matilde Lambiase
- Antonio Nolano
- Marina De Rosa
- Paola Izzo
- Francesca Duraturo
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Affiliations: Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, I‑80131 Napoli, Italy
Published online on: April 26, 2022 https://doi.org/10.3892/ijmm.2022.5137
Article Number: 81
Copyright: © Liccardo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The molecular characterization of patients with Lynch syndrome (LS) involves germline testing to detect a deleterious mutation in one of the genes of the mismatch repair (MMR) pathway. To date, however, a large proportion of patients with a clinical suspicion of LS who undergo genetic testing do not show a germline pathogenetic variant in these genes. Germline DNA from 73 patients with a clinical suspicion of LS was examined with next‑generation sequencing methods, using a multigene custom panel designed and standardized by our research group, that targets a set of 15 genes. Deleterious variants were identified in 5.6% of index cases, while unclassified variants were identified in 80.3% of probands. To evaluate the pathogenicity of these uncertain variants, the American College of Medical Genetics and Genomics criteria was used, also considering wherever possible the microsatellite instability (MSI) status detected on tumor tissues as pathogenic criterion. In this manner, 8 of these uncertain significance variants were classified as likely pathogenic variants. Notably, some of these likely pathogenetic variants were also identified in the MLH3 gene that is a gene not routinely analyzed for cases with a clinical suspicion of LS. The present study highlighted the importance of verifying the pathogenicity of the numerous variants of unknown significance identified in patients for whom heredity is already clinically confirmed suggesting the importance of considering the MSI‑H status on the tumor of patients carrying an uncertain variant to evaluate its pathogenicity. Moreover, the present study also suggested analyzing other MMR genes, such as MLH3, in panels used for the molecular screening of LS.

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1	Jasperson KW, Tuohy TM, Neklason DW and Burt RW: Hereditary and familial colon cancer. Gastroenterology. 138:2044–2058. 2010. View Article : Google Scholar : PubMed/NCBI
2	Kohlmann W: Lynch syndrome and breast cancer risk: Weighing the data. JCO Precis Oncol. Feb 26–2020.Epub ahead of print. View Article : Google Scholar
3	Cerretelli G, Ager A, Arends MJ and Frayling IM: Molecular pathology of lynch syndrome. J Pathol. 250:518–531. 2020. View Article : Google Scholar : PubMed/NCBI
4	Dodaro C, Grifasi C, Florio J, Santangelo ML, Duraturo F, De Rosa M, Izzo P and Renda A: The role of mutation analysis of the APC gene in the management of FAP patients. A controversial issue. Ann Ital Chir. 87:321–325. 2016.PubMed/NCBI
5	Duraturo F, Liccardo R, De Rosa M and Izzo P: Genetics, diagnosis and treatment of lynch syndrome: Old lessons and current challenges. Oncol Lett. 17:3048–3054. 2019.
6	Duraturo F, Liccardo R, Cavallo A, De Rosa M, Rossi GB and Izzo P: Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability. Int J Mol Med. 36:511–517. 2015. View Article : Google Scholar : PubMed/NCBI
7	Liccardo R, De Rosa M, Rossi GB, Carlomagno N, Izzo P and Duraturo F: Incomplete segregation of MSH6 frameshift variants with phenotype of lynch syndrome. Int J Mol Sci. 18:9992017. View Article : Google Scholar :
8	Liccardo R, De Rosa M, Izzo P and Duraturo F: Novel MSH2 splice-site mutation in a young patient with lynch syndrome. Mol Med Rep. 17:6942–6946. 2018.
9	Liccardo R, Della Ragione C, Mitilini N, De Rosa M, Izzo P and Duraturo F: Novel variants of unknown significance in the PMS2 gene identified in patients with hereditary colon cancer. Cancer. Manag Res. 18:6719–6725. 2019.
10	Liccardo R, De Rosa M, Izzo P and Duraturo F: Novel implications in molecular diagnosis of lynch syndrome. Gastroenterol Res Pract. 2017:25950982017. View Article : Google Scholar : PubMed/NCBI
11	Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, Church JM, Dominitz JA, Johnson DA, Kaltenbach T, et al: Guidelines on genetic evaluation and management of lynch syndrome: A consensus statement by the US multi-society task force on colorectal cancer. Gastroenterology. 147:502–526. 2014. View Article : Google Scholar
12	Duraturo F, Cavallo A, Liccardo R, Cudia B, De Rosa M, Diana G and Izzo P: Contribution of large genomic rearrangements in italian lynch syndrome patients: Characterization of a novel Alu-mediated deletion. Biomed Res Int. 2013:2198972013. View Article : Google Scholar : PubMed/NCBI
13	Tognetto A, Pastorino R, Castorina S, Condorelli DF, DeCensi A, De Vito C, Magnano A, Scaldaferri F, Villari P, Genuardi M and Boccia S: The current practice of lynch syndrome diagnosis and management in Italy: A qualitative assessment. Public Health Genomics. 22:189–207. 2019. View Article : Google Scholar : PubMed/NCBI
14	Lynch PM: The hMSH2 and hMLH1 genes in hereditary nonpolyposis colorectal cancer. Surg Oncol Clin N Am. 18:611–624. 2009. View Article : Google Scholar
15	Hendriks YM, Wagner A, Morreau H, Menko F, Stormorken A, Quehenberger F, Sandkuijl L, Møller P, Genuardi M, Van Houwelingen H, et al: Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: Impact on counseling and surveillance. Gastroenterology. 127:17–25. 2004. View Article : Google Scholar : PubMed/NCBI
16	Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, Lindblom A, Lagerstedt K, Thibodeau SN, Lindor NM, et al: The clinical phenotype of lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 135:419–428. 2008. View Article : Google Scholar : PubMed/NCBI
17	Wu Y, Berends MJ, Sijmons RH, Mensink RG, Verlind E, Kooi KA, van der Sluis T, Kempinga C, van dDer Zee AG, Hollema H, et al: A role for MLH3 in hereditary nonpolyposis colorectal cancer. Nat Genet. 29:137–138. 2001. View Article : Google Scholar
18	Moreira L, Balaguer F, Lindor N, de la Chapelle A, Hampel H, Aaltonen LA, Hopper JL, Le Marchand L, Gallinger S, Newcomb PA, et al: Identification of lynch syndrome among patients with colorectal cancer. JAMA. 17:1555–1565. 2012. View Article : Google Scholar
19	Gupta S, Provenzale D, Llor X, Halverson AL, Grady W, Chung DC, Haraldsdottir S, Markowitz AJ, Slavin TP Jr, Hampel H, et al: NCCN guidelines insights: Genetic/familial high-risk assessment: Colorectal, version 2. 2019.J Natl Compr Canc Netw. 17:1032–1041. 2019. View Article : Google Scholar : PubMed/NCBI
20	Vasen HF, Mecklin JP, Khan PM and Lynch HT: The International collaborative group on hereditary non-polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum. 34:424–425. 1991. View Article : Google Scholar : PubMed/NCBI
21	Vasen HF, Watson P, Mecklin JP and Lynch HT: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) Proposed By the International Collaborative Group on HNPCC. Gastroenterology. 116:1453–1456. 1999. View Article : Google Scholar
22	Gonzaga-Jauregui C, Lupski JR and Gibbs RA: Human genome sequencing in health and disease. Annu Rev Med. 63:35–61. 2012. View Article : Google Scholar : PubMed/NCBI
23	Turano M, Costabile V, Cerasuolo A, Duraturo F, Liccardo R, Delrio P, Pace U, Rega D, Dodaro CA, Milone M, et al: Characterisation of mesenchymal colon tumour-derived cells in tumourspheres as a model for colorectal cancer progression. Int J Oncol. 53:2379–2396. 2018.
24	Fecteau H, Vogel KJ, Hanson K and Morrill-Cornelius S: The evolution of cancer risk assessment in the era of next generation sequencing. J Genet Couns. 23:633–639. 2014. View Article : Google Scholar : PubMed/NCBI
25	Mardis ER: A decade's perspective on DNA sequencing technology. Nature. 470:198–203. 2011. View Article : Google Scholar : PubMed/NCBI
26	Lin EI, Tseng LH, Gocke CD, Reil S, Le DT, Azad NS and Eshleman JR: Mutational profiling of colorectal cancers with microsatellite instability. Oncotarget. 6:42334–42344. 2015. View Article : Google Scholar
27	Kim JC, Choi JS, Roh SA, Cho DH, Kim TW and Kim YS: Promoter methylation of specific genes is associated with the phenotype and progression of colorectal adenocarcinomas. Ann Surg Oncol. 17:1767–1776. 2010. View Article : Google Scholar : PubMed/NCBI
28	Liu C, Wang QS and Wang YJ: The CHEK2 I157T variant and colorectal cancer susceptibility: A systematic review and meta-analysis. Asian Pac J Cancer Prev. 13:2051–2055. 2012. View Article : Google Scholar
29	Han P, Liu G, Lu X, Cao M, Yan Y, Zou J, Li X and Wang G: CDH1 rs9929218 Variant at 16q22.1 contributes to colorectal cancer susceptibility. Oncotarget. 26:47278–47286. 2016. View Article : Google Scholar
30	Shenoy S: CDH1 (E-Cadherin) mutation and gastric cancer: Genetics, molecular mechanisms and guidelines for management. Cancer Manag Res. 13:10477–10486. 2019. View Article : Google Scholar
31	Elzagheid A, Buhmeida A, Laato M, El-Faitori O, Syrjänen K, Collan Y and Pyrhönen S: Loss of E-cadherin expression predicts disease recurrence and shorter survival in colorectal carcinoma. APMIS. 120:539–548. 2012. View Article : Google Scholar : PubMed/NCBI
32	Berndt SI, Platz EA, Fallin MD, Thuita LW, Hoffman SC and Helzlsouer KJ: Mismatch repair polymorphisms and the risk of colorectal cancer. Int J Cancer. 120:1548–1554. 2007. View Article : Google Scholar : PubMed/NCBI
33	Orimo H, Nakajima E, Yamamoto M, Ikejima M, Emi M and Shimada T: Association between single nucleotide polymorphisms in the hMSH3 gene and sporadic colon cancer with microsatellite instability. J Hum Genet. 45:228–230. 2000. View Article : Google Scholar
34	Jafary F, Salehi M, Sedghi M, Nouri N, Jafary F, Sadeghi F, Motamedi S and Talebi M: Association between mismatch repair gene MSH3 Codons 1036 and 222 polymorphisms and sporadic prostate cancer in the Iranian population. Asian Pac J Cancer Prev. 13:6055–6057. 2012. View Article : Google Scholar : PubMed/NCBI
35	Duraturo F, Liccardo R, Cavallo A, De Rosa M, Grosso M and Izzo P: Association of low-risk MSH3 and MSH2 variant alleles with lynch syndrome: Probability of synergistic effects. Int J Cancer. 129:1643–1650. 2011. View Article : Google Scholar
36	Adam R, Spier I, Zhao B, Kloth M, Marquez J, Hinrichsen I, Kirfel J, Tafazzoli A, Horpaopan S, Uhlhaas S, et al: Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis. Am J Hum Genet. 99:337–351. 2016. View Article : Google Scholar : PubMed/NCBI
37	Olkinuora A, Nieminen TT, Mårtensson E, Rohlin A, Ristimäki A, Koskenvuo L, Lepistö A; Swedish Extended Genetic Analysis of Colorectal Neoplasia (SWEN) Study Group; Gebre-Medhin S, Nordling M and Peltomäki P: Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition. Genet Med. 21:1868–1873. 2019. View Article : Google Scholar
38	Duraturo F, Liccardo R and Izzo P: Coexistence of MLH3 germline variants in colon cancer patients belonging to families with lynch syndrome-associated brain tumors. J Neurooncol. 129:577–578. 2016. View Article : Google Scholar : PubMed/NCBI
39	Titze S, Peters H, Währisch S, Harder T, Guse K, Buske A, Tinschert S and Harder A: Differential MSH2 promoter methylation in blood cells of Neurofibromatosis type 1 (NF1) patients. Eur J Hum Genet. 18:81–87. 2010. View Article : Google Scholar :
40	Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al: Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of medical genetics and genomics and the association for molecular pathology. Genet Med. 17:405–424. 2015. View Article : Google Scholar :
41	Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M and Béroud C: Human splicing finder: An online bio-informatics tool to predict splicing signals. Nucleic Acids Res. 37:e672009. View Article : Google Scholar
42	Ramensky V, Bork P and Sunyaev S: Human non-synonymous SNPs: Server and survey. Nucleic Acids Res. 30:3894–3900. 2002. View Article : Google Scholar : PubMed/NCBI
43	Rost B, Yachdav G and Liu J: The predictprotein server. Nucleic Acids Res. 32:W321–W326. 2004. View Article : Google Scholar :
44	Schwarz JM, Rödelsperger C, Schuelke M and Seelow D: Mutationtaster evaluates disease-causing potential of sequence alterations. Nat Methods. 7:575–576. 2010. View Article : Google Scholar
45	Choi Y, Sims GE, Murphy S, Miller JR and Chan AP: Predicting the functional effect of amino acid substitutions and indels. PLoS One. 7:e466882012. View Article : Google Scholar : PubMed/NCBI
46	Zhunussova G, Afonin G, Abdikerim S, Jumanov A, Perfilyeva A, Kaidarova D and Djansugurova L: Mutation spectrum of cancer-associated genes in patients with early onset of colorectal cancer. Front Oncol. 9:6732019. View Article : Google Scholar :
47	Liccardo R, Nolano A, Lambiase M, Della Ragione C, De Rosa M, Izzo P and Duraturo F: MSH2 overexpression due to an unclassified variant in 3-Untranslated region in a patient with colon cancer. Biomedicines. 8:1672020. View Article : Google Scholar
48	Arora S, Huwe PJ, Sikder R, Shah M, Browne AJ, Lesh R, Nicolas E, Deshpande S, Hall MJ, Dunbrack RL Jr and Golemis EA: Functional analysis of rare variants in mismatch repair proteins augments results from computation-based predictive methods. Cancer Biol Ther. 18:519–533. 2017. View Article : Google Scholar :
49	Jia X, Burugula BB, Chen V, Lemons RM, Jayakody S, Maksutova M and Kitzman JO: Massively parallel functional testing of MSH2 missense variants conferring lynch syndrome risk. Am J Hum Genet. 108:163–175. 2021. View Article : Google Scholar
50	Hegan DC, Narayanan L, Jirik FR, Edelmann W, Liskay RM and Glazer PM: Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6. Carcinogenesis. 27:2402–5408. 2006. View Article : Google Scholar : PubMed/NCBI
51	Loukola A, Vilkki S, Singh J, Launonen V and Aaltonen LA: Germline and somatic mutation analysis of MLH3 in MSI-positive colorectal cancer. Am J Pathol. 157:347–352. 2000. View Article : Google Scholar
52	Turano M, Delrio P, Rega D, Cammarota F, Polverino A, Duraturo F, Izzo P and De Rosa M: Promising colorectal cancer biomarkers for precision prevention and therapy. Cancers (Basel). 11:19322019. View Article : Google Scholar