PMS2 Pathogenic Variant in Lynch Syndrome-Associated Colorectal Cancer with Polyps

Abstract

Background Lynch syndrome (LS) is an autosomal dominant condition due to the germline mutation in the mismatch repair (MMR) genes including MLH1, MSH2, MSH6, and PMS2 (post-meiotic segregation increased 2). The MMR mutation carriers have high risk for cancers. Pathogenic PMS2 variants are rarely reported in LS-associated colorectal cancer (CRC) with colorectal polyps. The aim of the study was to investigate the genetic etiology of CRC in an individual with CRC with multiple colorectal polyps and a family history of cancers.Patients and Methods The index patient was an African male affected by CRC with multiple colorectal polyps. The clinical diagnostic for LS was based on the Amsterdam II criteria and pedigree. Next-generation sequencing with inherited cancer genes panel was used to detect the pathogenic variant.Results The patient fulfilled the Amsterdam II criteria and the pedigree revealed a family history of recurrent CRC. A deleterious PMS2 germline heterozygous mutation c.2192_2196delTAACT was detected.Conclusion Our study supports the notion that LS may be associated with polyps and shows the predisposition of PMS2 heterozygous mutation in LS-associated CRC at young age.

Keywords

lynch syndrome / PMS2 deficiency / mismatch repair gene / colorectal cancer

References

[1] Lepore Signorile M, Disciglio V, Di Carlo G, Pisani A, Simone C, Ingravallo G. From genetics to histomolecular characterization: an insight into colorectal carcinogenesis in Lynch syndrome. Int J Mol Sci 2021;22(13):6767

[2] Bucksch K, Zachariae S, Aretz S, et al; German Consortium for Familial Intestinal Cancer. Cancer risks in Lynch syndrome, Lynchlike syndrome, and familial colorectal cancer type X: a prospective cohort study. BMC Cancer 2020;20(01):460

[3] Rosenblum RE, Ang C, Suckiel SA, et al. Lynch syndrome-associated variants and cancer rates in an ancestrally diverse biobank. JCO Precis Oncol 2020;4(04):1429-1444

[4] Roberts ME, Jackson SA, Susswein LR, et al. MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med 2018;20(10): 1167-1174

[5] Bernstedt SW, Björk J, Fritzell K, Spigelman AD, Björck E, Backman AS. Roomfor improvement: one third of Lynch syndrome patients presenting for genetic testing in a highly specialised centre in Stockholm already have cancer. Hered Cancer Clin Pract 2021;19(01):18

[6] Poaty H, Aba Gandzion C, Soubeyran I, et al. The identification of Lynch syndrome in Congolese colorectal cancer patients. Bull Cancer 2017;104(10):831-839

[7] Niessen RC, Kleibeuker JH,Westers H, et al. PMS2 involvement in patients suspected of Lynch syndrome. Genes Chromosomes Cancer 2009;48(04):322-329

[8] Senter L, Clendenning M, Sotamaa K, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 2008;135(02):419-428

[9] Ramchander NC, Ryan NAJ, Crosbie EJ, Evans DG. Homozygous germ-line mutation of the PMS2 mismatch repair gene: a unique case report of constitutional mismatch repair deficiency (CMMRD). BMC Med Genet 2017;18(01):40

[10] Poaty H, Batamba Bouya L, Ondima IPL, et al. BMPR1A and SMAD4 mutations in juvenile polyposis syndrome: clinicopathological and genetic data from two congolese patients. Gene Rep 2021; 23:101141

[11] Blount J, Prakash A. The changing landscape of Lynch syndrome due to PMS2 mutations. Clin Genet 2018;94(01):61-69

[12] Zhu F, Pan D, Zhang H, Ye Q, Xu P, Pan J. Single-center study of Lynch syndrome screening in colorectal polyps. Hered Cancer Clin Pract 2019;17:9

[13] Burt RW. Colonic polyps in lynch syndrome. Dis Colon Rectum 2015;58(04):371-372

[14] Eleftheriadis N, Inoue H, Ikeda H, Onimaru M, Maselli R, Kudo SE. Polyps in Lynch syndrome. Differences in quality of colonoscopy between Western and Eastern endoscopists. Endoscopy 2015;47(01):89

[15] Guindalini RS, Win AK, Gulden C, et al. Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome. Gastroenterology 2015;149(06):1446-1453

[16] Talseth-Palmer BA, McPhillips M, Groombridge C, Spigelman A, Scott RJ. MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract 2010;8(01):5

[17] Worthley DL, Walsh MD, Barker M, et al. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology 2005;128(05):1431-1436

[18] Wang Q, Leclerc J, Bougeard G, et al; French Consortium of Oncogenetic laboratories for colorectal cancers, Unicancer Cancer Genetic Group (GGC) Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome. J Med Genet 2020;57(07):487-499

[19] van der Klift HM,Mensenkamp AR, Drost M, et al. Comprehensive mutation analysis of PMS2 in a large cohort of probands suspected of Lynch syndrome or constitutional mismatch repair deficiency syndrome. Hum Mutat 2016;37(11):1162-1179

[20] Goodenberger ML, Thomas BC, Riegert-Johnson D, et al. PMS2 monoallelic mutation carriers: the known unknown. Genet Med 2016;18(01):13-19

[21] Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005;352(18):1851-1860

[22] Nakagawa H, Lockman JC, Frankel WL, et al. Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. Cancer Res 2004;64(14):4721-4727

[23] Dominguez-Valentin M, Sampson JR, Seppälä TT, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the prospective Lynch syndrome database. Genet Med 2020;22(01):15-25

[24] Liu YL, Cadoo KA, Maio A, et al. Early age of onset and broad cancer spectrum persist in MSH6- and PMS2-associated Lynch syndrome. Genet Med 2022;24(06):1187-1195

[25] Guo X, Wu W, Gao H, et al. PMS2 germline mutation c.943C>T (p. Arg315_)-induced Lynch syndrome-associated ovarian cancer. Mol Genet Genomic Med 2019;7(06):e721

[26] Sheehan M, Heald B, Yanda C, et al. Investigating the link between Lynch syndrome and breast cancer. Eur J Breast Health 2020;16(02):106-109

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