Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family.

A) may result in either a splice or missense mutation in patients with X-linked severe combined immunodeficiency. Human Genetics, 104(1), 36-42. https://doi.org/10.1007/s004390050907.
Kariola, R., Raevaara, T. E., Lonnqvist, K. E., & Nystrom-Lahti, M. (2002). Functional analysis of MSH6 mutations linked to kindreds with putative hereditary non-polyposis colorectal cancer syndrome. Human Molecular Genetics, 11(11), 1303-1310. https://doi.org/10.1093/hmg/11.11.1303.
Karousis, E. D., & Muhlemann, O. (2019). Nonsense-mediated mRNA decay begins where translation ends. Cold Spring Harbor Perspectives in Biology, 11(2), a032862. https://doi.org/10.1101/cshperspect.a032862.
Klarskov, L., Holck, S., Bernstein, I., Okkels, H., Rambech, E., Baldetorp, B., & Nilbert, M. (2011). Challenges in the identification of MSH6-associated colorectal cancer: Rectal location, less typical histology, and a subset with retained mismatch repair function. The American Journal of Surgical Pathology, 35(9), 1391-1399. https://doi.org/10.1097/PAS.0b013e318225c3f0.
Kuiper, R. P., Vissers, L. E., Venkatachalam, R., Bodmer, D., Hoenselaar, E., Goossens, M., Haufe, A., Kamping, E., Niessen, R. C., Hogervorst, F. B., Gille, J. J., Redeker, B., Tops, C. M., van Gijn, M., van den Ouweland, A., Rahner, N., Steinke, V., Kahl, P., Holinski-Feder, E., … Ligtenberg, M. J. (2011). Recurrence and variability of germline EPCAM deletions in lynch syndrome. Human Mutation, 32(4), 407-414. https://doi.org/10.1002/humu.21446.
Kunkel, T. A., & Erie, D. A. (2005). DNA mismatch repair. Annual Review of Biochemistry, 74, 681-710. https://doi.org/10.1146/annurev.biochem.74.082803.133243.
Kurosaki, T., Popp, M. W., & Maquat, L. E. (2019). Quality and quantity control of gene expression by nonsense-mediated mRNA decay. Nature Reviews. Molecular Cell Biology, 20(7), 406-420. https://doi.org/10.1038/s41580-019-0126-2.
Latham, A., Srinivasan, P., Kemel, Y., Shia, J., Bandlamudi, C., Mandelker, D., Middha, S., Hechtman, J., Zehir, A., Dubard-Gault, M., Tran, C., Stewart, C., Sheehan, M., Penson, A., DeLair, D., Yaeger, R., Vijai, J., Mukherjee, S., Galle, J., … Stadler, Z. K. (2019). Microsatellite instability is associated with the presence of lynch syndrome pan-cancer. Journal of Clinical Oncology, 37(4), 286-295. https://doi.org/10.1200/JCO.18.00283.
Ligtenberg, M. J., Kuiper, R. P., Chan, T. L., Goossens, M., Hebeda, K. M., Voorendt, M., Lee, T. Y., Bodmer, D., Hoenselaar, E., Hendriks-Cornelissen, S. J., Tsui, W. Y., Kong, C. K., Brunner, H. G., van Kessel, A., Yuen, S. T., van Krieken, J., Leung, S. Y., & Hoogerbrugge, N. (2009). Heritable somatic methylation and inactivation of MSH2 in families with lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nature Genetics, 41(1), 112-117. https://doi.org/10.1038/ng.283.
Møller, P., Seppälä, T., Bernstein, I., Holinski-Feder, E., Sala, P., Evans, D. G., Lindblom, A., Macrae, F., Blanco, I., Sijmons, R., Jeffries, J., Vasen, H., Burn, J., Nakken, S., Hovig, E., Rødland, E. A., Tharmaratnam, K., de Vos tot Nederveen Cappel, W., Hill, J., … Mallorca Group (http://mallorca-group.eu). (2017). Cancer incidence and survival in lynch syndrome patients receiving colonoscopic and gynaecological surveillance: First report from the prospective lynch syndrome database. Gut, 66(3), 464-472. https://doi.org/10.1136/gutjnl-2015-309675.
Møller, P., Seppälä, T. T., Bernstein, I., Holinski-Feder, E., Sala, P., Gareth Evans, D., Lindblom, A., Macrae, F., Blanco, I., Sijmons, R. H., Jeffries, J., Vasen, H. F. A., Burn, J., Nakken, S., Hovig, E., Rødland, E. A., Tharmaratnam, K., de Vos tot Nederveen Cappel, W., Hill, J., … Mallorca Group. (2018). Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: A report from the prospective lynch syndrome database. Gut, 67(7), 1306-1316. https://doi.org/10.1136/gutjnl-2017-314057.
Niessen, R. C., Hofstra, R. M., Westers, H., Ligtenberg, M. J., Kooi, K., Jager, P. O., de Groote, M. L., Dijkhuizen, T., Olderode-Berends, M. J., Hollema, H., Kleibeuker, J. H., & Sijmons, R. H. (2009). Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of lynch syndrome. Genes, Chromosomes & Cancer, 48(8), 737-744. https://doi.org/10.1002/gcc.20678.
Overbeek, L. I., Kets, C. M., Hebeda, K. M., Bodmer, D., van der Looij, E., Willems, R., Goossens, M., Arts, N., Brunner, H. G., van Krieken, J., Hoogerbrugge, N., & Ligtenberg, M. J. (2007). Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer. British Journal of Cancer, 96(10), 1605-1612. https://doi.org/10.1038/sj.bjc.6603754.
Peterlongo, P., Nafa, K., Lerman, G. S., Glogowski, E., Shia, J., Ye, T. Z., Markowitz, A. J., Guillem, J. G., Kolachana, P., Boyd, J. A., Offit, K., & Ellis, N. A. (2003). MSH6 germline mutations are rare in colorectal cancer families. International Journal of Cancer, 107(4), 571-579. https://doi.org/10.1002/ijc.11415.
Raskin, L., Schwenter, F., Freytsis, M., Tischkowitz, M., Wong, N., Chong, G., Narod, S. A., Levine, D. A., Bogomolniy, F., Aronson, M., Thibodeau, S. N., Hunt, K. S., Rennert, G., Gallinger, S., Gruber, S. B., & Foulkes, W. D. (2011). Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing lynch syndrome. Clinical Genetics, 79(6), 512-522. https://doi.org/10.1111/j.1399-0004.2010.01594.x.
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., Voelkerding, K., Rehm, H. L., & ACMG Laboratory Quality Assurance Committee. (2015). 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. Genetics in Medicine, 17(5), 405-424. https://doi.org/10.1038/gim.2015.30.
Rubenstein, J. H., Enns, R., Heidelbaugh, J., Barkun, A., & Clinical Guidelines Committee. (2015). American Gastroenterological Association Institute guideline on the diagnosis and management of lynch syndrome. Gastroenterology, 149(3), 777-782; quiz e716-777. https://doi.org/10.1053/j.gastro.2015.07.036.
Sjursen, W., McPhillips, M., Scott, R. J., & Talseth-Palmer, B. A. (2016). Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations. Molecular Genetics & Genomic Medicine, 4(2), 223-231. https://doi.org/10.1002/mgg3.198.
Susswein, L. R., Marshall, M. L., Nusbaum, R., Vogel Postula, K. J., Weissman, S. M., Yackowski, L., Vaccari, E. M., Bissonnette, J., Booker, J. K., Cremona, M. L., Gibellini, F., Murphy, P. D., Pineda-Alvarez, D. E., Pollevick, G. D., Xu, Z., Richard, G., Bale, S., Klein, R. T., Hruska, K. S., & Chung, W. K. (2016). Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genetics in Medicine, 18(8), 823-832. https://doi.org/10.1038/gim.2015.166.
Tamura, K., Kaneda, M., Futagawa, M., Takeshita, M., Kim, S., Nakama, M., Kawashita, N., & Tatsumi-Miyajima, J. (2019). Genetic and genomic basis of the mismatch repair system involved in lynch syndrome. International Journal of Clinical Oncology, 24(9), 999-1011. https://doi.org/10.1007/s10147-019-01494-y.
Tutlewska, K., Lubinski, J., & Kurzawski, G. (2013). Germline deletions in the EPCAM gene as a cause of lynch syndrome - literature review. Hereditary Cancer in Clinical Practice, 11(1), 9. https://doi.org/10.1186/1897-4287-11-9.
Vasen, H. F. (2005). Clinical description of the lynch syndrome [hereditary nonpolyposis colorectal cancer (HNPCC)]. Familial Cancer, 4(3), 219-225. https://doi.org/10.1007/s10689-004-3906-5.
Vettore, S., de Rocco, D., Gerber, B., Scandellari, R., Bianco, A. M., Balduini, C. L., Pecci, A., Fabris, F., & Savoia, A. (2010). A G to C transversion at the last nucleotide of exon 25 of the MYH9 gene results in a missense mutation rather than in a splicing defect. European Journal of Medical Genetics, 53(5), 256-260. https://doi.org/10.1016/j.ejmg.2010.06.010.
Wijnen, J., de Leeuw, W., Vasen, H., van der Klift, H., Moller, P., Stormorken, A., Meijers-Heijboer, H., Lindhout, D., Menko, F., Vossen, S., Möslein, G., Tops, C., Bröcker-Vriends, A., Wu, Y., Hofstra, R., Sijmons, R., Cornelisse, C., Morreau, H., Fodde, R., & Fodde, R. (1999). Familial endometrial cancer in female carriers of MSH6 germline mutations. Nature Genetics, 23(2), 142-144. https://doi.org/10.1038/13773.
Wijnen, J. T., Vasen, H. F., Khan, P. M., Zwinderman, A. H., van der Klift, H., Mulder, A., Tops, C., Møller, P., & Fodde, R. (1998). Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. The New England Journal of Medicine, 339(8), 511-518. https://doi.org/10.1056/NEJM199808203390804.
Yamada, K., Fukao, T., Zhang, G., Sakurai, S., Ruiter, J. P., Wanders, R. J., & Kondo, N. (2007). Single-base substitution at the last nucleotide of exon 6 (c.671G>a), resulting in the skipping of exon 6, and exons 6 and 7 in human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene. Molecular Genetics and Metabolism, 90(3), 291-297. https://doi.org/10.1016/j.ymgme.2006.10.010.
You, J. F., Buhard, O., Ligtenberg, M. J., Kets, C. M., Niessen, R. C., Hofstra, R. M., Wagner, A., Dinjens, W. N., Colas, C., Lascols, O., Collura, A., Flejou, J. F., Duval, A., & Hamelin, R. (2010). Tumours with loss of MSH6 expression are MSI-H when screened with a pentaplex of five mononucleotide repeats. British Journal of Cancer, 103(12), 1840-1845. https://doi.org/10.1038/sj.bjc.6605988.
Yurgelun, M. B., Allen, B., Kaldate, R. R., Bowles, K. R., Judkins, T., Kaushik, P., Roa, B. B., Wenstrup, R. J., Hartman, A. R., & Syngal, S. (2015). Identification of a variety of mutations in cancer predisposition genes in patients with suspected lynch syndrome. Gastroenterology, 149(3), 604-613 e620. https://doi.org/10.1053/j.gastro.2015.05.006. -->
Grant Information: P30 CA008748 United States CA NCI NIH HHS; P50 CA211015 United States CA NCI NIH HHS
Contributed Indexing: Keywords: Lynch syndrome; MSH6; c.4001G > C; germline; splice site variant
Substance Nomenclature: EC 3.6.1.3 (MutS Homolog 2 Protein)
0 (DNA-Binding Proteins)
EC 3.6.1.3 (MutL Protein Homolog 1)
Entry Date(s): Date Created: 20230124 Date Completed: 20230224 Latest Revision: 20230623
Update Code: 20230624
PubMed Central ID: PMC9938752
DOI: 10.1002/mgg3.2104
PMID: 36691871
Autor: Yang C; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Misyura M; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Kane S; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Rai V; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Latham A; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Zhang L; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA.
Jazyk: angličtina
Zdroj: Molecular genetics & genomic medicine [Mol Genet Genomic Med] 2023 Feb; Vol. 11 (2), pp. e2104. Date of Electronic Publication: 2023 Jan 24.
DOI: 10.1002/mgg3.2104
Abstrakt: Background: Germline variants in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) cause Lynch syndrome, an autosomal dominant hereditary cancer susceptibility syndrome. The risk for endometrial cancer is significantly higher in women with MSH6 pathogenic/likely pathogenic (P/LP) variants compared with that for MLH1 or MSH2 variants.
Methods: The proband was tested via a clinical testing, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). RT-PCR was performed using patient's blood DNA and cDNA was analyzed by DNA sequencing and a cloning approach.
Results: We report a 56-year-old female with endometrial cancer who carries a germline variant, MSH6 c.4001G > C, located at the last nucleotide of exon 9. While the pathogenicity of this variant was previously unknown, functional studies demonstrated that this variant completely abolished normal splicing and caused exon 9 skipping, which is expected to lead to a prematurely truncated or abnormal protein.
Conclusion: Our results indicate that this variant likely contributes to cancer predisposition through disruption of normal splicing, and is classified as likely pathogenic.
(© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje