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Abstract
Among the full spectrum of activating mutations in RAS/BRAF oncogenes, colorectal cancer (CRC) arising in patients with MUTYH-associated polyposis (MAP) exclusively exhibits the c.34G>T (p.G12C) substitution in the KRAS gene, which is relatively uncommon in sporadic CRC. This feature is frequently used to identify cases of MAP: detection of the KRAS G12C mutation should be employed as a criterion for selecting patients with CRC for diagnostic testing of this recessive syndrome, which is typically associated with oligopolyposis. This report describes an atypical finding. A patient with synchronous multiple CRC and oligopolyposis was found to harbor a "double" mutation, p.G12C (1 %) and p.G12D (12 %), in the KRAS gene in tumor tissue. Subsequent MUTYH analysis revealed compound heterozygous carriage of two pathogenic mutations: c.933+3A>C and c.1187G>A (p.Gly396Asp). Microdissection of the histological specimen revealed that it contained both a tubulovillous adenoma and carcinoma: the p.G12C mutation originated from the carcinoma, whereas the p.G12D mutation derived from the adenoma. Additionally, a case of BRAFV600E-positive adenoma was identified in another patient with MAP. Thus, while MUTYH-associated carcinoma is characterized by the KRAS G12C substitution, adenomas in MAP may also harbor other mutations in the RAS-MAPK cascade genes. Beyond its immediate clinical relevance, this observation is of fundamental interest: adenomas with mutations other than KRAS G12C appear to be less susceptible or not susceptible to malignant transformation in MAP.
References
Thet M., Plazzer J.P., Capella G., et al. Phenotype correlations with pathogenic DNA variants in the MUTYH gene: A review of over 2000 cases. Hum Mutat. 2024; 8520275.-DOI: 10.1155/2024/8520275.
Zaffaroni G., Mannucci A., Koskenvuo L., et al. Updated European guidelines for clinical management of familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), gastric adenocarcinoma, proximal polyposis of the stomach (GAPPS) and other rare adenomatous polyposis syndromes: a joint EHTG-ESCP revision. Br J Surg. 2024; 111(5): znae070.-DOI: 10.1093/bjs/znae070.
Al-Tassan N., Chmiel N.H., Maynard J., et al. Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors. Nat Genet. 2002; 30(2): 227-32.-DOI: 10.1038/ng828.
Georgeson P., Pope B.J., Rosty C., et al. Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers. Gut. 2021; 70(11): 2138-2149.-DOI: 10.1136/gutjnl-2019-320462.
Walker R., Joo J.E., Mahmood K., et al. Adenomas from individuals with pathogenic biallelic variants in the MUTYH and NTHL1 genes demonstrate base excision repair tumour mutational signature profiles similar to colorectal cancers, expanding potential diagnostic and variant classification applications. Transl Oncol. 2025; 52: 102266.-DOI: 10.1016/j.tranon.2024.102266.
Lipton L., Halford S.E., Johnson V., et al. Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway. Cancer Res. 2003; 63(22): 7595-7599.-DOI: 10.1158/0008-5472.CAN-03-2256.
van Puijenbroek M., Nielsen M., Tops C.M., et al. Identification of patients with (atypical) MUTYH-associated polyposis by KRAS2 c.34G > T prescreening followed by MUTYH hotspot analysis in formalin-fixed paraffin-embedded tissue. Clin Cancer Res. 2008; 14(1): 139-42.-DOI: 10.1158/1078-0432.CCR-07-1705.
Aimé A., Coulet F., Lefevre J.H., et al. Somatic c.34G>T KRAS mutation: a new prescreening test for MUTYH-associated polyposis? Cancer Genet. 2015; 208(9): 390-395.-DOI: 10.1016/j.cancergen.2015.04.005.
Yanus G.A., Akhapkina T.A., Ivantsov A.O., et al. Spectrum of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. Clin Genet. 2018; 93(5): 1015-1021.-DOI: 10.1111/cge.13228.
Boparai K.S., Dekker E., Van Eeden S., et al. Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis. Gastroenterology. 2008; 135(6): 2014-2018.-DOI: 10.1053/j.gastro.2008.09.020.
Venesio T., Balsamo A., Errichiello E., et al. Oxidative DNA damage drives carcinogenesis in MUTYH-associated-polyposis by specific mutations of mitochondrial and MAPK genes. Mod Pathol. 2013; 26(10): 1371-1381.-DOI: 10.1038/modpathol.2013.66.
Thomas L.E., Hurley J.J., Meuser E., et al. Burden and profile of somatic mutation in duodenal adenomas from patients with familial adenomatous- and MUTYH-associated polyposis. Clin Cancer Res. 2017; 23(21): 6721-6732.-DOI: 10.1158/1078-0432.CCR-17-1269.
Viel A., Bruselles A., Meccia E., et al. A specific mutational signature associated with DNA 8-oxoguanine persistence in MUTYH-defective colorectal cancer. EBioMedicine. 2017; 20: 39-49.-DOI: 10.1016/j.ebiom.2017.04.022.
Cook J.H., Melloni G.E.M., Gulhan D.C., et al. The origins and genetic interactions of KRAS mutations are allele- and tissue-specific. Nat Commun. 2021; 12: 1808.-DOI: 10.1038/s41467-021-22125-z.
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