Germline MutY Human Homologue Mutations and Colorectal Cancer: A Multisite Case-Control Study

Abstract

Background & Aims-The MutY human homologue (MYH) gene is a member of the base-excision repair pathway involved in the repair of oxidative DNA damage. The objective of this study was to determine colorectal cancer (CRC) risk associated with mutations in the MYH gene.

Biallelic MUTYH mutations can mimic Lynch syndrome

“…At least one of these two hotspot mutations is found in 82-98% of all MAP cases in Caucasian, Canadian, American and Australian populations 12,22 and in our own unpublished cohort. In a further step, sequencing has been completed for all 16 coding exons and flanking regions of MUTYH (GenBank: NM_001128425.1; NG_008189.1) for 73 patients, 12 patients could not be analysed completely due to lack of DNA.…”

“…To our knowledge, in the literature six MAP patients with MSI-H tumours were described, 15,16 three of them with an IHC MLH1-deficiency in their MSI-H CRC. [10][11][12] The loss of MLH1 staining in those three MAP tumours with MSI-H was caused by a somatic MAP-specific mutation in MLH1 together with a second undetectable defect, 10 whereas biallelic methylation of the MLH1 promoter was causing the MLH1-deficiency in the other MAP patient. 11 Here we present a MAP-patient, in which BER deficiency was associated with the development of two somatic MAP-specific G4T transversion mutations in the MSH2 gene in the tumour resulting in MMR deficiency, MSI-H and a loss of MSH2 and MSH6 expression in the patient's sebaceous gland carcinoma.…”

“…3,[26][27][28] In the control cohort the MUTYH mutation frequency of 1.24% was comparable to the frequencies of 0%-4.8% reported in the general population. 12,22,29 As MAP can manifest in an extremely variable phenotype, MUTYH mutation analysis should also be considered in patients with a low number of adenomas, early-onset or synchronous or metachronous CRC and in patients with MSS tumours. 30,31 With an incidence of only 1.18% in MMR-deficient CRC patients with typical histological features of LS and several adenomas MAP can mimic LS.…”

“…[4][5][6][7][8][9] So far, three MAP patients have been described in the literature with an IHC loss of MLH1 protein staining and an MSI-H tumour: one male with a biallelic MUTYH germline mutation c.1227_28dupGG; p.(Glu410Glyfs*43) affecting the base excision repair (BER), and one somatic mutation in the MLH1 gene detected in his left-sided CRC at age of 49 years, 10 the second with two heterozygous MUTYH mutations c.536A4G; p.(Tyr179Cys) and c.1187G4A; p.(Gly396Asp) and biallelic methylation of the MLH1 promoter in her caecal carcinoma at the age of 50 years 11 and the third with homozygous MUTYH mutation c.536A4G; p.(Tyr179Cys) and no analyses for methylation or somatic mutation in MLH1 performed in the right-sided colon carcinoma diagnosed at age 50 years. 12 In some publications CRC patients with MSI-H tumours were excluded for MUTYH analyses or MSI was not analysed. 13,14 Three further MAP patients were identified with MSI-H tumours but no information on IHC for MMR proteins was given, 15,16 whereas other studies detected no biallelic MUTYH mutation carrier in patients with MSI-H tumours.…”

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

“…Interestingly, increases in frequency of residual polyp adjacent to carcinoma have also been reported for biallelic and compound heterozygote MUTYH mutation carriers. 36 An important feature of the tumors in those particular patients is the high rate of KRAS mutation, with over 60% of tumors harboring the c.35G4A transition. 37 Only a minority of adenomatous and serrated polyps have the capacity for malignant transformation.…”