Mutation analysis of POLE gene in patients with early-onset colorectal cancer revealed a rare silent variant within the endonuclease domain with potential effect on splicing

A disproportionately large number of young (less than 50 years) black patients present with colorectal cancer (CRC) in South Africa. Although a phenomenon previously described elsewhere in Africa, its specific molecular basis, whether sporadic or hereditary, has not been established. Molecular analysis of these tumours could link them to the features known to be associated with specific types of hereditary colorectal cancer, specifically through examination of levels of microsatellite instability, promoter methylation and the presence or absence of KRAS and BRAF mutations. The molecular features of cancer tissue samples from 44 CRC cases of black and white patients in South Africa were accordingly retrospectively analysed without knowledge of family history. Compared with samples from older blacks (>50 years), those from young black patients presented more often with a low methylation phenotype (CIMP-L) and high levels of microsatellite instability (MSI-H). Furthermore, as determined by real-time PCR using probe technology, the tissues from 35% of young blacks showed mutations within exon 1 of the KRAS gene. The BRAF-V600E mutation was only evident in the case of a single young black patient. Based on these results it seems likely that a proportion of CRC cases in young black patients from South Africa develop through the accumulation of mutations resulting in a mismatch repair deficiency linked to MSI-H and, possibly, germline mutations in the mismatch repair genes. The features in these patients are consistent with a diagnosis of the Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome. This finding has important implications for patient management and suggests that family members may be at high risk for CRC.

Microsatellite Instability

10.1590/s0038-23532009000100023

Cite

Citations (5)

Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells

Nature Communications (2022)

Philip S. Robinson Laura E. Thomas Federico Abascal Hyunchul Jung Luke M. R. Harvey

Abstract Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequence normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 4-fold in all individuals, except for one showing a 31-fold increase, and were also increased in other tissues. The increased mutation burdens were of multiple mutational signatures characterised by C > A changes. Different mutation rates and signatures between individuals are likely due to different MUTYH mutations or additional inherited mutations in other BER pathway genes. The elevated base substitution rate in normal cells likely accounts for the predisposition to neoplasia in MAP. Despite ubiquitously elevated mutation rates, individuals with MAP do not display overt evidence of premature ageing. Thus, accumulation of somatic mutations may not be sufficient to cause the global organismal functional decline of ageing.

MUTYH

Mutation Accumulation

10.1038/s41467-022-31341-0

Cite

Citations (45)

The role of MYH and microsatellite instability in the development of sporadic colorectal cancer

British Journal of Cancer (2006)

Andrew J. Colebatch Megan P. Hitchins Rachel Williams Alan P. Meagher Nicholas J. Hawkins

Biallelic germline mutations in MYH are associated with colorectal neoplasms, which develop through a pathway involving somatic inactivation of APC. In this study, we investigated the incidence of the common MYH mutations in an Australian cohort of sporadic colorectal cancers, the clinicopathological features of MYH cancers, and determined whether inactivation of mismatch repair and base excision repair (BER) were mutually exclusive. The MYH gene was sequenced from lymphocyte DNA of 872 colorectal cancer patients and 478 controls. Two compound heterozygotes were identified in the cancer population and all three cancers from these individuals displayed a prominent infiltration of intraepithelial lymphocytes. In total, 11 heterozygotes were found in the cancer group and five in the control group. One tumour from an individual with biallelic germline mutation of MYH also demonstrated microsatellite instability (MSI) as a result of biallelic hypermethylation of the MLH1 promoter. Although MYH-associated cancers are rare in a sporadic colorectal population, this study shows that these tumours can develop through either a chromosomal or MSI pathway. Tumours arising in the setting of BER or mismatch repair deficiency may share a biological characteristic, which promotes lymphocytic infiltration.

MUTYH

Microsatellite Instability

MLH1

10.1038/sj.bjc.6603421

Cite

Citations (51)

Advances in diagnosis and treatment of hereditary nonpolyposis colorectal cancer

Zhongguo aizheng zazhi (2001)

Cai San

Hereditary nonpolyposis colorectal cancer (HNPCC) is a distinct autosomal dominant syndrome, accounting for 5%-10% of the total colorectal cancer population. To date, we have noticed that patients with HNPCC inherit a germline mutation in one of the genes responsible for repair of DNA mismatch errors. Tumors of HNPCC show a high frequency of microsatellite instability. Identifying individuals afflicted with HNPCC has implications for surgical management, prognosis, follow up, and surveillance of HNPCC patients and family members at risk.

Microsatellite Instability

Source

Cite

Citations (0)

Detection of genetic alterations in hereditary colorectal cancer screening☆

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (2009)

Marta Pineda Sara González Conxi Lázaro Ignacio Blanco Gabriel Capellá

MUTYH

PMS2

MSH2

MSH6

Lynch Syndrome

MLH1

Microsatellite Instability

10.1016/j.mrfmmm.2009.11.002

Cite

Citations (36)

Hereditary non-polyposis colorectal cancer

Guoji zhongliuxue zazhi (2009)

Mao Jian-feng

Hereditary non-polyposis colorectal cancer(HNPCC) is an autosomal-dominantly inherited disease which is associated with germline mutations in mismatch repair(MMR) genes and microsatellite instability (MSI). As an important clinical subtype of colorectal cancer, HNPCC is accounting for 5%～15% of colorectal cancer. It' s focus research of colon cancer and hereditary tumor currently because of the special genetic etiopathogenisis and the prominent clinical pathology characteristic. Key words: Hereditary nonpolyposis ; Colorectal neoplasms; Base pair mismatch; Microsatellite instability

Microsatellite Instability

Inherited disease

Lynch Syndrome

10.3760/cma.j.issn.1673-422x.2009.06.023

Cite

Citations (0)

Somatic Mutations in MLH1 and MSH2 Are a Frequent Cause of Mismatch-Repair Deficiency in Lynch Syndrome-Like Tumors

Gastroenterology (2013)

Arjen R. Mensenkamp Ingrid P. Vogelaar Wendy A.G. van Zelst–Stams Monique Goossens Hicham Ouchene

Lynch Syndrome

MLH1

MSH2