Case Report: The Role of Molecular Analysis of the MUTYH Gene in Asymptomatic Individuals.

MUTYH-associated polyposis (MAP) is a rare hereditary condition caused by the biallelic mutation in the MUTYH gene encoding MUTYH glycosylase. This enzyme is a key member of the base excision repair (BER) pathway responsible for the repair of DNA lesions formed by reactive oxygen species (ROS). We report two cases of MAP. In case 1, a 67-year-old woman who presented with a personal history of colorectal and endometrial cancer and a family history of cancer syndromes underwent multigene panel testing that revealed a germline homozygous (biallelic) pathogenic variant c.1187G > A (p.Gly396Asp) in the MUTYH gene. Subsequent sequencing analysis performed in the offspring of the proband identified all three asymptomatic offspring as carriers of this pathogenic variant. In case 2, a 40-year-old woman with a strong family history of colorectal cancer [the proband's sister was a carrier of the pathogenic variant c.536A > G (p.Tyr179Cys) of the MUTYH gene] and renal cancer underwent sequencing analysis of the MUTYH gene. The pathogenic heterozygous (monoallelic) variant c.536A > G (p.Tyr179Cys) of the MUTYH gene was identified in the proband. We found another pathogenic variant of the MUTYH gene-heterozygous (monoallelic) mutation c.1187G > A (p.Gly396Asp) in the genome of the proband's husband. Molecular analysis of their offspring revealed that they are compound heterozygotes for MUTYH pathogenic variants c.536A > G (p.Tyr179Cys)/c.1187G > A (p.Gly396Asp). This paper shows the importance of genetic testing of asymptomatic relatives of the proband to ensure an early surveillance and management of individuals positive for pathogenic variant (s) in the MUTYH gene.

Molecular biomarkers in the diagnostic of patients with colorectal cancer.

Colorectal cancer (CRC) is currently a well-known and studied issue in experimental research. Worldwide it is the third most common cancer in men and the second most common cancer in women. 70-80% of cases occur sporadically. Most CRCs develop from adenomas. The transition from normal epithelium to adenoma and finally into carcinoma is associated with acquired molecular events. In 5-10 % of cases, CRC develops from germline mutations in cancer-predisposing genes. 15% of patients have a family history of CRC that suggests a hereditary contribution, common exposures or shared risk factors among family members. Genetic alterations in cancer-related genes represent prognostic and predictive CRC biomarkers. Genetic testing of individuals with newly diagnosed CRC as well as of asymptomatic relatives can lead to improved outcomes for the patient and at-risk family members. Discovery of circulating cell-free tumor DNA (ctDNA) promises an improvement of the CRC diagnostics. ctDNA shares common genetic alterations with the primary tumor so it allows non-invasive monitoring of the disease over time. This review is focused on the principal molecular biomarkers associated with CRC and on the key characteristics of initiation and progression of CRC including chromosomal instability, microsatellite instability and signaling pathways where this deregulation leads to tumorigenesis.