Heterozygous deleterious MUTYH variants as a driver for tumorigenesis

MUTYH is a glycosylase involved in the base excision repair of the DNA. Biallelic mutations in the MUTYH gene cause the autosomal recessive condition known as MUTYH‐associated adenomatous polyposis and increase colorectal cancer risk. However, the cancer risk associated with germline variants in individuals carrying only one MUTYH defective allele is controversial and based on studies involving few samples. Here, we described a comprehensive investigation of monoallelic deleterious MUTYH carriers among approximately 10,400 patients across 33 different tumor types and more than 117 thousand samples of normal individuals. Our results indicate MUTYH deficiency in heterozygosity can lead to tumorigenesis through a mechanism of Loss Of Heterozygosity (LOH) of the functional MUTYH allele. We confirmed that the frequency of damaging MUTYH monoallelic variant carriers is higher in individuals with cancer than in the general population, though its frequency is not homogeneous among tumor types. We also demonstrate that MUTYH related mutational signature is elevated only in those patients with loss of the functional allele. We also find that MUTYH characteristic base substitution (C>A) increases stop codon generation and we identify key genes affected during tumorigenesis. In conclusion, we propose that deleterious germline monoallelic MUTYH variant carriers are at a higher risk of developing tumors, specially those types with frequent LOH events, such as adrenal adenocarcinoma.

MUTYH as an Emerging Predictive Biomarker in Ovarian Cancer

Approximately 18% of ovarian cancers have an underlying genetic predisposition and many of the genetic alterations have become intervention and therapy targets. Although mutations in MutY homolog (MUTYH) are best known for MUTYH associated polyposis and colorectal cancer, it plays a role in the development of ovarian cancer. In this review, we discuss the function of the MUTYH gene, mutation epidemiology, and its mechanism for carcinogenesis. We additionally examine its emerging role in the development of ovarian cancer and how it may be used as a predictive and targetable biomarker. MUTYH mutations may confer the risk of ovarian cancer by the failure of its well-known base excision repair mechanism or by failure to induce cell death. Biallelic germline MUTYH mutations confer a 14% risk of ovarian cancer by age 70. A monoallelic germline mutation in conjunction with a somatic MUTYH mutation may also contribute to the development of ovarian cancer. Resistance to platinum-based chemotherapeutic agents may be seen in tumors with monoallelic mutations, but platinum sensitivity in the biallelic setting. As MUTYH is intimately associated with targetable molecular partners, therapeutic options for MUTYH driven ovarian cancers include programed-death 1/programed-death ligand-1 inhibitors and poly-adenosine diphosphate ribose polymerase inhibitors. Understanding the function of MUTYH and its associated partners is critical for determining screening, risk reduction, and therapeutic approaches for MUTYH-driven ovarian cancers.

Clinical and genetic features in patients with MutYH-associated polyposis

Aim. MutYH-associated polyposis is a rare polyposis syndrome with an autosomal recessive type of inheritance, phenotypically often similar to an attenuated form of Familial adenomatous polyposis (FAP). In different populations, patients with MAP have clinical and genetic features. The article presents the features of the clinical picture and the spectrum of mutations in the MutYH gene in patients with MutYH-associated polyposis in the Russian population. Materials and methods. The material for the study was clinical data of 20 patients with a genetically confirmed diagnosis of MutYH-associated polyposis underwent treatment at National Medical Research Centre for Coloproctology named after A.N. Ryzhikh». Results. The male to female ratio among patients with MAP was 7:13. The average age of diagnosis was 49.7 (19-70) years. The average number of polyps in the colon was 91 (24-420), while in most patients (70%; 14/20) they were distributed evenly in all parts of the colon, in 6 patients, most were located in the right sections. The most common pathogenic mutations in the MutYH gene were missense mutations p.G382D (33%; 13/40), p.Y165C (15%; 6/40), p.G169D (15%; 6/40) and p .R231H (15%; 6/40), also found in two patients c.462 + 19_462 + 31del. The frequency of other mutations that occurred only once was 17% (7/40). It was revealed that 12 out of 20 patients (60%) had colorectal cancer (CRC) at the time of MAP diagnosis, while the average age for diagnosing MAP without CRC was 37.5 (19-50) years, and the average age of CRC diagnosing for patients with MAP background - 57.9 (42-70) years. Conclusions. Clinical and genetic characteristics of patients with MutYH-associated polyposis were identified in the Russian population.

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.

MUTYH Deficiency Is Associated with Attenuated Pulmonary Fibrosis in a Bleomycin-Induced Model

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible lung disease of unknown etiology with limited survival. IPF incidence and prevalence increase significantly with aging, which is associated with an age-related accumulation of oxidative DNA damage. The Mutyh gene is involved in the base excision repair (BER) system, which is critical for repairing the misincorporated adenine that is opposite to the oxidized guanine base, 8-oxoguanine, and maintaining the fidelity of DNA replication. We used Mutyh knockout mice and a bleomycin-induced pulmonary fibrosis model to test the effect of MUTYH deficiency on lesion progression. Unexpectedly, a much less severe lesion of pulmonary fibrosis was observed in Mutyh-/- than in Mutyh+/+mice, which was supported by assay on protein levels of TGF-β1 and both fibrotic markers, α-SMA and Vimentin, in pulmonary tissues of the model animals. Mechanically, MUTYH deficiency prevented the genomic DNA of pulmonary tissue cells from the buildup of single-strand breaks (SSBs) of DNA and maintained the integrity of mtDNA. Furthermore, increased mitochondrial dynamic regulation and mitophagy were detected in pulmonary tissues of the bleomycin-induced Mutyh-/- model mice, which could reduce the pulmonary epithelial cell apoptosis. Our results suggested that MUTYH deficiency could even induce protective responses of pulmonary tissue under severe oxidative stress.

Adenomatous polyposis syndromes: from genetics to clinic

Аденоматозные полипозные синдромы являются тяжелыми наследственными заболеваниями, которые характеризуются развитием десятков и сотен полипов в толстой кишке пациента и высоким риском возникновения колоректального рака на их фоне при отсутствии своевременного хирургического лечения. Было проведено молекулярно-генетическое обследование 240 российских пациентов с количеством аденоматозных полипов от 20 до нескольких сотен. Герминальные мутации в гетерозиготном состоянии в гене APC выявлены у 157 человек, а биаллельные мутации в гене MutYH - у 14 больных. Для пациентов с количеством полипов более 100 был определен возраст выполнения операции по удалению толстой кишки - до 25 лет. Adenomatous polyposis syndromes are severe hereditary diseases, characterized by the development of tens and hundreds colonic polyps and an extremely high risk of colorectal cancer without timely surgical treatment. Two hundred and forty Russian patients with more than 20 adenomatous colonic polyps were included in genetic study. Hereditary heterozygous mutations in the APC gene were detected in 157 patients, and biallelic mutations in the MutYH gene - in 14 patients. According to our results, patients with more than 100 polyps should undergo colectomy before 25 y.o.