Hereditary colorectal cancer (CRC) is mostly caused by mutations in the APC (adenomatous polyposis coli) gene or mismatch repair genes (MLH1, MSH2, MSH3, MSH6, PMS2, and EPCAM2).

In 2002, Al-Tassan et al. first described inherited variants in the MUTYH gene that led to an increased number of somatic inactivating mutations in the APC gene. Most of these somatic mutations were G:C to T:A transversions as a result of the impaired (defective) base excision repair (BER; Al-Tassan et al., 2002). The BER pathway, involving the DNA repair glycosylase MUTYH, repairs DNA lesions formed by reactive oxygen species (ROS).

ROS are natural by-products of normal aerobic metabolism. Elevated production of ROS arises from cellular exposure to toxins, ultraviolet light, and ionizing radiation. 8-Oxo-7,8-dihydroguanine (8-oxoG) is the most common, stable, and mutagenic oxidatively damaged guanine lesion (Banda et al., 2017). This nucleotide mispairs with adenine and MUTYH glycosylase removes these mispaired adenines (Terdiman, 2009).

MUTYH-associated polyposis (MAP) is an autosomal recessive disorder that can be diagnosed in patients with an attenuated colonic polyposis phenotype (Kidambi et al., 2018). Detection of germline MUTYH mutations is recommended in individuals affected by multiple colorectal adenomas in whom no mutation in the APC gene had been identified (Isidro et al., 2004). MAP is caused by biallelic pathogenic variants in the MUTYH gene and is characterized by the presence of 15–100 colorectal polyps and an increased carrier’s risk of colorectal adenomas and carcinomas. Patients are diagnosed with MAP at a mean age of 45 years. The chance of developing CRC reaches 20–80% in patients aged from 50 to 80 years (Lubbe et al., 2009; Castillejo et al., 2014). MAP is estimated to account for 0.7% of all CRC and between 0.5 and 6% of cohorts of familial or early-onset CRC in which affected individuals have a low number of adenomas (<15–20) (Sieber et al., 2003; Cleary et al., 2009; Lubbe et al., 2009; Landon et al., 2015; Pearlman et al., 2017). Seventy percent of MUTYH mutations involve c.1187G > A (p.Gly396Asp) and c.536A > G (p.Tyr179Cys) mutations (Sampson and Jones, 2009).

MUTYH mutations can contribute to the development of sporadic gastric cancer. The presence of MUTYH pathogenic variants is an independent predictor of poor prognosis in sporadic gastric cancer and in salivary gland secretory carcinoma, while its inhibition has been shown to reduce the survival of pancreatic ductal adenocarcinoma cells (Curia et al., 2020).

Biallelic (compound heterozygous or homozygous) MUTYH mutations inherited from both parents occur in 0.01–0.04% of the Caucasian population and are associated with an 18- to 100-fold increased risk of CRC compared with the general population. Carriers of biallelic MUTYH mutation have an increased risk of extracolonic cancers such as ovarian cancer, urinary bladder cancer, cancer of the upper gastrointestinal tracts, breast cancer, endometrial cancer, and skin cancer compared with the general population (Win et al., 2016; Table 1).

Monoallelic (heterozygous) MUTYH mutations, inherited from only one parent, occur in 1–2% of the Caucasian population and are associated with a moderately increased risk of CRC (Win et al., 2016). Carriers of monoallelic mutation have on average an approximately 2.5-fold increased risk of CRC compared with the general population (Win et al., 2014). It is estimated that there are an elevated risk of liver and gastric cancers and a slightly increased risk of breast cancer for carriers with monoallelic MUTYH mutation (Zhu et al., 2011; Rennert et al., 2012).

It is appropriate to perform molecular genetic analysis of asymptomatic relatives for the MUTYH pathogenic variants identified in the proband to ensure appropriate surveillance (beginning at the age of 10–15 years) and early identification of polyps (Nielsen et al., 2012, updated 2019).

These two cases demonstrate the importance of genetic testing of asymptomatic partners and the proband or carrier offspring of the pathogenic variant. We identified in our probands and their relatives pathogenic variants in the MUTYH gene by next-generation sequencing (NGS) panel testing and Sanger sequencing.

Variants c.1187G > A (p.Gly396Asp) and c.536A > G (p.Tyr179Cys) are the two most common pathogenic variants in the MUTYH gene responsible for the MAP. MAP is associated with an increased lifetime risk of CRC development. Other features involve thyroid nodules, benign adrenal lesions, jawbone cysts, and congenital hypertrophy of the retinal pigment epithelium (Nielsen et al., 2012, updated 2019). The risk of CRC is strongly age dependent, with incomplete penetrance at the age of 60 (Lubbe et al., 2009). Several studies found the association between MUTYH variants and the risk of breast cancer. In a case-control study, 930 women with a high prevalence of MUTYH mutations were investigated for the two variants c.1187G > A (p.Gly396Asp) and c.536A > G (p.Tyr179Cys), and patients with breast cancer revealed a 6.7% prevalence of c.1187G > A (p.Gly396Asp) (Rennert et al., 2012).

Recently, it has been estimated that MUTYH mutations could cause some diseases that are not associated with polyposis, such as Parkinson’s disease, Alzheimer’s disease, Friedreich’s ataxia, Huntington’s disease, retinitis pigmentosa, and neurofibromatosis (Curia et al., 2020).

Several functional assays have shown that the MUTYH glycosylase activity is greatly reduced for the MUTYH pathogenic variant c.536A > G (p.Tyr179Cys) (a 98% reduction of glycosylase activity) compared with the MUTYH pathogenic variant c.1187G > A (p.Gly396Asp) (an 86% reduction of glycosylase activity) (Al-Tassan et al., 2002; Nielsen et al., 2009; Banda et al., 2017). MAP patients harboring homozygous MUTYH pathogenic variant c.536A > G (p.Tyr179Cys) showed more severe clinical features than those with homozygous MUTYH pathogenic variant c.1187G > A (p.Gly396Asp). Furthermore, patients with a homozygous c.1187G > A (p.Gly396Asp) mutation or compound heterozygous c.1187G > A (p.Gly396Asp)/c.536A > G (p.Tyr179Cys) mutations have a lower risk of CRC development as compared with patients with a homozygous c.536A > G (p.Tyr179Cys) mutation.

According to the functional studies mentioned above, the mean age of CRC diagnosis is 46 years for the homozygous c.536A > G (p.Tyr179Cys) mutation, 52 years for the heterozygous c.1187G > A (p.Gly396Asp)/c.536A > G (p.Tyr179Cys) mutation, and 58 years for the homozygous c.1187G > A (p.Gly396Asp) mutation.

It is suitable to begin surveillance earlier for p.Tyr179Cys homozygotes than for p.Gly396Asp homozygotes and p.Gly396Asp/p.Tyr179Cys compound heterozygotes (Nielsen et al., 2011).

According to the NCCN guidelines (2019), the management of monoallelic MUTYH pathogenic variant carriers involved undergoing colonoscopy every 5 years beginning at the age of 40 years. The identification of monoallelic carriers of MUTYH pathogenic variants is very important to select individuals who might benefit from preventive strategies.

It is appropriate to clarify the genetic status of apparently asymptomatic individuals to reduce morbidity and mortality in those who would benefit from appropriate surveillance (beginning at the age of 10–15 years) and early identification and treatment of polyps. That is why we recommended for both children to undergo colonoscopy and upper endoscopy (the frequency of colonoscopy is recommended every 1–2 years starting at the age of 25 in case of a negative result, the frequency of upper endoscopy every 3–4 years starting at the age of 30). We also recommended thyroid ultrasound and skin examination by a dermatologist for both children. For girls, we recommended regular gynecologic and mammalogical dispensarization starting at the 21st year.

Identification of mutations in cancer predisposition genes is a challenge for current cancer risk management, counseling, and treatment decision-making regarding patients and their families.

Polyposis syndromes are not only due to mutations in well-known and well-explored cancer predisposition genes. Here, we suggest the need for the extension of molecular analysis for genes that are mutated with a relatively low frequency but with a strong impact on CRC development. Mutations in the MUTYH gene are associated with an 18- to 100-fold increased risk of CRC and an elevated risk of extracolonic cancers in comparison with the general population (Win et al., 2016).

Genetic counseling and testing with a multigene panel could be considered for all patients with a personal or family history of cancer syndromes. Genetic screening can provide early diagnosis and improve prognosis.

Potential future implementation of the exome sequencing indicates the discovery and investigation of new candidate genes involved in the etiology of the CRC.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethical approval was not provided for this study on human participants because this research was performed as a part of a routine molecular diagnostic of patients. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s) legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

All authors listed have made substantial, direct and intellectual contribution to the work and approved it for publication.