MUTYH (MutY homolog)

Compared with non-carriers, MAP patients had an earlier CRC onset (49 vs. 59 years, p = 0.008), a higher prevalence of polyps (OR = 5.26; CI 95% 1.49-18.59; p = 0.036) and a family history of cancers (84.6% vs. 48.9%, p = 0.014), but fewer occurrences of metastasis (30.7% vs. 68.3%, p = 0.006) and stage IV tumors (30.8% vs. 68.3%, p = 0.029). Notably, most MAP cases (11/15) were not previously diagnosed, demonstrating that the strong association between KRAS-G12C mutations and the presence of MUTYH GPVs supports its use as a biomarker for referring patients to germline MUTYH testing, enabling appropriate follow-up, surveillance and preventive strategies for individuals at risk.

Blood samples were collected, and gene polymorphisms were identified using PCR-RFLP technique. Our study results revealed a statistically significant association between gene polymorphisms OGG1-Ser326Cys (p = 0.008), XRCC1-Arg194Trp (p = 0.009), XRCC1-Arg399Gln (p < 0.001), APEX1-Asp148Glu (p < 0.001) and the occurrence of leukoplakia, OSMF and OSCC.

A second strong predisposition to CRC is MAP, characterized by biallelic pathogenic variants in the MUTYH gene, with a phenotype similar to FAP. This mini review focuses on potential approaches to improve the diagnosis of patients in whom pathogenic variants in the APC and MUTYH genes are not detected by routine testing.

Using standard NGS panels or whole exome sequencing (WES) would not have detected these variants. Our results demonstrate that WGS is a useful genetic testing method for young patients with over 100 adenomatous colonic polyps, when routine DNA diagnostic methods fail to establish the genetic cause of the disease.

APC gene mutations lead to FAP and subsequent colorectal cancer, and may also predispose individuals to thyroid disorders, including malignancies, benign nodules, and endocrine dysfunction. Therefore, we recommend that young patients diagnosed with thyroid cancer undergo a thorough evaluation of family history for hereditary conditions. Additionally, consideration should be given to gastrointestinal endoscopic and ophthalmologic screening, as well as molecular genetic testing. When multiple gastric and colorectal polyps are detected, genetic alterations in APC or MUTYH should be suspected. In particular, female patients diagnosed with FAP before the age of 31 should undergo annual thyroid ultrasound surveillance.

Interestingly, the mother also constantly develops numerous paranasal polyps, which may prompt researchers to investigate the role of this gene in the formation of polyps. Finally, the study highlighted the importance of further investigation into the pathogenicity of this variant and emphasized the significance of identifying novel genes.

In this study, a heterozygous pathogenic variant in the MUTYH gene was identified as the possible cause of BC in a multi-cancer family using ES. While the potential association between mono-allelic MUTYH mutations and an elevated risk of BC remains controversial, these findings highlight the necessity for a careful interpretation when assessing the role of MUTYH mutations in BC risk.

These findings highlight the utility of NGS in identifying germline variants linked to hereditary CRC syndromes and emphasize the need for functional studies to assess the pathogenicity of VUS.

The higher MUTYH mutation rate observed in the cancer cohort compared with the control group; cancer recurrence observed in the heterozygous carriers and in both maternal and paternal family branches of patients harboring a DM suggests that MUTYH PVs may play a role in cancer predisposition and progression, even when monoallelic.

Median follow-up was 13 months with no recurrences. eNSM is a feasible and effective option for patients with high-risk genetic mutations, offering oncologic safety and high satisfaction in our initial Latin American experience.