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KRAS-G12C: The neglected biomarker for identifying MUTYH-associated polyposis patients

Grant number: 23/01303-9
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): September 01, 2023
Effective date (End): April 30, 2025
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Giovana Tardin Torrezan
Grantee:Ana Beatriz Deleame Medeiros
Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil


MUTYH-associated polyposis (MAP) is responsible for 0.7% of all colorectal cancers (CRC) and 13% of all colorectal polyposis. MUTYH gene plays a role in the base excision repair system of DNA, and when it is mutated, leads to GC:TA transversions in several genes, including KRAS and PIK3CA. In CRC, KRAS mutations are observed in 50% of the cases and they are mainly missense mutations in codons 12 and 13. The somatic mutation c.34G>T; G12C is a rare mutation, occurring in less than 10% of the patients with KRAS mutation. Previous studies have shown a high rate of KRAS-G12C somatic mutation in MAP patients, and around 25% of CRC KRAS-G12C patients have biallelic pathogenic variants in MUTYH. The aim of the present study is to evaluate the detection rate of pathogenic/likely pathogenic (P/LP) germline variants in MUTYH gene in patients with colorectal cancer and KRAS-G12C somatic mutation; evaluate the need of investigate KRAS-G12C and PIK3CA-Q546K in CRC and adenomas tissues to classify variants of uncertain significance (VUS) in MUTYH. For this, DNA was extracted from fresh tumor, formalin-fixed and paraffin-embedded tumor (FFPE) and leukocyte. For the first aim, the 5 most frequent pathogenic variants (PVs) in MUTYH in the Brazilian population (p.Tyr151Cys, p.Gly368Asp, p.Arg213Trp, p.Ala357fs e deleção dos éxons 4 a 16) will be evaluated through multiplex PCR followed by amplification analysis in agarose gel and next-generation sequencing (NGS) of amplicons. Patients with only 1 variant in heterozygosis will be evaluated by complete sequencing of MUTYH gene, and the results will be described with descriptive statistics. For the second aim, we will evaluate the detection rate of KRAS-G12C and PIK3CA-Q546K somatic mutations in CRC and adenomas tissues from MAP patients (biallelics) and suspected MAP patients (with the presence of VUS in MUTYH). We expect that our study enables an improvement in the diagnosis strategies to identify MAP patients and their families, allowing follow-up, surveillance and adequate preventive measures for these individuals.

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