Dados do Resumo

Título

KRAS-G12C: a neglected biomarker to detect patients with MUTYH-associated polyposis

Introdução

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 mutated, leads to G:C-T:A transversions in multiple genes, including KRAS and PIK3CA. The KRAS c.34G>T; G12C is a rare somatic mutation occuring in less than 10% of sporadic CRCs and in more than 80% of MAP patients; PIK3CA c.1636C>A p.Q546K, on the other hand, occurs in 0.7% and 37%, respectively. Previous studies have demonstrated that the presence of either these two mutations detects MAP patients with a sensitivity of around 90%.

Objetivo

The aims of the study are: to evaluate the detection rate of germline pathogenic/likely pathogenic variants (GPVs) in MUTYH in patients with colorectal cancer and KRAS-G12C somatic mutation; to evaluate the utility of investigate KRAS-G12C and PIK3CA-Q546K in adenomas and CRCs tissues from MAP patients to classify variants of uncertain significance (VUS) in MUTYH.

Métodos

For the first aim, we are evaluating the MUTYH five most common variants in the Brazilian population (p.Tyr151Cys, p.Gly368Asp, p.Arg213Trp, p.Ala357fs and deletion of exons 4 to 16) through multiplex PCR followed by next-generation sequencing (NGS) of amplicons. Patients with only 1 variant in heterozygosis are being evaluated by MUTYH complete sequencing, and the results will be described by descriptive statistics. For the second aim, we are evaluating the detection frequency of KRAS-G12C and PIK3CA-Q546K somatic mutations in CRC and adenomas tissues of diagnosed MAP patients (biallelics) and suspected MAP patients (presenting a VUS in MUTYH).

Resultados

Of the 220 KRAS-G12C patients evaluated, 25 (11.4%) have shown GVPs in MUTYH and 16 (7.3%) were classified as MAP. The MAP detection rate in patients under 60 years old was 17.2%. GPVs were associated with an earlier age of CRC onset (p=0.002) and the presence of polyps (p=0.004). Regarding the second aim, of the 16 MAP patients used as positive controls for the KRAS-G12C and PIK3CA-Q546K evaluation, 12 (75%) were positive for KRAS-G12C and 4 (26.6%) were positive for PIK3CA-Q546K. In adenomas, 47% were positive for KRAS-G12C and none for PIK3CA-Q546K; in adenocarcinomas, the frequencies observed were 92.3% and 33.3%, respectively. Adenomas/CRC from two suspected MAP patients harboring a MUTYH VUS (p.Pro273Arg and p.Lys422Met) revealed the presence of KRAS-G12C in the p.Pro273Arg carrier, supporting its classification as likely pathogenic (PP3_strong, PM2_supp, PP4).

Conclusões

In conclusion, the high detection rate of GPVs in MUTYH in CRC and KRAS-G12C patients indicates its potential use as a biomarker to expand the detection of MAP patients, and the high frequency of KRAS-G12C and PIK3CA-Q546K somatic mutations in adenocarcinomas confirms its possible role in MUTYH VUS reclassification.

Financiador do resumo

FAPESP 2023/01303-9

Palavras Chave

MUTYH-associated polyposis; KRAS-G12C; Colorectal cancer