KRAS ‐G12C: The neglected biomarker to detect patients with MUTYH ‐associated polyposis

TL;DR

KRAS-G12C mutations are linked to MUTYH-associated polyposis, a rare colorectal cancer syndrome, suggesting they can help identify patients needing genetic testing.

Contribution

KRAS-G12C mutations are proposed as a biomarker for identifying MUTYH-associated polyposis patients.

Findings

11.4% of KRAS-G12C CRC patients carried at least one MUTYH germline pathogenic variant.

MAP patients had earlier cancer onset, more polyps, and fewer metastases compared to non-carriers.

11 out of 15 MAP cases were previously undiagnosed, highlighting the potential of KRAS-G12C as a screening tool.

Abstract

MUTYH‐associated polyposis (MAP) is an underdiagnosed recessive syndrome that predisposes individuals to colorectal cancer (CRC) and exhibits phenotypic variability. Biallelic MUTYH inactivation leads to a somatic mutational signature with frequent KRAS‐G12C mutations; however, despite being proposed as a marker for MAP, germline MUTYH testing in these patients remains limited. We assessed the utility of screening germline pathogenic variants (GPVs) in MUTYH among CRC cases with KRAS‐G12C. A cohort of 220 KRAS‐G12C CRC patients from two Brazilian oncology centers underwent targeted amplicon sequencing for the most prevalent MUTYH GPVs in Brazil. Comprehensive MUTYH sequencing was subsequently performed for monoallelic carriers. Overall, 25 (11.4%) patients carried at least one MUTYH GPV; among these, 15 (6.8%) were biallelic and classified as MAP and 10 (4.5%) were monoallelic. The MAP detection rate was 10.9% in patients <60 years. 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.

What's new?

MUTYH‐associated polyposis is an underdiagnosed recessive syndrome that predisposes individual to colorectal cancer and frequently displays KRAS‐G12C mutations. By analyzing a large cohort of colorectal cancer patients routinely tested for KRAS, the authors assessed whether KRAS‐G12C detection could serve as a pre‐screening tool for the syndrome. Approximately 11% of the patients with KRAS‐G12C mutations carried at least one germline pathogenic variant in MUTYH, with 6.8% of these patients being biallelic and diagnosed with MUTYH‐associated polyposis. The findings support the use of KRAS‐G12C as a biomarker for referring patients to germline MUTYH testing, enabling appropriate follow‐up and surveillance strategies for these patients.

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