KRAS-G12C: The neglected biomarker to detect patients with MUTYH-associated polyposis
Ana Beatriz Deleame Medeiros1, Gabriel Oliveira Dos Santos2, José Claudio Casali-da-Rocha3
1Clinical and Functional Genomics, A. C. Camargo Cancer Center, São Paulo, Brazil.
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.
Insights
Screening for MUTYH pathogenic variants in colorectal cancer patients with KRAS-G12C mutations identifies a significant number of individuals with MUTYH-associated polyposis (MAP). This highlights KRAS-G12C as a potential biomarker for early MAP diagnosis and intervention.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- MUTYH-associated polyposis (MAP) is an underdiagnosed genetic syndrome predisposing to colorectal cancer (CRC).
- Biallelic MUTYH inactivation is linked to KRAS-G12C mutations in CRC, yet germline MUTYH testing is underutilized.
Purpose of the Study:
- To evaluate the utility of screening for germline pathogenic variants (GPVs) in MUTYH among colorectal cancer patients harboring KRAS-G12C mutations.
- To determine the diagnostic yield of MUTYH GPVs in this patient cohort.
Main Methods:
- Targeted amplicon sequencing of prevalent MUTYH GPVs was performed on 220 KRAS-G12C CRC patients.
- Comprehensive MUTYH sequencing was conducted for identified monoallelic carriers.
Main Results:
- Overall, 11.4% of patients carried at least one MUTYH GPV, with 6.8% classified as biallelic MAP.
- MAP patients exhibited earlier CRC onset, increased polyp prevalence, and a stronger family history of cancer compared to non-carriers.
- A significant proportion of MAP cases (11/15) were undiagnosed prior to this study.
Conclusions:
- The frequent co-occurrence of KRAS-G12C mutations and MUTYH GPVs supports using KRAS-G12C as a biomarker for germline MUTYH testing referrals.
- This approach facilitates early diagnosis of MAP, enabling timely surveillance and preventive strategies for at-risk individuals.
