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Published on: October 8, 2015
Clinical features and mutation analysis of class 1/2/3 BRAF mutation colorectal cancer
Yingying Huang1, Wenzhuo Jia2, Gang Zhao2
1Department of Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China.
Background:
BRAF (B-Raf proto-oncogene, serine/threonine kinase)-mutated colorectal cancer (CRC) still has poor prognostic. The efficacy of BRAF inhibitor is unpredictable just that intrinsic genetic complexity, immune microenvironment and partially unknown reason. Understanding the co-mutation mechanism can help improve treatment and follow-up strategies.
Methods:
We retrospectively analyzed 35 (BRAF-mutated/BRAF wild-type) Chinese CRC and 125 Western CRC who underwent next-generation sequencing (NGS). Co-occurrence mutation analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was enabled in this study.
Results:
Thirty-five (10.32%) patients were BRAF-mutated, with 17 patients were BRAF V600E in Beijing Hospital. Patients with BRAF mutation had significant association with high tumor mutational burden (TMB-H) (P=0.0004) and high microsatellite instability (MSI-H) (P=0.0003) than those with BRAF wild-type. In 125 BRAF-mutated Western CRC patients, the frequency of age at diagnosis, gender, sample type, Tumor-Node-Metastasis (TNM), MSI, TMB, and BRAF mutation type was consistent with Chinese data. However, the primary tumor location showed significant statistical differences (P<0.0001). Class 1 were more likely to occur in elder and female. Western cohort was consistent with above in Chinese cohort. Other clinicopathological features were not significantly associated with mutation type. However, Western cohort showed class 1 exhibited primary sample type predominance in both class 1 vs. others (P<0.05) and class 1 vs. class 3 (P<0.05). Meanwhile, the data showed TMB-H (57.69% vs. 11.76%, P<0.001) and MSI-H (28.21% vs. 0%, P<0.05) of the class 1 BRAF mutation proportion were significantly higher, compared with class 3 BRAF mutation. In concurrent oncogenic mutations, compared with non-class 1 BRAF mutation, class 1 are more likely to co-occur with passenger mutation. Data from Western populations showed similar results. We also found that the class 1 mutation was mutually exclusive with co-KRAS (Kirsten rat sarcoma viral oncogene homologue) mutation in CRC, and co-APC (APC regulator of WNT signaling pathway) mutation appeared more frequently in non-class 1 BRAF mutation. KEGG pathway showed that fewer proto-cancer signaling pathways were enriched in the class 1, which further confirmed that this type had stronger tumorigenicity. GO enrichment also proved that class 1 had stronger tumorigenicity. Finally, prognostic analysis showed median overall survival (mOS) of 19.43 months in class 1 vs. 47.57 months in non-class 1 (P=0.0002). Further study showed that the mOS of class 1, class 2, class 3 and class NA (unknown) was 19.43, 28.50, 47.57 months and not reached (P=0.0001), respectively.
Conclusions:
This study showed class 1/non-class 1 BRAF mutation in CRC had significantly differences in co-mutation features, genomic markers and prognostic. Understanding BRAF mutation types and co-mutation mechanism will contribute to accurately grasping treatment and follow-up strategies and promoting the development of precision therapy for CRC in the future.
Insights
BRAF-mutated colorectal cancer (CRC) subtypes show distinct co-mutation profiles and prognoses. Class 1 BRAF mutations are linked to higher tumor mutational burden and microsatellite instability, impacting overall survival in CRC patients.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- BRAF-mutated colorectal cancer (CRC) presents a poor prognosis with unpredictable BRAF inhibitor efficacy.
- Intrinsic genetic complexity and the tumor immune microenvironment contribute to treatment challenges.
- Understanding co-mutation mechanisms is crucial for improving CRC treatment and follow-up strategies.
Purpose of the Study:
- To investigate the co-mutation patterns and prognostic differences between BRAF mutation classes in colorectal cancer.
- To compare genomic features and clinical outcomes of BRAF-mutated CRC across different populations.
- To elucidate the role of co-mutations in BRAF-mutated CRC for precision therapy development.
Main Methods:
- Retrospective analysis of 35 Chinese and 125 Western CRC patients undergoing next-generation sequencing (NGS).
- Co-occurrence mutation analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis.
- Comparison of clinicopathological features, tumor mutational burden (TMB), and microsatellite instability (MSI) between BRAF mutation groups.
Main Results:
- BRAF mutations were associated with high tumor mutational burden (TMB-H) and high microsatellite instability (MSI-H).
- Class 1 BRAF mutations showed distinct co-mutation profiles, including mutual exclusivity with KRAS and higher co-occurrence with APC mutations compared to non-class 1.
- Class 1 BRAF mutations were linked to stronger tumorigenicity, higher TMB-H and MSI-H rates, and significantly poorer overall survival (19.43 months vs. 47.57 months).
Conclusions:
- Significant differences exist in co-mutation features, genomic markers, and prognosis between class 1 and non-class 1 BRAF mutations in CRC.
- Understanding BRAF mutation types and co-mutation mechanisms is vital for refining CRC treatment and follow-up strategies.
- This research supports the advancement of precision therapy for colorectal cancer based on specific BRAF mutation characteristics.
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