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Target gene mutational pattern in Lynch syndrome colorectal carcinomas according to tumour location and germline
Manuela Pinheiro1, Carla Pinto1, Ana Peixoto1
1Department of Genetics, Portuguese Oncology Institute, Rua Doutor António Bernardino Almeida, 4200-072 Porto, Portugal.
Background:
We previously reported that the target genes in sporadic mismatch repair (MMR)-deficient colorectal carcinomas (CRCs) in the distal colon differ from those occurring elsewhere in the colon. This study aimed to compare the target gene mutational pattern in microsatellite instability (MSI) CRC from Lynch syndrome patients stratified by tumour location and germline mutation, as well as with that of sporadic disease.
Methods:
A series of CRC from Lynch syndrome patients was analysed for MSI in genes predicted to be selective MSI targets and known to be involved in several pathways of colorectal carcinogenesis.
Results:
The most frequently mutated genes belong to the TGF-β superfamily pathway, namely ACVR2A and TGFBR2. A significantly higher frequency of target gene mutations was observed in CRC from patients with germline mutations in MLH1 or MSH2 when compared with MSH6. Mutations in microsatellite sequences (A)7 of BMPR2 and (A)8 of MSH3 were significantly more frequent in the distal CRC. Additionally, we observed differences in MSH3 and TGFBR2 mutational frequency between Lynch syndrome and sporadic MSI CRC regarding tumour location.
Conclusions:
Our results indicate that the pattern of genetic changes differs in CRC depending on tumour location and between Lynch syndrome and sporadic MSI CRC, suggesting that carcinogenesis can occur by different pathways even if driven by generalised MSI.
Insights
Genetic mutations in colorectal cancer (CRC) differ based on tumor location and whether it is Lynch syndrome or sporadic mismatch repair (MMR)-deficient. These findings suggest varied pathways in CRC development, even with MSI.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Sporadic mismatch repair (MMR)-deficient colorectal carcinomas (CRCs) exhibit distinct target gene mutations in the distal colon.
- Microsatellite instability (MSI) is a key feature in certain colorectal cancers.
Purpose of the Study:
- To compare target gene mutational patterns in MSI CRC from Lynch syndrome patients.
- To stratify Lynch syndrome CRC by tumor location and germline mutation.
- To compare Lynch syndrome CRC with sporadic MSI CRC.
Main Methods:
- Analysis of MSI in a series of colorectal cancer (CRC) cases from Lynch syndrome patients.
- Focus on genes involved in colorectal carcinogenesis pathways and selective MSI targets.
Main Results:
- TGF-β superfamily pathway genes (ACVR2A, TGFBR2) were most frequently mutated.
- Higher mutation frequencies in CRC with germline MLH1 or MSH2 mutations compared to MSH6.
- Distal CRC showed more frequent mutations in BMPR2 and MSH3 microsatellite sequences.
- Differences in MSH3 and TGFBR2 mutation frequency were noted between Lynch syndrome and sporadic MSI CRC based on tumor location.
Conclusions:
- Genetic alteration patterns in CRC vary by tumor location.
- Distinct genetic profiles exist between Lynch syndrome and sporadic MSI CRC.
- Generalised MSI can drive colorectal carcinogenesis through different molecular pathways.
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