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. 2015 Aug 11;113(4):686-92.
doi: 10.1038/bjc.2015.281. Epub 2015 Aug 6.

Target gene mutational pattern in Lynch syndrome colorectal carcinomas according to tumour location and germline mutation

Manuela Pinheiro  1 , Carla Pinto  1 , Ana Peixoto  1 , Isabel Veiga  1 , Paula Lopes  2 , Rui Henrique  3 , Helena Baldaia  4 , Fátima Carneiro  5 , Raquel Seruca  6 , Ian Tomlinson  7 , Michal Kovac  8 , Karl Heinimann  8 , Manuel R Teixeira  9
Affiliations

Target gene mutational pattern in Lynch syndrome colorectal carcinomas according to tumour location and germline mutation

Manuela Pinheiro et al. Br J Cancer. .

Abstract

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.

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Figures

Figure 1
Figure 1
Box-plot analyses of the frequency of target gene mutations (Y axis) in CRC samples from the test series categorised by MMR germline mutation (X axis). The mean comparison was calculated using the one-way ANOVA test. Statistical significance among the samples was assessed using the Scheffe's multiple comparison test.
Figure 2
Figure 2
Mutational frequency of the microsatellite sequences (A)7 of BMPR2 and (A)8 of MSH3 according to tumour location in tumours from both series of Lynch syndrome patients.
Figure 3
Figure 3
Mutational frequency in TGFBR2 (A)10 and MSH3 (A)8 microsatellite sequences categorised by tumour location in sporadic (Pinheiro et al, 2010) and Lynch syndrome MSI CRC (present report).
See this image and copyright information in PMC

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