Abstract 4804
Background
Inactivation of MLH1 due to promoter hypermethylation strongly suggests a sporadic origin, and nearly half sporadic colorectal cancer patients harbor BRAF mutation, providing exclusion criteria for Lynch syndrome (LS). However, there was little evidence from Chinese population. The aim of this study was to compare the utility of two tests, and explore the possibility of substituting BRAF immunohistochemical staining (IHC) for real-time PCR.
Methods
We reviewed MMR expression status of consecutive patients who had undergone surgery for colorectal cancer between 2012.1.1 and 2014.12.30 in Chinese National Cancer Center. Among 317 patients who were identified as dMMR, 170 patients with MLH1 immunoloss were taken into final analysis. MLH1 methylation status was evaluated by MS-PCR(methylation – specific PCR) ,BRAF mutation was tested by IHC and real-time PCR.Table: 527P
| Feature | MLH1 methylated n = 90 | MLH1 unmethylated n = 80 | P | BRAF mutation n = 24 | BRAF wild-type n = 146 | p |
|---|---|---|---|---|---|---|
| Median age | 62y | 50y | 64y | 54y | ||
| Synchronic CRC | 3(3.3) | 8(10.0) | 0.078 | 1(4.2) | 10(6.8) | 0.962 |
| FDR or SDR with LS-related tumor | 17(18.9) | 14(17.5) | 0.815 | 3(12.5) | 28(19.2) | 0.617 |
| FDR or SDR with CRC | 12(13.3) | 32(40) | 0.000 | 0 | 44(30.1) | 0.002 |
| FDR with CRC | 9(10.0) | 27(35.0) | 0.000 | 0 | 36(24.7) | 0.016 |
| Revised Bethesda guidelines | 43(47.8) | 69(86.3) | 0.000 | 8(33.3) | 104(71.2) | 0.000 |
Results
52.9%patients display MLH1 promoter hypermethylation. As for BRAF status, the mutation rate tested by IHC and real-time PCR was 14.1% and17.1%, respectively, and the concordance rate was 92.1%. BRAF mutation did better on ruling out patients whose relatives had CRC history. Although patients who had unmethylated CRCs had a notably stronger family history of CRC, there were still 13.3% patients in the hypermethylation group having family history of CRC, indicating a likelihood of LS.
Conclusions
The mutation rate of BRAF in Chinese population with MSI CRCs was significantly lower than that in western countries, leading to a decreased specificity. Thus, BRAF mutation alone was not efficient to be a negative predictor of LS. Due to the high specificity of MLH1 methylation test and the high concordance rate of IHC and real-time PCR for BRAF mutation, patients who have MLH1 hypermethylation, BRAF wild-type tested by IHC and family history of CRC should be recommended for germline mutation test additional to those with MLH1 unmethylated CRCs.
Clinical trial identification
Legal entity responsible for the study
National Cancer Center, China.
Funding
Chinese Academy of Medical Science.
Editorial Acknowledgement
Disclosure
All authors have declared no conflicts of interest.
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