BRAF mutation or MLH1 methylation analysis combined with MSI testing could be a good alternative to screen Lynch syndrome patients in a cost effective manner.
Screening for the Lynch syndrome with immunohistochemistry followed by BRAF mutation testing only up to age 70 years cost $44,000 per incremental life-year gained compared with screening only up to age 60 years, and screening without an upper age limit cost $88,700 per incremental life-year gained compared with screening only up to age 70 years.
In a series of 38 patients who met clinical criteria for Lynch syndrome genetic testing, with loss of MLH1 expression in the tumor and with no germline mutations in the MLH1 gene (35/38) or with tumors presenting the BRAFp.Val600Glu mutation (3/38), we screened for constitutional methylation of the MLH1 gene promoter using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in various biological samples.
AGPS advocates appropriate government funding for the molecular tests necessary for Lynch syndrome screening (BRAF mutation, MLH1 methylation testing).
Of the 24 patients enrolled, four subjects (16.7%) had MSI high tumors: one subject was found to harbor a biallelic PMS2 mutation, one subject had Lynch syndrome (LS) with MSH6 mutation and two subjects had a loss of MLH1/PMS2 proteins/BRAF <sup>wild type</sup>/normal MLH1 sequence.
Detection of the V600E hotspot mutation in BRAF oncogene is extremely useful for the screening of hereditary non-polyposis colorectal cancer (Lynch's syndrome) and for the prediction of sensitivity to MEK inhibitors.
This study demonstrates that the IHC approach for both MMR deficiency and V600EBRAF mutation detections is the most efficient approach for Lynch syndrome screening in the Italian population.
The detection of BRAF mutation in colorectal cancer has several clinical applications: enabling the discrimination between sporadic and Lynch syndrome-related colorectal carcinoma, and providing warning of a poorer prognosis.
In this review the morphological correlates of five molecular subtypes are outlined: Type 1 (CIMP-high/MSI-H/BRAF mutation), Type 2 (CIMP-high/MSI-L or MSS/BRAF mutation), Type 3 (CIMP-low/MSS or MSI-L/KRAS mutation), Type 4 (CIMP-neg/MSS) and Type 5 or Lynch syndrome (CIMP-neg/MSI-H).
On the basis of the MMR expression pattern and BRAF mutation, the Concordant and Discordant groups were suspected to include Lynch syndrome, Lynch-like syndrome and sporadic MLH1 promoter hypermethylated CRC.
BRAF mutations have been proposed as a marker to exclude LS because they are generally absent in LS patients and present in sporadic colorectal cancer (sCRC) with MSI due to promoter hypermethylation of the MLH1 gene.
We conclude that BRAF IHC is highly concordant with 2 commonly used PCR-based BRAFV600E assays; it performed well in identifying MLH1 mutation carriers from the ACCFR and identified all cases of proven LS among the 1403 CRCs.
A total of 253 individuals with an MMRD CRC or EC from one institution were included for analysis in one of four groups: LS; MMRD+/germ-line-; MMRD tumor with variant of uncertain significance (MMRD+/VUS); and sporadic MSI-H (MMRD tumor with MLH1 promoter hypermethylation or BRAF mutation).
Hereditary non-polyposis colorectal cancer (HNPCC) may be the result of Lynch syndrome (LS) caused by mutations in mismatch repair (MMR) genes, a syndrome of unknown etiology called familial colorectal cancer type-X (FCCTX), or familial serrated neoplasia associated with the colorectal cancer (CRC) somatic BRAF mutation.
We propose the following algorithm: (1) no further molecular analysis should be performed for CRC exhibiting MLH1 methylation and BRAF mutation, and these cases should be considered as sporadic CRC; (2) CRC with unmethylated MLH1 and negative forBRAF mutation should be considered as Lynch syndrome; and (3) only a small fraction of CRC with MLH1 promoter methylation but negative forBRAF mutation should be true Lynch syndrome patients.
Testing for BRAF mutations in colorectal carcinoma (CRC) is important in the screening pathway for Lynch syndrome and is of prognostic value to guide management.
The cases demonstrated diffuse MLH1 loss associated with BRAF mutations and MLH1 promoter hypermethylation in keeping with sporadic dMMR, with presumed additional double hit mutations in MSH2+/-MSH6 rather than underlying LS.
HER2 overexpression (3+) was observed in 2 out of 62 patients, overexpression of p53 in 26 out of 62, abnormal expression of β-catenin in 12 out of 61, KRAS mutation in 21 out of 49, BRAFV600E mutation in 1 out of 40 patients, MMR deficiency (dMMR) in 14 out of 61 and was consistent with Lynch syndrome in 9 out of 14 patients.