Four disease groups and their healthy family members were assembled according to the presentation of gastric cancer: FG, familial clustering of gastric cancer (n = 32); CG, family with one or more colorectal and gastric cancers in first-degree relatives (n = 22); HS, seven HNPCC families corresponding to the Amsterdam criteria (AMS+) and 12 suspected HNPCC families which did not satisfy one of the criteria (AMS-), but no gastric cancer among first- and second-degree relatives (n = 19); and SG, sporadic gastric cancer (n = 33).
In an analysis of data from almost 4000 carriers of Lynch syndrome-associated mutations, we found history of gastric cancer to be independently associated with male sex, older age, mutations in MLH1 or MSH2, and with having a first-degree relative with gastric cancer.
Genetic and epigenetic analyses were positive in 6/36 MSI-H CRCs and 0/23 MSI-H GCs with pathological mutation in major mismatch repair genes, and in 7/36 MSI-H CRCs and 18/23 MSI-H GCs with methylated hMLH1 promoter (P<0.01), respectively.
Hereditary non-polyposis colorectal cancer is the most common known genetic syndrome that predisposes to various types of cancer including gastric cancer and occures mainly due to pathogenic germline mutations in DNA mismatch repair (MMR) genes, such as MLH1, MSH2 and MSH6.
Five different classes of methylation behaviors were found: (1) genes methylated in GC only (GSTP1 and RASSF1A); (2) genes showing low methylation frequency (<12%) in CG, IM, and GA, but significantly higher methylation frequency in GC (COX-2, hMLH1, and p16); (3) a gene with low and similar methylation frequency (8.8-21.3%) in four-step lesions (MGMT); (4) genes with high and similar methylation frequency (53-85%) in four-step lesions (APC and E-cadherin); and (5) genes showing an increasing tendency with or without fluctuation of the methylation frequency along the progression (DAP-kinase, p14, THBS1, and TIMP3).
We detected the epidermal growth factor receptor L858R, MSH2 R929* and telomerase reverse transcriptase amplification in the lung cancer specimen; CDH1 c.1320+1G>T mutation in the gastric cancer (GC) specimen; and MLH1 c.1896+5G>A germline mutation in the lung and GC specimens by 450 cancer-related gene mutations detection using next-generation sequencing technology.
The complete association between HM in hMLH1-C and MSI phenotype with gastric cancer provides an alternative diagnostic tool for detecting a favorable prognostic subgroup with MSI by using simple methylation analysis.
Families with clinical diagnosis of HNPCC (i.e. family history which fulfills the Amsterdam I/II criteria) was the strongest predictor for finding a deleterious mutation, and stomach cancer was the most commonly reported extra-colonic cancer in families found with a deleterious MLH1 or MSH2 mutation.
We verified that the frequency of MSI was similar in familial and sporadic GC settings, demonstrating that this molecular phenotype is not a hallmark of familial GC in contrast to what is verified in HNPCC.
One hundred and sixty-five GCs were classified into five subgroups using immunohistochemistry (IHC) and in situ hybridization (ISH) methods, based on a panel of seven markers (MLH1, PMS2, MSH2, MSH6, E-cadherin, P53, and Epstein-Barr virus mRNA).
A correlation was found only with tumor size and diffuse-type histology in MLH1-lost gastric carcinoma, but no correlation was observed in EBV(+) gastric carcinoma.
Previously, we suggested that HM in the proximal region of the hMLH1 promoter plays a critical role in progression of gastric cancer with MSI and this specific region should be analyzed for diagnostic use of hMLH1 HM.
We also observed a reduction of MSI phenotype after aspirin or sulindac treatment in a hMLH1-defective gastric cancer cell line SNU-1, which lacks COX-2 expression.Int.J.Cancer (Pred.Oncol.)84:400-403, 1999.