Bisulfite analysis suggests that the mechanisms of hMLH1 silencing may depend on CpG density rather than site-specific methylation.Cancer 2003;98:1540-6.
Risk-reducing hysterectomy and bilateral salpingo-oophorectomy may be considered in women with Lynch/HNPCC to prevent gynecologic cancers and their associated morbidities.
In clinical applications RUNX3 and TSLC1 methylation may be utilized as molecular diagnostic markers, and hMLH1 and p16 methylation as predictors of malignancy in the stomach.
It is suggested that an understanding of the function of the FAP and HNPCC genes will lead to the development of cancer prevention strategies aimed at blocking the earliest stages of neoplastic development.
The methylation level of CDKN2A was higher in cancer with the L-haplotype of MTHFR than in that with the H-haplotype when cancers of proximal origin were considered (p=0.029). hMLH1 methylation also tended to be higher in proximal colon cancers of MTHFR L-haplotype (p=0.059).
The expression of hMLH1, hMSH2 and hMSH6 proteins evaluated by immunohistochemistry was altered in 39% of the cancers, whereas microsatellite instability assessed by PCR was detected in 43%.
miR-155 is an oncogenic miRNA that is often overexpressed in cancer and is associated with poor prognosis. miR-155 can target several DNA repair factors, including RAD51, MLH1, and MSH6, and its overexpression results in an increased mutation frequency in vitro, although the mechanism has yet to be fully understood.
Besides of colorectal cancer, extracolonic tumors occurred in stomach, endometrium, hepatobiliary system, and so on (8 gastric cancers, 6 endometrial cancers, 6 hepatobiliary system cancers and 19 others) can also be seen in Chinese ICG-HNPCC and sHNPCC families.
Loss of MLH1 and/or MSH2 gene expression significantly correlated with increases in malignancy, as evidenced by increases in the existence of metastatic lymph nodes (P = 0.0056), extensive invasion (P = 0.0007), and poor differentiation (P = 0.0992).
Our genome-wide expression profiling experiment demonstrates that cancer preceding changes are already seen in histologically normal colon mucosa and that decreased expressions of Mlh1 and other chromosomal segregation genes may form a field-defect in mucosa, which trigger MMR-proficient, chromosomally unstable CRC.
When losses of both MLH1 and PMS2 proteins are observed by IHC, MLH1 promoter methylation analysis is conducted to distinguish Lynch syndrome-associated endometrial cancer from sporadic cancer.
A borderline significant association between the MLH1-93 G/A polymorphism and cancer risk was observed in overall analysis [heterozygote: odds ratio (OR) = 1.15; 95% confidence interval (CI) 1.05-1.26; homozygote: OR = 1.21; 95% CI, 1.04-1.40; dominant model: OR = 1.13; 95% CI 1.01-1.26; recessive model: OR = 1.21; 95% CI 1.07-1.35, respectively].
Lynch syndrome (Hereditary non-polyposis colorectal cancer/HNPCC) is a cancer susceptibility syndrome which is caused by germline mutations in DNA mismatch repair (MMR) genes, in particular MLH1 and MSH2.
While somatic mutation is a major mechanism of the hMLH1 gene inactivation in hereditary form of human cancer, promoter hypermethylation appears to be primarily involved in the inactivation of the hMLH1 gene in sporadic form of human cancers.
Previously we showed that most missense variants in MSH6 do not impair MMR capability and are associated with no or low cancer susceptibility, whereas in MLH1, functional studies distinguished nontruncating mutations with severe defects from those not or slightly impaired in protein expression or function.
Inactivating mutations in the MLH1 gene cause the cancer predisposition Lynch syndrome, but for small coding genetic variants it is mostly unclear if they are inactivating or not.
Using The Cancer Genome Atlas RNA-seq datasets with the greatest MSI-H incidence, i.e. those from colon (n = 208), stomach (n = 269), and endometrial (n = 241) cancers, we trained an algorithm to predict tumor MSI from under-expression of the mismatch repair genes MLH1, PMS2, MSH2, and MSH6 and from 10 additional genes with strong pan-cancer associations with tumor hypermutation.
The results of many studies demonstrate the usefulness of IHC tests with monoclonal antibodies MSH2 and MLH1 in screening the microsatellite sequence instability within both spontaneous and hereditary malignant neoplasms.
The low frequency of mutations in MLH1 and MSH2 in this large series of cancers suggests that other MMR genes are responsible for the RER phenotype in endometrial cancers.
For patients with Lynch Syndrome (LS) (formerly known as hereditary nonpolyposis colorectal cancer or HNPCC), inheritance of one of several mutated mismatch repair genes (MMR) results in an increased risk for a variety of malignancies including colon, rectal, endometrial, urinary tract, gastric, small bowel and others [1].