Non-truncating hMLH1 variants identified in Slovenian gastric cancer patients are not associated with Lynch Syndrome: a functional analysis report.
Summary of "Non-truncating hMLH1 variants identified in Slovenian gastric cancer patients are not associated with Lynch Syndrome: a functional analysis report."
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. Impaired MMR activity can lead to microsatellite instability (MSI) in tumor tissues. Interpreting the pathogenic significance of identified mutations in MMR genes, especially missense alterations and short in-frame deletions and insertions is challenging and functional analysis is often needed to accurately assess their pathogenicities. The purpose of this study was to evaluate functional significance of MLH1 missense mutations, previously identified in unrelated Slovenian patients with MSI-positive gastric carinomas. A novel in vivo yeast-based approach and in silico predictions were used. Variant E433Q was characterized for the first time and was shown to have no effect on MLH1 protein function. Functional analysis of amino acid rearrangement K618A, with previously reported contradictory results of its pathogenicity, suggests that the variant is a neutral polymorphism. Results of our study imply that there is either germline mutation or an epigenetic inactivation of another MMR gene, which causes MSI phenotype in the referred gastric cancer cases.
Affiliation
Department for Biosynthesis and Biotransformation, National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia, matjaz.vogelsang@ki.si.
Journal Details
This article was published in the following journal.
Name: Familial cancer
ISSN: 1573-7292
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21136174
- DOI: http://dx.doi.org/10.1007/s10689-010-9409-7
Medical and Biotech [MESH] Definitions
Gastric Stump
That portion of the stomach remaining after gastric surgery, usually gastrectomy or gastroenterostomy for cancer of the stomach or peptic ulcer. It is a common site of cancer referred to as stump cancer or carcinoma of the gastric stump.
Mucin 5ac
A gel-forming mucin that is primarily found on the surface of gastric epithelium and in the RESPIRATORY TRACT. Mucin 5AC was originally identified as two distinct proteins, however a single gene encodes the protein which gives rise to the mucin 5A and mucin 5C variants.
Wnt2 Protein
A proto-oncogene protein and member of the Wnt family of proteins. It is frequently up-regulated in human GASTRIC CANCER and is a tumor marker (TUMOR MARKERS, BIOLOGICAL) of gastric and COLORECTAL CANCER.
Gastric Dilatation
Abnormal distention of the STOMACH due to accumulation of gastric contents that may reach 10 to 15 liters. Gastric dilatation may be the result of GASTRIC OUTLET OBSTRUCTION; ILEUS; GASTROPARESIS; or denervation.
Cancer Care Facilities
Institutions specializing in the care of cancer patients.
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