Methods Patients with loss of MLH1/MSH2 on immunohistochemistry (IHC) or with microsatellite instability (MSI)high tumors were identified in our institutional LS database (February 1992–June 2010). Patients who subsequently underwent MLH1/MSH2 mutation analysis were reviewed. Patients with no identifiable MLH1 germline mutation were excluded if MLH1 promoter methylation was present or not asses...

BACKGROUND A positive family history, germline mutations in DNA mismatch repair genes, tumours with high microsatellite instability, and loss of mismatch repair protein expression are the hallmarks of hereditary non-polyposis colorectal cancer (Lynch syndrome). However, in ~10-15% of cases of suspected Lynch syndrome, no disease-causing mechanism can be detected. METHODS Oligo array analysis ...

PURPOSE MLH1 is a key DNA mismatch repair (MMR) protein involved in maintaining genomic stability by participating in the repair of endogenous and exogenous mispairs in the daughter strands during S phase. Exogenous mispairs can result following treatment with several classes of chemotherapeutic drugs, as well as with ionizing radiation. In this study, we investigated the role of the MLH1 prote...

PURPOSE Germline mutations in DNA mismatch repair genes, mainly MLH1 or MSH2, have been shown to predispose with high penetrance for the development of the clinical phenotype of hereditary nonpolyposis colorectal cancer (Lynch syndrome). Here, we describe the discovery and first functional characterization of a novel germline MLH1 mutant allele. EXPERIMENTAL DESIGN A large kindred including 5...

The antineoplastic activity of HDAC inhibitors is an unquestionable property of these compounds, but recent studies in tumor cells have revealed the potential of HDAC inhibitors (e.g., suberoylanilide hydroxamic acid SAHA, valproic acid VPA) to cause acquisition of HDAC inhibitor resistance. We report that trichostatin A (TSA), an HDAC inhibitor structurally related to SAHA, causes the acquisit...

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome characterized by predisposition to early-onset cancers. HNPCC is caused by heterozygous loss-of-function mutations within the mismatch repair genes MLH1, MSH2, MSH6, PMS1, and PMS2. We genotyped the MLH1 and MSH2 genes in patients suffering from Lynch syndrome and in 11 unrelated patients who were diagnosed wit...

While searching for germline mutations in MLH1 and MSH2 mismatch repair genes in patients aVected with hereditary non-polyposis colorectal cancer (HNPCC), we have observed that human chromosome 3 carries two main haplotypes of the housekeeping gene MLH1. This so called caretaker gene acts as a major guardian of the genome, and cells in which MLH1 is inactivated develop a characteristic mutator ...

While searching for germline mutations in MLH1 and MSH2 mismatch repair genes in patients aVected with hereditary non-polyposis colorectal cancer (HNPCC), we have observed that human chromosome 3 carries two main haplotypes of the housekeeping gene MLH1. This so called caretaker gene acts as a major guardian of the genome, and cells in which MLH1 is inactivated develop a characteristic mutator ...

PURPOSE Loss of function or expression of the mismatch repair gene MLH1 has been implicated in experimentally acquired resistance to cisplatin (CDDP) and other anticancer agents. The clinical significance of MLH1 expression was evaluated in advanced thoracic squamous cell carcinoma of the esophagus (ESCC) treated by neoadjuvant chemotherapy. EXPERIMENTAL DESIGN We investigated MLH1 and P53 ex...

DNA repair gene expression in a set of gastric cancers suggested an inverse association between the expression of the mismatch repair (MMR) gene MLH1 and that of the base excision repair (BER) gene DNA polymerase β (Polβ). To gain insight into possible crosstalk of these two repair pathways in cancer, we analysed human gastric adenocarcinoma AGS cells over-expressing Polβ or Polβ active site mu...