ABSTRACT
Lynch syndrome (LS), the most common form of familial CRC predisposition that causes tumor onset at a young age, is characterized by the presence of microsatellite instability (MSI) in tumors due to germline inactivation of mismatch repair (MMR) system. Two MMR genes namely MLH1 and MSH2 account for majority of LS cases while MSH6 and PMS2 may account for a minor proportion. In order to identify MMR genes causing LS in India, we analyzed MSI and determined expression status of the four MMR genes in forty eight suspected LS patient colorectal tumor samples. Though a majority exhibited MSI, only 58% exhibited loss of MMR expression, a significantly low proportion compared to reports from other populations. PCR-DNA sequencing and MLPA-based mutation and exonic deletion/duplication screening respectively, revealed genetic lesions in samples with and without MMR gene expression. Interestingly, tumor samples with and without MMR expression exhibited significant differences with respect to histological (mucin content) and molecular (instability exhibited by mononucleotide microsatellites) features. The study has revealed for the first time a significant proportion of LS tumors not exhibiting loss of MMR expression.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Mismatch Repair/genetics , Gene Expression/genetics , Adult , Aged , Colorectal Neoplasms/genetics , Female , Humans , India , Male , Middle Aged , Mutation/geneticsABSTRACT
PTEN is a well-defined tumor suppressor gene that antagonizes the PI3K/Akt pathway to regulate a multitude of cellular processes, such as survival, growth, motility, invasiveness, and angiogenesis. While the functions of PTEN have been studied extensively, the regulation of its activity during normal and disease conditions still remains incompletely understood. In this study, we identified the protein phosphatase-1 nuclear targeting subunit PNUTS (PPP1R10) as a PTEN-associated protein. PNUTS directly interacted with the lipid-binding domain (C2 domain) of PTEN and sequestered it in the nucleus. Depletion of PNUTS leads to increased apoptosis and reduced cellular proliferation in a PTEN-dependent manner. PNUTS expression was elevated in certain cancers compared with matched normal tissues. Collectively, our studies reveal PNUTS as a novel PTEN regulator and a likely oncogene.
Subject(s)
DNA-Binding Proteins/metabolism , Neoplasms/metabolism , Nuclear Proteins/metabolism , PTEN Phosphohydrolase/metabolism , Proto-Oncogenes/physiology , RNA-Binding Proteins/metabolism , Cell Line, Tumor , Cell Nucleus/metabolism , DNA-Binding Proteins/genetics , Fluorescent Antibody Technique , Humans , Immunoblotting , Immunohistochemistry , Immunoprecipitation , Neoplasms/genetics , Nuclear Proteins/genetics , Protein Transport/physiology , Proto-Oncogene Mas , RNA Interference , RNA, Small Interfering , RNA-Binding Proteins/genetics , Reverse Transcriptase Polymerase Chain Reaction , TransfectionABSTRACT
A 42-year-old continuous ambulatory peritoneal dialysis patient had presented to us with symptoms and signs of peritonitis, complicated by intestinal obstruction. On fourth day after admission, the Tenckhoff catheter was removed, as there was no response to intraperitoneal antibiotic. He developed hypotension during one of the hemodialysis sessions and was found to have low hemoglobin of 4 g/dL. Computed tomography revealed high-density fluid suggestive of fresh blood and clots in the peritoneal cavity. Conventional visceral angiogram with selective inferior mesenteric arterial cannulation revealed pseudoaneurysm arising from the descending branch of the left colic artery. An effort to embolize the pseudoaneurysm failed on 2 occasions. At laparotomy the pseudoaneurysm of the left colic artery was identified after evacuation of blood clots. The pseudoaneurysm was then excised and a lateral rent in the descending branch of left colic artery was repaired. The pus showed septate hyphae on potassium hydroxide mount. He was treated with injections of amphotericin B and oral voriconazole as the culture showed growth of Aspergillus flavus. The early fibrinous, ''easy'' flimsy adhesions formed during the initial intestinal obstruction phase might have resulted in formation of the pseudoaneurysm when the Tenckhoff catheter was removed with traction. The removal of the Tenckhoff catheter, drop in hemoglobin and distension of the abdomen were temporally so closely related that the pseudoaneurysm as a result of the traction removal of the catheter was undeniable. A controlled trial would provide firm evidence either in favor or against formal dissection for the removal of Tenckhoff catheters.
