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B Bapat

Publications and source records attributed to B Bapat.

At least 37 records · Page 2Linked to original sources
PubMed1998

Overexpression of the nonpancreatic secretory group II PLA2 messenger RNA and protein in colorectal adenomas from familial adenomatous polyposis patients.

The synovial fluid or group II secretory phospholipase A2 (sPLA2) has been implicated in various inflammatory processes and has been shown to release arachidonic acid for prostaglandin biosynthesis. In human colorectal cancer, both arachidonic acid and eicosanoid levels are elevated. Recently, sPLA2 has been identified as a candidate gene that modifies the Apc gene in the Min mouse, a murine model for familial adenomatous polyposis (FAP). Loss of sPLA2 gene function results in susceptibility to the Min phenotype and the formation of multiple intestinal polyps, whereas mice expressing an active sPLA2 gene are resistant to polyp formation. Therefore, there are two potentially contrasting roles for sPLA2 in colon cancer; one is protection against polyp formation, and the other, the release of arachidonic acid for prostaglandin production and subsequent tumor promotion. To investigate these contrasting dual roles of sPLA2, we have examined the expression and sequence of the sPLA2 mRNA in normal mucosa and duodenal and colorectal polyps from FAP patients. In 11 of 14 patients, there was a significant increase in sPLA2 mRNA levels in the adenoma over the normal tissue. In some cases, there was over 100-fold increase in mRNA levels in the adenoma compared with normal tissue. Analysis of multiple adenomatous polyps from individual patients revealed that not all polyps contained elevated levels of sPLA2 mRNA. Immunoblot analysis also showed that sPLA2 protein expression was elevated in adenoma over normal tissue in five of six FAP patients analyzed. Furthermore, sequence analysis of sPLA2 mRNA present in these samples did not reveal mutations in the coding region. The implications of the up-regulation of sPLA2 in FAP is not clear, but unlike the Min mouse model, it does not seem to have a significant effect on polyp formation. In contrast, the high level of sPLA2 expression is more likely contributing to the elevated levels of arachidonic acid found in colorectal cancer and, in conjunction with the elevated expression of cyclooxygenase-2, could be another factor in tumor formation.

Adenoma↗
PubMed1998

Adenomatous polyposis coli gene mutation alters proliferation through its beta-catenin-regulatory function in aggressive fibromatosis (desmoid tumor).

Aggressive fibromatosis is a monoclonal proliferation of spindle (fibroblast-like) cells. A subset of lesions contain somatic truncating adenomatous polyposis coli (APC) gene mutations, and all of the lesions contain an elevated beta-catenin protein level. A major function of APC is to regulate beta-catenin protein level. Beta-catenin has a dual function in the cell: it is a member of the adherens junction, and it binds transcription factors in the tcf-lef family, transactivating transcription. Cell cultures from aggressive fibromatoses containing an APC mutation were studied. Transient transfection of the full-length APC gene caused decreased proliferation and beta-catenin protein level in these cultures. To determine whether beta-catenin protein level was responsible for the change in proliferation rate, stable transfections of deltaN89beta-catenin (a stabilized form that is not degraded by APC, but retains all other functions) were achieved in half of the cultures derived from each tumor, whereas the other half were transfected with an empty vector. Transfection of the full-length APC gene in cultures that were stably transfected with deltaN89beta-catenin did not result in a change in proliferation. The type I promotor of p56lck contains an HMG consensus region, to which members of the tcf-lef family can bind. p56lck was expressed in cultures not transfected with the full-length APC gene and in cultures transfected with the full-length APC gene and deltaN89beta-catenin, but not in cultures transfected with only the full-length APC gene. These data show that APC truncating mutations give aggressive fibromatosis cells a proliferative advantage through beta-catenin and suggest that beta-catenin acts to transactivate transcription.

Apoptosis↗
PubMed1998

Genotype-phenotype correlations in attenuated adenomatous polyposis coli.

Germ-line mutations of the tumor suppressor APC are implicated in attenuated adenomatous polyposis coli (AAPC), a variant of familial adenomatous polyposis (FAP). AAPC is recognized by the occurrence of <100 colonic adenomas and a later onset of colorectal cancer (age >40 years). The aim of this study was to assess genotype-phenotype correlations in AAPC families. By protein-truncation test (PTT) assay, the entire coding region of the APC gene was screened in affected individuals from 11 AAPC kindreds, and their phenotypic differences were examined. Five novel germ-line APC mutations were identified in seven kindreds. Mutations were located in three different regions of the APC gene: (1) at the 5' end spanning exons 4 and 5, (2) within exon 9, and (3) at the 3' distal end of the gene. Variability in the number of colorectal adenomas was most apparent in individuals with mutations in region 1, and upper-gastrointestinal manifestations were more severe in them. In individuals with mutations in either region 2 or region 3, the average number of adenomas tended to be lower than those in individuals with mutations in region 1, although age at diagnosis was similar. In all AAPC kindreds, a predominance of right-sided colorectal adenomas and rectal polyp sparing was observed. No desmoid tumors were found in these kindreds. Our data suggest that, in AAPC families, the location of the APC mutation may partially predict specific phenotypic expression. This should help in the design of tailored clinical-management protocols in this subset of FAP patients.

Adenomatous Polyposis Coli↗
PubMed1997

Familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC): a review of clinical, genetic and therapeutic aspects.

Familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) are two syndromes of colorectal cancer predisposition, inherited in an autosomal dominant fashion. They account for about 1% and 5-7% of all colorectal cancer cases, respectively. FAP is caused by germline mutations of a tumour suppressor gene, the adenomatous polyposis coli (APC) gene, whereas HNPCC results from genetic alterations of the DNA mismatch repair genes. Clinical manifestations in FAP include colonic as well as extracolonic sites (duodenum, eye, dental, nervous or connective tissues). In FAP, prophylactic colectomy is required in all affected patients and regular endoscopic check-up of the upper gastrointestinal tract is necessary to detect malignant transformation of duodenal polyps; medical management of complex desmoid tumours is preferred rather than surgery. In HNPCC, there are extracolonic associated endometrial, gastric, small bowel or brain carcinomas. At present time, for HNPCC patients, only preventive measures such as regular colonoscopic or gynecologic examinations are recommended, since prophylactic colectomy or hysterectomy are not considered to be routine procedures.

Adenomatous Polyposis Coli↗
PubMed1997

Using genetic information to make surgical decisions: report of a case of a 13-year-old boy with colon cancer.

PURPOSE: We report the case of a boy aged 13 years who was diagnosed with a Dukes B obstructing cancer of the sigmoid colon. At the time of diagnosis, he underwent a Hartmann's procedure with end colostomy. Because of his unusually young age, he was referred to the Familial GI Cancer Registry at Mount Sinai Hospital for genetic assessment. A detailed pedigree revealed no significant history other than lung cancer in his maternal grandfather. METHODS: We obtained his tumor specimen and performed molecular analysis of both normal colonic and tumor DNA. Specifically, we identified replication errors (RER) in the patient's tumor DNA when compared with normal colonic DNA. RER has been found in more than 90 percent of tumors from patients with Hereditary Nonpolyposis Colon Cancer (HNPCC) and is, thus, considered to be one of the hallmarks of this disease. Because HNPCC patients have a 40 percent risk of synchronous or metachronous tumors, the recommended surgery for HNPCC should be at least a subtotal colectomy with ileorectal anastomosis. RESULTS: Based on molecular results, we were able to recommend that the patient have a subtotal colectomy performed instead of merely colostomy closure, to reduce his lifetime risk of developing further colon tumors and to make surveillance of the remaining rectum relatively easy. In this patient, we subsequently identified a germline mutation of the mismatch repair gene hMSH2 that is implicated in HNPCC. The possibility of HNPCC should be considered in adolescents who are diagnosed with colorectal cancer, so appropriate surgical decisions can be made.

Adenocarcinoma, Mucinous↗
PubMed1996

MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma.

The MAD-related (MADR) family of proteins are essential components in the signaling pathways of serine/threonine kinase receptors for the transforming growth factor beta (TGFbeta) superfamily. We demonstrate that MADR2 is specifically regulated by TGFbeta and not bone morphogenetic proteins. The gene for MADR2 was found to reside on chromosome 18q21, near DPC4, another MADR protein implicated in pancreatic cancer. Mutational analysis of MADR2 in sporadic tumors identified four missense mutations in colorectal carcinomas, two of which display a loss of heterozygosity. Biochemical and functional analysis of three of these demonstrates that the mutations are inactivating. These findings suggest that MADR2 is a tumor suppressor and that mutations acquired in colorectal carcinomas may function to disrupt TGFbeta signaling.

Amino Acid Sequence↗
PubMed1996

Spontaneous intestinal carcinomas and skin neoplasms in Msh2-deficient mice.

Hereditary nonpolyposis colorectal cancer is associated with defects in DNA mismatch repair. Here, we characterize tumor susceptibility of the recently described Msh2-deficient mouse model. Within the first year of observation, all homozygous mice succumbed to disease, with lymphomas observed in at least 80% of the cases. The majority (70%) of animals 6 months or older developed intestinal neoplasms associated with APC inactivation. Microsatellite instability was more common in carcinomas than in adenomas, but uncommon in normal tissues. Some animals (7%) developed a variety of skin neoplasms analogous to the Muir-Torre syndrome. Msh2-/- mice implicate a direct role for mismatch repair in several neoplasms with striking phenotypic similarities to humans.

Adenomatous Polyposis Coli Protein↗
PubMed1996

A truncated hMSH2 transcript occurs as a common variant in the population: implications for genetic diagnosis.

Germline mutations of the hMSH2 gene are responsible for many cases of hereditary nonpolyposis colorectal cancer. While screening for hMSH2 gene mutations in hereditary nonpolyposis colorectal cancer kindreds, we observed that a previously reported germline mutation is in fact a common, alternatively spliced variant in the population. Using RT-PCR and the protein truncation test, the hMSH2 exon 13 deletion variant was found in more than 90% of individuals. The exon 13 deletion transcript was only present in lymphocyte RNA, no abnormalities were detected in genomic DNA flanking exon 13, and the deletion transcript is apparently not translated. These findings highlight further that caution should be exercised in providing genetic risk assessment on the basis of currently used germline mutation detection strategies.

Colorectal Neoplasms↗
PubMed1995

Evidence for a novel exon in the coding region of the adenomatous polyposis coli (APC) gene.

Germline mutations of the tumor suppressor gene APC cause familial adenomatous polyposis. Somatic APC alterations are involved in several sporadic neoplasms, including colorectal, duodenal, gastric, and esophageal carcinoma. The APC mRNA is encoded by 15 exons. Additional transcripts have been reported, due to alternative splicing of coding as well as noncoding regions. Two mRNA isoforms occur due to a deletion of exon 7 or a partial deletion of exon 9. We have identified a novel exon, flanked by APC exons 10 and 11, which is expressed as an alternatively transcribed product of the gene. Further, we have shown that the novel exon consists of a heptad repeat motif and is conserved across species.

Adenomatous Polyposis Coli↗
PubMed1995

MSH2 deficient mice are viable and susceptible to lymphoid tumours.

Alterations of the human MSH2 gene, a homologue of the bacterial MutS mismatch repair gene, co-segregate with the majority of hereditary non-polyposis colon cancer (HNPCC) cases. We have generated homozygous MSH2-/- mice. Surprisingly, these mice were found to be viable, produced offspring in a mendelian ratio and bred through at least two generations. Starting at two months of age homozygous-/- mice began, with high frequency, to develop lymphoid tumours that contained microsatellite instabilities. These data establish a direct link between MSH2 deficiency and the pathogenesis of cancer. These mutant mice should be good models to study the progression of tumours and also to screen carcinogenic and anti-cancer agents.

Animals↗
PubMed1994

Characterization of two novel adenomatous polyposis coli (APC) gene mutations in patients with familial adenomatous polyposis (FAP).

Patients with Familial Adenomatous Polyposis (FAP) manifest numerous colorectal adenomas as well as benign and malignant extra-colonic lesions. Adenomatous polyposis coli (APC) gene mutations are the underlying genetic defect in FAP. We analyzed germline DNA of 81 unrelated FAP patients and evaluated correlation of APC mutation genotype and clinical phenotype. Germline APC mutations were identified in 18 FAP patients including two novel 2 bp deletions at APC codons 1067 and 1259. FAP patients were screened for hypertrophic ocular fundus lesions, desmoids and peri-ampullary adenomas. As reported previously (Olshwang et al 1993b), a positive correlation for the frequency of retinal lesions and germline APC mutation was observed among all FAP patients except one. No significant correlation was observed for APC mutation genotype and the occurrence of desmoids and peri-ampullary adenomas. Genetic factors contributing to familial segregation of these lesions need further investigation.

Adenomatous Polyposis Coli↗
PubMed1994

Colorectal tumourigenesis.

Colorectal cancer is significant because of its lethality and high incidence in the Western world. Furthermore, it is a particularly suitable model for studying the events involved in the progression from normal tissue to invasive cancer. There is a great deal of epidemiological and histopathologic evidence to implicate the adenomatous polyp as the precursor to colorectal cancer. Moreover in recent years investigators have uncovered some of the molecular genetic events that underlie the progression from normal epithelium to polyp to cancer. It is hoped that an increased understanding of the molecular changes will afford opportunities for new diagnostic, prognostic and therapeutic strategies in the management of this disease.

Adenoma↗
PubMed1993

Improved predictive carrier testing for familial adenomatous polyposis using DNA from a single archival specimen and polymorphic markers with multiple alleles.

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition caused by mutations in a candidate tumor suppressor gene, adenomatous polyposis coli. Predictive carrier testing for FAP can be accomplished by DNA linkage or mutation detection analysis. In many FAP families all affected individuals are deceased. Archival tissue specimens, if available from such patients, are a useful source of DNA for molecular analysis. We investigated the carrier risk of a presymptomatic 5-year-old girl with a family history of FAP. An archival specimen of normal colonic tissue was only available from the proband's affected deceased father. We screened DNA extracted from this specimen with dinucleotide repeat (CA/GT)n polymorphic marker (D5S346) linked to the adenomatous polyposis coli gene and established that the proband is at more than 99% risk of developing FAP. The proband's increased risk status was subsequently confirmed by identification of a germline adenomatous polyposis coli gene mutation consisting of a 5 base pair deletion at codon 1061. This strategy of using DNA from archival specimens of affected, unavailable FAP patients will increase the number of at-risk individuals that can be diagnosed presymptomatically.

Adenomatous Polyposis Coli↗