Four genetic polymorphisms in the APC and MCC genes at chromosome 5q21 were analysed for loss of heterozygosity (LOH) in 97 primary squamous carcinomas and adenocarcinomas of the lung. LOH was ...identified in at least two polymorphic loci in 41 percent of informative cases. There was no significant difference in the frequency of LOH between squamous carcinomas and adenocarcinomas. Within the adenocarcinoma group, however, LOH appeared to be more common in tumours having a bronchial origin (5/9; 56 per cent) than in parenchymal adenocarcinoma (6/21; 29 per cent). All 32 tumours showing LOH at one or more polymorphic sites were examined for mutations in the mutation cluster region (MCR) of APC by single‐strand conformational polymorphism (SSCP) analysis. Mutations were not detected in any of these cases. We therefore propose that it is likely that a tumour suppressor gene on 5q other than APC is involved in the pathogenesis of lung cancer.
Samples of Barrett metaplastic specialized epithelium (SE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive adenocarcinoma (CA) derived from 36 esophagectomy specimens were ...studied for loss of heterozygosity (LOH) in APC and MCC and for expression of APC protein. Of 18 cases that were heterozygous (informative) for APC, LOH was found in none of 14 SE samples, 2 of 8 LGD samples, 3 of 11 HGD samples, and 5 of 17 CA samples. Immunohistochemically, markedly reduced expression of APC protein (< 50% positive cells) was found in 3 of 19 HGD samples and 4 of 35 CA samples but not in SE or LGD samples. Of 17 cases informative for the MCC gene, LOH was detectable in 1 of 14 SE samples, none of 7 LGD samples, none of 9 HGD samples, and 4 of 16 CA samples. Allelic loss of APC and/or loss of APC protein expression occurs earlier in the metaplasia-dysplasia-carcinoma sequence in Barrett esophagus than LOH in the MCC gene. The determination of alterations at APC or MCC would be of limited importance for the surveillance of patients with Barrett esophagus.
To investigate the role of loss of heterozygosity (LOH) in tumor suppressor genes (TSG) and microsatellite instability (MSI) in hepatocarcinogenesis, as well as their correlation with ...clinicopathologic features.
LOH in 6 TSG (APC, DCC, MCC, OGG1, p53 and RB1) was detected in 36 informative cases of hepatocellular carcinoma (HCC), among 92 surgically resected HCC. Thirteen polymorphic microsatellite markers were also studied in 15 of these cases by microdissection-based PCR amplification and direct DNA sequencing. The correlation between genetic alterations and clinicopathologic features was analyzed.
The overall incidence of LOH in HCC was 41.7% (15/36). There was no LOH in MCC gene. 46.2% (6/13) microsatellites showed LOH in 9 of the 15 cases of HCC (60%). Certain clinicopathologic differences were observed between cases (number = 7) with LOH in APC, OGG1 and DCC ("type I") and cases (number = 8) with LOH in p53 and RB1 ("type II"). The mean tumor size of these two types was 2.9 (+/- 1.7) cm and 7.2 (+/- 3.4
We present the clinical and laboratory findings in an institutionalised adult patient originally referred for autism. A high risk of colorectal cancer was predicted when an interstitial deletion of ...the long arm of chromosome 5, del(5)(q15q22.3), was detected in her lymphocytes and deletion of the MCC and APC genes confirmed by molecular analysis. Adenomatous polyposis coli and carcinoma of the rectum were subsequently diagnosed in the patient. She was profoundly mentally retarded, autistic, and had minor dysmorphic features consistent with those of previous patients with similar deletions. The deletion arose as a result of recombination within the small insertion loop formed at meiosis by the direct insertion (dir ins(5)(q22.3q14.2q15)) found in the patient's mother. This family further confirms the cytogenetic mapping of both MCC and APC genes to 5q22 and comparison with other recent cases suggests that both genes and their closely linked markers lie within the 5q22.1 subband.
To determine if the MCC, DCC or p53 gene is associated with susceptibility to hereditary non-polyposis colorectal cancer (HNPCC), these genes in normal cells from 12 HNPCC patients were analysed by ...polymerase chain reaction-single strand conformation polymorphism analysis. No changes which may alter the amino acid sequences of these genes were detected, suggesting that these genes are not associated with the susceptibility to HNPCC. Only one of nine HNPCC cancers showed mutations in the MCC and p53 genes on the same analysis. Loss of heterozygosity in chromosomes 5q, 17p, 18q and 22 was detected in four of the nine cancers, all of them being positive as to metastasis to lymph nodes. Abnormalities of the (CA)n repeat were found in six cancers, including all four without metastasis. These data indicate that tumor suppressor genes in chromosomes 5q, 17p, 18q and 22 are associated with the late stage of colorectal tumorigenesis in HNPCC, whereas the (CA)n repeat abnormalities are an early event of tumorigenesis and more essential to HNPCC.
Tumor suppressor genes APC and MCC were identified recently, and their chromosomal location was ascribed to chromosome 5q21.
Mutations in the APC gene give rise to familial adenomatous polyposis and ...occur in many perhaps even the majority, of sporadic
colon cancers. Loss of heterozygosity has been described in other human tumors such as lung and esophageal cancers. Here we
show loss of heterozygosity (LOH) in 87 patients with breast cancer for the APC and/or MCC loci using a polymerase chain reaction-LOH
assay. LOH affected loci in APC exons 11 and 15 in 9 of 35 (25%) and 4 of 34 (11%) heterozygous patients, respectively. LOH
at the MCC exon 10 locus occurred in 7 of 40 (17%) informative samples. These data suggest that allelic deletion of APC and/or
MCC is probably involved in the pathogenesis and/or progression of a subset of breast cancers.
A comprehensive mutation detection assay is described for the entire coding region and all splice site junctions of TP53. The assay is based on denaturing gradient gel electrophoresis, which follows ...either multiplex polymerase chain reaction (PCR) applied to DNA extracted from fresh or frozen tissue samples or nested PCR applied to DNA extracted from paraffin-embedded tissue samples. In both instances, the analysis can be performed under a single set of conditions. When testing the assay on DNA from cultured lung cancer cell lines and from paraffin-embedded Dukes C colorectal carcinomas, significant TP53 mutations were observed at high frequencies in 15 of 16 lung cancer cell lines (94%) and in 21 of 30 paraffin-embedded tissue samples of Dukes C colorectal carcinomas (70%). A substantial proportion of these significant mutations occurred outside the evolutionary conserved region of TP53 in 4 of 16 lung cancer cell lines (25%) and in 11 of 30 paraffin-embedded colorectal carcinomas (37%). This underscores the importance of a comprehensive TP53 mutation analysis in those instances that TP53 mutation is taken into account for diagnostic and prognostic purposes.
Loss of heterozygosity (LOH) at adenomatous polyposis coii (APC) and mutated in colon cancer (MCC) genes was investigated in 37 untreated human primary oral squamous cell carcinomas (SCCs) using the ...polymerase chain reaction. LOH was observed in 14 of 26 (53.8%) heterozygous (informative) patients at APC and 9 of 13 (69.2%) heterozygous patients at MCC. Homozygous deletion of MCC was detected in one patient. Of the 37 patients. 29 were informative at APC or MCC or both: LOH at APC and/or MCC was detected in 68.9% (20/29) of the cases. Ten cases were informative for both genes; LOH at both loci was found in only three of these cases. LOH at the APC and/or MCC was found in both early and advanced stages of oral SCCs. No significant correlation was observed between LOH at the APC and/or MCC locus and the patients' tobacco/betel quid consumption, tumour location. TNM status, or histological differentiation. These results suggest that LOH at the APC and/or MCC may be an early event and may play role in the pathogenesis of human oral SCCs in Taiwan.
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