Oncogenes and tumor suppressor genes involved in human lung carcinogenesis.
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Biomedical subjects
Publications and source records attributed to H Sugimura.
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A survey of hepatitis B virus (HBV) markers of Japanese immigrants, their descendants and native Bolivians was performed in two agricultural settlements in Bolivia. The prevalence of HBV markers in sera, either hepatitis B surface antigen (HBsAg) or its antibody (HBsAb), was higher in the Japanese (46.4%) than in the native Bolivian (12.9%) adult generations of both colonies. There was no significant difference between Japanese (4.3%) and Bolivian (0.9%) school children in one colony, but a high percentage (32.6%) was recognized among Japanese children in the other colony. The numbers of adw subtypes were unexpectedly high among these HBsAg positive Japanese children, compared to those in Japan. Antibody to hepatitis delta virus (HDV) was detected in one case. These data suggested that although horizontal transmission of adw HBV had occurred within the Japanese population, HBV and HDV were not endemic to this geographic area.
The extensive metabolizer phenotype of debrisoquine has been associated with increased risk of lung cancer, and it has been proposed that a molecular test for this phenotype is feasible. DNA restriction fragment length polymorphisms of the human debrisoquine 4-hydroxylase gene locus (CYP2D6), and the metabolic phenotype for debrisoquine have been studied in a group of healthy volunteers, a group of lung cancer patients and two control groups (chronic obstructive pulmonary disease patients and patients with cancers at sites other than the lung). Confirmation of four distinct XbaI allelic fragments (44, 29, 16/9 and 11.5 kb), previously identified among caucasians, was obtained. The 29 kb alleles were the most frequently observed in both poor and extensive metabolizers of debrisoquine. Alleles of 44 kb were found with approximately equal frequency among both poor and extensive metabolizers. The data are consistent with the hypothesis that the 11.5 and 44 kb fragments are associated with mutant alleles of the CYP2D6 gene, but the power of phenotype prediction by these alleles was less than that previously reported for a European (Swiss-German) population. Similarly, the data also show that 8% of 29 kb homozygotes are poor metabolizers (indicating that at least 28% of 29 kb fragments are also associated with mutant alleles) and are not therefore informative for predicting the debrisoquine phenotype. The 16/9 allele may represent either wild-type or mutant alleles. Restriction fragments of 44 kb were found more frequently among cancer patients and chronic obstructive pulmonary disease patients (30%) than among the healthy volunteer group (7%). Genotypes observed were not related to lung tumor histology. Furthermore, at least three EcoRI alleles were found to be in linkage disequilibrium with the 'mutant' 44 kb allele. These data suggest that the 44 kb allele can comprise three distinct haplotypes, in contrast to studies of a European population. These studies indicate that no single mutant CYP2D6 allele as determined by EcoRI appears to be associated with lung cancer, despite the findings that these patients are invariably of the extensive metabolizer phenotype.
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Activation of protooncogenes and inactivation of putative tumor suppressor genes are genetic lesions considered to be important in lung carcinogenesis. Fifty-four cases of non-small-cell lung cancer (23 adenocarcinomas, 23 squamous-cell carcinomas, and 8 large-cell carcinomas) were examined for loss of DNA sequences at 13 polymorphic genetic loci. Loss of heterozygosity was seen more frequently in squamous-cell carcinoma than in adenocarcinoma. The loss of DNA sequences from the short arm of chromosome 17 (D17S1 locus) was detected in 8 of 9 heterozygous cases of squamous-cell carcinoma and in only 2 of 11 heterozygous cases of adenocarcinomas. Furthermore, in 7 of these 8 squamous-cell carcinomas, loss of heterozygosity from chromosome 17 was accompanied by loss of DNA sequences from chromosome 11. The spectrum of allelic sequences lost from chromosome 11 was, however, similar in every type of carcinoma studied, and the data show two regions commonly deleted from chromosome 11 (11pter-p15.5 and 11p13-q13) that may have a role in the pathogenesis of all these types of non-small-cell bronchogenic carcinoma. Loss of DNA sequences from chromosome 3 was seen in 16 of 31 cases where the constitutive DNA was heterozygous-i.e., informative. These data included only 6 of 16 cases where loss of heterozygosity involved a chromosomal locus previously shown to be lost consistently in small-cell lung cancer (DNF15S2). Loss of heterozygosity at the chromosome 13q locus, D13S3, was seen in 9 of 21 informative cases, and in 2 cases, both adenocarcinomas, duplication of the intact DNA sequences suggested the possibility that mitotic recombination had occurred. Frequent DNA sequence deletions, including those from chromosome 17, in squamous-cell carcinomas may reflect the extensive mutagenic and clastogenic effects of tobacco smoke that may lead to inactivation of putative tumor-suppressor genes.
Fv-4 is a mouse gene which controls susceptibility to infection by ecotropic murine leukemia virus (MuLV). We previously cloned part of an endogenous MuLV associated with the resistance allele of the Fv-4 gene (Fv-4r). In this report, we describe an extended clone of the Fv-4r allele consisting of a 17-kilobase DNA fragment containing the retroviral sequence and its 5'-flanking sequence. The new DNA clone contains a truncated MuLV with delta pol-env-long terminal repeat sequences but no other MuLV-reactive sequence within 13 kilobases upstream of the truncated MuLV. Transfection of this clone into mouse cells led to transcription of Fv-4 env mRNA, expression of the Fv-4r-specific MuLV envelope protein, and resistance to infection with ecotropic MuLV but not amphotropic and dualtropic MuLVs. Restriction of ecotropic viruses appears to occur at or before viral cDNA synthesis. This result is consistent with a model of receptor interference for Fv-4 restriction. Our data also suggest that the 5' non-MuLV sequence is important for biological function, since a DNA clone which lacks most of the 5'-flanking sequence did not efficiently confer the resistance phenotype.
An asymptomatic 37-year-old woman visited our outpatient clinic for evaluation of an abnormal shadow of the right thorax detected by a mass roentgenographic survey. P-A chest roentgenogram showed a round homogeneous mass with a convex superior margin in the posterior portion of the right thorax. The CT with contrast enhancement and intravenous pyelography demonstrated the ectopic high location of the right kidney. Renal arteriography showed the right renal artery originated from the abdominal aorta at a normal level. Renal function tests showed no abnormality.
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Serologic tests for human T lymphotropic virus type I (HTLV-I) and hepatitis B virus infections were conducted in 1986 in two Japanese immigrant colonies located in Santa Cruz, Bolivia. A total of 322 adults (283 Japanese and 39 Bolivians) over age 35 years and 305 children (166 Japanese, 124 Bolivians, and 15 of mixed blood) aged 8-17 years were sampled at the time of a routine health checkup. The prevalence of antibody to HTLV-I was 17% in first-generation Japanese immigrants and 6% in second- or third-generation Japanese children. Prevalences among native Bolivians were 3% and 5% in adults and children, respectively. Seropositive Japanese immigrants and mothers showed clustering according to birthplace in endemic areas of Japan. The prevalence of either hepatitis B virus surface antigen (HBsAg) or antibody to HBsAg was 48% in Japanese adults, 21% in Japanese children, 13% in Bolivian adults, and 1% in Bolivian children. Seropositive adults did not show clustering according to birthplace, but children in one colony showed clustering and a narrow age range. A correlation of seropositivity between husbands and wives was found only for HTLV-I. The seropositivity was independent of whether an HTLV-I or a hepatitis B virus infection marker was present.
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An 83-year-old woman suffered from malignant astrocytoma originating in the temporal lobe. Autopsy revealed its extracranial metastasis to the liver, lung and bone marrow. The tumor tissue at the primary site was composed of plump, process-forming cells and small cells with scanty cytoplasm, and showed dural invasion. In the metastatic areas, most of the tumor cells were small cells, although proliferation of the plump cells in contact with perivascular connective tissue was marked, particularly in the liver. These plump cells were positively stained with antiserum to glial fibrillary acidic protein (GFAP), showing that the collagenous tissue was able to induce increased production of GFAP by the glial tumor cells.
Three cases of Peutz-Jeghers polyposis with carcinoma of the digestive organs are studied. Although mucocutaneous pigmentation was not present in two of the three patients, the features of intestinal polyposis are consistent with those of Peutz-Jeghers syndrome. One patient had a carcinoma of the pancreas and the other two had carcinomas with colonic Peutz-Jeghers polyps. Previous reports on carcinomas associated with Peutz-Jeghers syndrome are reviewed. An unusual location in the gastrointestinal tract, together with occurrence at an early age, characterize the carcinoma in Peutz-Jeghers syndrome. In Japanese patients, the large bowel is the site of the greatest number of carcinomas. On the other hand, Western patients showed a relatively even distribution. A possible surveillance protocol for early detection of gastrointestinal carcinoma in patients with Peutz-Jeghers syndrome is discussed.
Nine liver biopsies from six renal allografted patients suffering from liver injury were examined by light and electron microscope and immunostaining. The patients had never been on liver dysfunction prior to renal transplantation and after renal transplantation had been administered azathioprine continuously. These patients had shown HBs antigen negative sera. Three of these patients restored normal liver function after withdrawal of azathioprine. Accordingly, the liver diseases of the three were supposedly caused by azathioprine. The liver biopsies of six patients were histologically diagnosed as follows: chronic active hepatitis with severe cholestasis (1 patient), liver cirrhosis with cholestasis (1 patient), acute hepatitis (1 patient), and mild hepatitis (3 patients). The common pathological findings of six patients were degeneration of interlobular bile ducts and ductules, as well as degeneration of liver cells, and mild to moderate inflammatory cell infiltration of portal tracts and sinusoids. The degeneration of bile ductal and ductular cells were classified into two types: light microscopical finding showed vacuolar or eosinophilic cytoplasm and electron microscopic compatible findings showed hydropic cytoplasm scant of free ribosome and organelles, or dense cytoplasm rich in free ribosome and degenerated organelles. The basement membranes of interlobular bile ducts and ductules were always preserved.
A hospital based case-control study was conducted to investigate the factors affecting the development of lung cancer among young adults. A total of 185 inpatients (males: 128, females: 57) aged from 30 to 49 have been histologically classified in the National Cancer Center Hospital during the last 10 years. Most frequent was adenocarcinoma in both males (57.0%) and females (73.7%). Basic factors were obtained from clinical charts including smoking history, occupation and family history of cancers. Elevated risks were found for squamous cell carcinoma in patients with a history of smoking (all had smoked v. 15/20 for controls) and an occupation possibly related to respiratory irritations (15/20 v. 3/20 for controls). Heavy smokers were distributed more in the cancer patients. Moreover, the average Smoking Index among those without "at risk" occupation was 1,002 with the least being 700, while that with such an occupation was 723. Heavy smoking alone and a smoking/occupation combination could contribute to an early onset of squamous cell carcinoma. On the other hand, there were no significant risk factors for adenocarcinoma, the relative risk from a history of smoking being less than 1.00 and from a family history of cancer, approximately 1.00.
The recently increasing trend of lung cancer mortality in Japan was qualitatively analyzed. As the percentages of cases undergoing pathological autopsies in Tokyo were thirty for males and twenty-six for females during the period from 1979 to 1983, the histologically classified death rates in Tokyo could be estimated by combining the reported cases of death from lung cancer with the proportion of these of known histological type. The results indicated an increase in adenocarcinoma, and a decrease in squamous-cell carcinoma, except for the older age-group of men. The latter result suggested that the results were affected by the decreasing proportion of smokers and by the improvement in cigarette quality. The increase in small-cell and large-cell carcinoma, and the decrease in undifferentiated carcinomas, could be explained by problems associated with differing diagnostic standards. However, when these three different types of carcinoma were considered as a single type, the death rate was shown to be increased except in younger age-groups of women.
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Between 1965 and 1985, 72 (64 male and 8 female) cases of multiple primary lung cancer (MPLC) in the National Cancer Center Hospital, Japan, were reviewed, and a retrospective hospital-based case-control study was performed with special reference to the patients' smoking and family histories. Control cases were selected from patients with unicentric lung cancer (ULC) with a longer survival time than that for other patients with whom they were matched for age, sex, histologic examination of primary lung cancer, and residence in prefecture. The overall percentage of MPLC was higher in males (3.1%) than in females (1.8%). Of the total number of cases, 46 were synchronous and 26, metachronous. The same histology was recognized in 38 cases (53%), and squamous cell carcinomas were observed in 65% of MPLC cases, all of whom were smokers. At least half of the MPLC found in nonsmokers were adenocarcinomas. Habitual smokers, with a Brinkman index (BI) of more than 50, accounted for 90% of all cases of MPLC, although 81% of the controls were also habitual smokers. A positive relationship dependent on the number of cigarettes smoked was observed between the BI of smokers and the proportion suffering MPLC. There was a family history of cancer in 47% of MPLC cases while, for controls, this figure was 40%. It was found that 67% of patients with MPLC and 61% with ULC were drinkers. The influence of cigarette smoking on MPLC was confirmed, especially in the cases of squamous cell carcinoma and small-cell carcinoma.