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H Rothschild

Publications and source records attributed to H Rothschild.

At least 19 recordsLinked to original sources
PubMed2004

A major lung cancer susceptibility locus maps to chromosome 6q23-25.

Lung cancer is a major cause of death in the United States and other countries. The risk of lung cancer is greatly increased by cigarette smoking and by certain occupational exposures, but familial factors also clearly play a major role. To identify susceptibility genes for familial lung cancer, we conducted a genomewide linkage analysis of 52 extended pedigrees ascertained through probands with lung cancer who had several first-degree relatives with the same disease. Multipoint linkage analysis, under a simple autosomal dominant model, of all 52 families with three or more individuals affected by lung, throat, or laryngeal cancer, yielded a maximum heterogeneity LOD score (HLOD) of 2.79 at 155 cM on chromosome 6q (marker D6S2436). A subset of 38 pedigrees with four or more affected individuals yielded a multipoint HLOD of 3.47 at 155 cM. Analysis of a further subset of 23 multigenerational pedigrees with five or more affected individuals yielded a multipoint HLOD score of 4.26 at the same position. The 14 families with only three affected relatives yielded negative LOD scores in this region. A predivided samples test for heterogeneity comparing the LOD scores from the 23 multigenerational families with those from the remaining families was significant (P=.007). The 1-HLOD multipoint support interval from the multigenerational families extends from C6S1848 at 146 cM to 164 cM near D6S1035, overlapping a genomic region that is deleted in sporadic lung cancers as well as numerous other cancer types. Parametric linkage and variance-components analysis that incorporated effects of age and personal smoking also supported linkage in this region, but with somewhat diminished support. These results localize a major susceptibility locus influencing lung cancer risk to 6q23-25.

Chromosome Mapping↗
PubMed1998

Human longevity determinant genes.

Two recent major developments in the molecular biology of lower organisms point to genes as determinants of longevity. The first line of evidence is a selection system that established the participation of genes in aging and subsequently showed longevity to be a polygenic characteristic in Drosophila. The second validation of a genetic role in aging came from studies in which a mutation in an individual gene was found to modulate life span in nematodes. The achievements of genetics in the analysis of aging in mammals are less impressive than they have been for lower organisms, but this situation is changing. Although no genes have yet been directly implicated in prolonging life span in mammals, studies with mice have related immune function to longevity.

Aging↗
PubMed1994

Segregation analysis of smoking-associated malignancies: evidence for Mendelian inheritance.

Tobacco consumption is an established risk factor for cancer at a number of sites: oral cavity, esophagus, nasopharynx, lung, larynx, pancreas, bladder, kidney, and uterine cervix. These sites also demonstrate familial aggregation. To determine if evidence exists for a major gene controlling susceptibility to smoking-associated cancers, maximum likelihood segregation analyses were performed on 337 families (3,276 individuals) ascertained through a deceased lung cancer proband. Models were fitted that allowed for personal tobacco use and variable age of onset. The hypotheses of environmental transmission and no major gene were rejected (P < 0.005), but none of the Mendelian models could be distinguished. According to Akaike's Information Criterion, Mendelian dominant inheritance of an allele that produces cancer at an earlier age of onset provided the best fit to the data. The model suggests that 62% of the population are susceptible, and that the mean age-of-onset differs for men and women: at the mean level of tobacco exposure, female gene carriers are affected, on average, 24 years earlier than non-carriers (77 vs. 101), while in males the difference was 20 years (71 vs. 91). These findings extend our earlier observations on the genetic epidemiology of lung cancer and suggest that Mendelian factors may influence the risk of cancers that are known to be smoking associated.

Environment↗
PubMed1993

Evidence for a major gene effect in early-onset lung cancer.

Genetic segregation analyses that allowed for variable age of onset of lung cancer and smoking history were performed on 337 families, each ascertained through a lung cancer patient. Results indicated compatibility of the data with Mendelian codominant inheritance of a rare major autosomal gene that acts in concert with smoking to predispose carriers to lung cancer, by producing earlier onset of the cancer when controlling for equivalent smoking levels. Segregation at this locus could account for 69% and 47% of the cumulative incidence of lung cancer in individuals up to ages 50 and 60 respectively, but only 22% of all lung cancers in persons up to age 70. This decrease in the importance of the gene's contribution to overall lung cancer rates at later ages is most likely a reflection of an increasing proportion of noncarriers succumbing to the effects of long-term exposure to tobacco. A significant cohort effect was found, most likely due to differing smoking patterns before and after World War I, but in both cohorts the effect of a major locus could not be rejected.

Data Collection↗
PubMed1992

Lung cancer detection and prevention: evidence for an interaction between smoking and genetic predisposition.

The initiation and promotion of cancer is thought to result from a series of genetic mutations, some of which may be inherited. Our analysis of 337 lung cancer families suggested that, after allowing for an individual's pack-years of tobacco use, the pattern of disease was best explained by Mendelian codominant inheritance of an allele that produced earlier age of onset. Since lung cancer rarely occurs in the absence of exposure to tobacco, differences in the prevalence of smoking across generations could have a profound influence on the fit of genetic models. In the present study, families were partitioned into two groups, based on the birth cohort of the proband, i.e., born before World War I (age at death, greater than or equal to 60 years) or born after World War I (age at death, less than 60 years). This partition was chosen because the year 1915 signaled the start of the dramatic rise in tobacco use in the United States. In younger proband families, in which parents were more likely to smoke, Mendelian codominant inheritance provided the best fit to the data. In older proband families, for whom smoking among parents was less prevalent, the "no major gene" and "environmental" hypotheses were rejected; however, no Mendelian models could be distinguished. If the results on the families with the most homogeneous exposure to tobacco across generations (born after World War I) reflect the true underlying biology, then the influence of genetic factors in the pathogenesis of lung has been underestimated; the cumulative probability of lung cancer at age 80 for a noncarrier of the gene, at the average level of tobacco consumption, is close to zero, implying that virtually all lung cancer occurs among gene carriers. Identification of this putative genetic factor has profound implications for the detection and prevention of lung cancer.

Aged↗
PubMed1992

Lung cancer histologic type and family history of cancer.

The authors studied 300 patients with pathologically confirmed cancer of the trachea, bronchus, or lung in a 16-parish (county) area of southern Louisiana. Squamous-cell carcinoma was observed most frequently among these patients (39.3%), with nearly equal numbers of adenocarcinoma (25.0%) and small cell varieties (25.5%). Patients with large cell cancer, the least frequent type (10.3%), were 4.6 years younger on average than those with small cell (P less than 0.05) or squamous cell (P less than 0.05) neoplasias. Squamous cell neoplasia was more frequent among men (45.5%) than women (22.0%) (P less than 0.05). To assess whether family history differed according to the histologic cell type of the index family member, 248 patients were interviewed with regard to a family history of neoplasia. Those with small cell cancer had the highest family-size adjusted mean number of lung cancers per family (0.28). This was 2.2 times greater than the mean number of affected persons among relatives of patients with adenocarcinoma and 1.5 times greater than the mean for the families of patients with large or squamous cell types. However, none of these differences was statistically significant. Similar results were obtained when the total number of cancers at all sites was tabulated. Probands with small cell neoplasia were again most likely to have a positive family history, but the differences between histologic types were small. Although these data suggest an association, a larger study sample is required to determine conclusively whether or not a family history of lung cancer differs according to histologic type.

Adult↗
PubMed1992

Effect of cohort differences in smoking prevalence on models of lung cancer susceptibility.

Data on 337 lung cancer families were analyzed to determine if known cohort differences in parental cigarette consumption influence parameters from a segregation analysis. Previous results suggested that, after allowing for an individual's pack-years of tobacco exposure, Mendelian codominant inheritance of an allele that produced an earlier age of onset provided a good fit to the data. In the present study, the data were split into two groups of families: probands age 60 and over (born before WWI) and probands younger than age 60. This partition of the data by age of the proband was done to separate families in which there were parents who were less likely to smoke from those with parents more likely to smoke--predicated on the known increase of smoking prevalence after World War I. For the younger proband families (those with parents more likely to smoke), only Mendelian codominant inheritance adequately fit the data. The hypotheses of no major type, environmental transmission, and Mendelian dominant or recessive inheritance were rejected. In contrast to our earlier findings, the estimate of population susceptibility increased from 28% in the total data to 60% in this subset. In the older proband families (those with parents less likely to smoke), the no major type and environmental hypotheses were rejected; further, none of the Mendelian models could be distinguished. Our results demonstrate that cohort differences, probably in exposure to tobacco, can confound parameters of a segregation analysis, and suggest that the genetic component of lung cancer may be greater than previously estimated. It further suggests that susceptibility to lung cancer occurs as a function of susceptibility to the effects of tobacco smoking.

Adult↗
PubMed1990

Evidence for mendelian inheritance in the pathogenesis of lung cancer.

Segregation analyses that allowed for variable age of onset of lung cancer and smoking history were performed on 337 families, each ascertained through a lung cancer proband. Results indicated compatibility of the data with mendelian codominant inheritance of a rare major autosomal gene that produces earlier age of onset of the cancer. Segregation at this putative locus could account for 69% and 47% of the cumulative incidence of lung cancer in individuals up to ages 50 and 60, respectively. The gene was involved in only 22% of all lung cancers in persons up to age 70, a reflection of an increasing proportion of noncarriers succumbing to the effects of long-term exposure to tobacco.

Adult↗
PubMed1989

Replication of baboon endogenous virus in human cells. Kinetics of DNA synthesis and integration.

For the baboon endogenous virus to infect human cells a specific region on chromosome 6 is required for viral DNA replication and integration. In studying the kinetics of baboon endogenous virus DNA replication we show that linear DNA was synthesized as the predominant species after infection and that unintegrated DNA persisted after many cell passages. Examination of integrated DNA revealed the failure of the virus to integrate at early passages. With continuous replication, however, virus integration was observed, but at multiple sites in the host cell.

Animals↗
PubMed1988

Familial risk of cancer among randomly selected cancer probands.

Several investigators have reported that relatives of lung cancer probands have a greater-than-normal likelihood for developing some form of cancer. To evaluate whether this familial risk is general for probands with cancer at any site or limited to lung cancer probands, we did a case-control study in which probands having cancer affecting any body site were identified and their pedigree data were tabulated. Telephone interviews and a mailed questionnaire were used to obtain cancer histories and environmental exposures on the families of 41 lung cancer probands, 105 probands with cancer other than lung, and 127 spouse families. Cumulative tobacco exposure (P less than .05), occupational hazards (P less than .005), and age of the family relatives (P less than .0001) were found to be statistically significant predictors of cancer risk. With consideration given for these variables, we determined that siblings of lung cancer probands were at slightly greater risk of cancer of any kind (odds ratio [OR] = 1.43, P = .06) than siblings in the control group. Much of the elevated risk was attributable to an excess of lung cancer (OR = 2.49, P = .06). Siblings of non-lung/non-breast cancer probands were also determined to be at increased risk of lung cancer as well (OR = 1.61, P = .06). For parents, the risk was lower, although parental information may have been underreported.

Family↗
PubMed1987

Increased familial risk for non-lung cancer among relatives of lung cancer patients.

Reports of two or more anatomically distinct cancer types clustering in families suggest the possible existence of a susceptibility-to-cancer gene. To determine whether a genetic predisposition accounts for such familial aggregation, a retrospective case-control study was conducted in 1976-1979 of 337 southern Louisiana families in each of which a deceased lung cancer patient was used as the proband. A comparison of first-degree relatives of proband families with spouse (control) families revealed a significantly greater overall risk of cancer (odds ratio (OR) = 2.0, p less than 0.0001) in the proband group. Using logistic regression techniques to control for the confounding effects of age, sex, cigarette smoking, and occupational/industrial exposures, relatives of lung cancer probands maintained an increased risk of non-lung cancer (p less than 0.05). The crude odds ratio of a proband family having one family member with cancer was 1.67 compared with control families. Proband families were 2.16 times more likely to have two other family members with cancer. For three cancers and four or more cancers, the risk increased to 3.66 and 5.04, respectively. Each risk estimate was significant at the 0.01 level. The most striking differences in cancer prevalence between proband and control families were noted for cancer of the nasal cavity/sinus, mid-ear, and larynx (OR = 4.6); trachea, bronchus and lung (OR = 3.0); skin (OR = 2.8); and uterus, placenta, ovary, and other female organs (OR = 2.1). These data support the hypothesis of a genetic susceptibility to cancer in families with lung cancer.

Aged↗
PubMed1986

Increased familial risk for lung cancer.

For the determination of whether lung cancer clusters in families, an analysis was conducted on demographic and morbidity-mortality data, occupational and industrial experiences, and tobacco use practices for family members of 336 deceased lung cancer probands and 307 controls (probands' spouses). First-degree relatives of probands, compared with first-degree relatives of controls, showed a strong excess risk for lung cancer. Overall, male relatives of probands had a greater risk for lung cancer than did their female counterparts, and the risk was fourfold for parents of probands as compared with parents of spouses. Female relatives of probands over 40 years old were at nine times higher risk than similarly aged female controls, even among those who were non-smokers and who had not reported excessive exposure to hazardous occupations; the risk was fourfold to sixfold for heavy smokers. After control for the confounding effects of age, sex, cigarette smoking, and occupational and industrial exposures, relationship to proband remained a significant determinant of lung cancer, with a 2.4-fold greater risk among relatives of probands.

Adult↗
PubMed1983

Histopathology of corneal leukoma and fibroma in the ACL syndrome.

Corneal tissues of four persons and a buccal fibroma from one of these persons with ACL syndrome, an autosomal dominant disorder, were evaluated clinically and microscopically. The corneal lesions appeared as a gray epithelial infiltrate over the cornea, destroying Bowman's membrane. Light and electron microscopic images of both types of lesions showed abnormal accumulation of granular mucopolysaccharide material and extensive aberrant orientation of collagen fibers. The authors postulate that the mucopolysaccharide accumulation is involved in the pathogenesis of the syndrome.

Acromegaly↗
PubMed1983

Sugarcane farming--is there a link with cancer?

In the United States, there is an epidemic of lung cancer, which causes more deaths annually than any other form of cancer. During 1950-1969, 27 of Louisiana's 64 parishes ranked in the upper 100 US countries for lung cancer mortality. Many of the rural southern parishes in the upper decile for lung cancer were geographically associated with sugarcane production and processing area. In a retrospective case-control study of this excess lung cancer mortality it was found that persons engaged in sugarcane farm-related occupations have a significantly increased risk of mortality due to this disease. To expand this observation, a survey of the environmental exposures of sugarcane workers is being conducted.

Arsenicals↗
PubMed1982

Histologic typing of lung cancer in Louisiana.

To determine whether histologic patterns differed in the high- and low-lung cancer mortality parishes (counties) of Louisiana and whether the findings in the state differed from those in other parts of the United states, we studied the available histopathologic materials for 272 persons of the 815 who died of lung cancer in ten southern, nonurban Louisiana parishes during a seven-year period from 1971-1977. Squamous-cell carcinoma and small-cell anaplastic carcinoma were the most common tumor types, closely followed in frequency by adenocarcinoma, confirming reports by other investigators of a change during the past decade in the prevalence of various histopathologic types of lung cancer. The distribution of histopathologic types was not different for high- and low-mortality parishes but differed significantly from other areas of the U. S. Three persons had diagnoses consistent with pleural mesothelioma. Occupational histories obtained from relatives showed that one of those persons was a homemaker and the other two were sugarcane farmers with no discernable exposure to asbestos.

Adenocarcinoma↗
PubMed1982

An increased risk for lung cancer mortality associated with sugarcane farming.

In a study to determine putative occupation-related factors responsible for the excessive mortality due to lung cancer in southern Louisiana, the next-of-kin were interviewed of 284 of 400 persons (71%) randomly sampled from a total of 815 persons who died of lung cancer during 1971 through 1977 and had lived in any of 10 parishes (counties) of southern Louisiana. Of the decedents, 108 (38%) had been employed for at least 6 months as sugarcane farm workers at some time during their lives. Logistic regression analysis indicated this industrial involvement differed significantly (P less than 0.0001) from that of a control group, consisting of persons who had died of any cause other than lung cancer and who were matched for year of death, age, sex race, and parish of residence; only 58 (20%) matched controls had had sugarcane farm employment (odds ratio = 2.4; 95% confidence interval, 2.0-2.9). Employment in other industries or tobacco consumption could not account for the elevated risk of lung cancer mortality associated with sugarcane farming. After adjustment for smoking, the relative risk estimate of lung cancer mortality for sugarcane farm workers was 2.4 (95% confidence limits, 1.7-3.6). The sugarcane farmers who died with lung cancer had worked for longer periods in the sugarcane farm industry than did those sugarcane farmers in whom lung cancer did not develop (P = 0.006). No specific histopathologic cell type was noted to be increased in persons who had been employed in sugarcane farming; however, 2 sugarcane farmers had had mesotheliomas.

Age Factors↗