Charles L. Chase

Incidence of Cancer in 161 Families Affected by Ataxia–Telangiectasia

BACKGROUND Ataxia-telangiectasia is an autosomal recessive syndrome in which cancers develop in affected homozygotes at a rate approximately 100 times higher than in unaffected age-matched subjects. Retrospective studies have shown that persons heterozygous for the ataxia-telangiectasia gene, who make up about 1 percent of the general population, also have an excess risk of cancer, particularly breast cancer in women. Patients with ataxia-telangiectasia and cells derived from homozygotes and heterozygotes are unusually sensitive to ionizing radiation. METHODS Cancer incidence and mortality, mortality from ischemic heart disease, and mortality from all causes were compared prospectively for a mean of 6.4 years in 1599 adult blood relatives of patients with ataxia-telangiectasia and 821 of their spouses, who served as controls, in 161 families affected by ataxia-telangiectasia. In a case-control substudy, we compared documented occupational and fluoroscopic diagnostic exposures to radiation in the 19 female blood relatives in whom breast cancer was first diagnosed during the period of prospective observation with the exposures in 57 matched blood relatives who did not have breast cancer. RESULTS Cancer rates were significantly higher in the group of blood relatives than in their spouses, specifically in the subgroup of 294 blood relatives who were known to be heterozygous for the ataxia-telangiectasia gene. The estimated risk of cancer of all types among heterozygotes as compared with noncarriers was 3.8 in men and 3.5 in women, and that for breast cancer in women was 5.1. Among the blood relatives, women with breast cancer were more likely to have been exposed to selected sources of ionizing radiation than controls without cancer (odds ratio = 5.8, P = 0.005). Male and female blood relatives also had 3-fold and 2.6-fold excess mortality from all causes, respectively, from the ages of 20 through 59 years. CONCLUSIONS The ataxia-telangiectasia gene predisposes heterozygotes to cancer, particularly breast cancer in women. There is also excess mortality from all causes in adults under the age of 60. Diagnostic or occupational exposure to ionizing radiation probably increases the risk of breast cancer in women heterozygous for ataxia-telangiectasia.

Breast and Other Cancers in Families with Ataxia-Telangiectasia

Patients who are homozygous for ataxia-telangiectasia have an exceptionally high incidence of cancer. In a group of families expected to have a high proportion of heterozygotes for ataxia-telangiectasia, we tested the hypothesis that such heterozygotes, estimated to make up 0.68 to 7.7 percent of the U.S. white population, also have an excess cancer risk. Retrospective cancer incidence rates in adult blood relatives of patients with ataxia-telangiectasia in 110 white non-Amish families were significantly elevated over the incidence rates in spouse controls (rate ratios, 1.6 for men [P = 0.032]; 2.0 for women [P = 0.013]). For persons who are heterozygous for ataxia-telangiectasia, the relative risk of cancer was estimated to be 2.3 for men (P = 0.014) and 3.1 for women (P = 0.004). Breast cancer in women was the cancer most clearly associated with heterozygosity for ataxia-telangiectasia (rate ratio, 3.0 [P = 0.028]; heterozygote relative risk, 6.8 [P = 0.006]). On the basis of this estimated relative risk of 6.8 and an estimated heterozygote frequency in the general population of 1.4 percent, 8.8 percent of patients with breast cancer in the U.S. white population would be heterozygous for ataxia-telangiectasia. We conclude that heterozygous carriers of the gene for ataxia-telangiectasia have an excess risk of cancer, particularly breast cancer in women.

Cancer predisposition of ataxia-telangiectasia heterozygotes☆

Ataxia-telangiectasia (A-T) is a progressive neurologic disorder in which there is varied immune dysfunction, an excess sensitivity to ionizing radiation, and a striking predisposition to cancer. It is the autosomal recessive syndrome for which there is the strongest evidence, derived from retrospective studies of cancer incidence and mortality in A-T families, that the heterozygote is predisposed to cancer. We present, in tabular form, the specific cancer sites or types most likely to be associated with A-T heterozygosity. These include solid tumors of the breast, pancreas, stomach, bladder, and ovary, and chronic lymphocytic leukemia. We also introduce a new method to test these associations. As soon as molecular probes for the A-T allele(s) are available, this new research design will be used to test rigorously each association, hypothesized on the basis of previous data, between a specific cancer site and A-T heterozygosity.

Cancers in 44 families with ataxia-telangiectasia

Cancer incidence was measured retrospectively in 574 close blood relatives of white ataxia-telangiectasia (A-T) patients and 213 spouse controls in 44 previously unreported families. The cancer incidence rate in the adult blood relatives was significantly elevated over the rate in the spouse controls (rate ratio = 3.9, p less than 0.01). For heterozygous carriers of the A-T gene, the relative risk of cancer was estimated to be 6.1 (p less than 0.005) as compared with nonheterozygotes. The most frequent cancer site in the blood relatives was the female breast, with nine cancers observed. These findings provide further support for the hypothesis that heterozygotes for the A-T gene are predisposed to cancer.

Skin Color, Status, and Mate Selection'

Data from a sample of 350 Negro married couples in Washington, D. C., are analyzed to examine the changing relationship between status attributes, mate selection, and skin color, by comparison of duration-of-marriage cohorts. We find that the traditional status advantage of light-skinned women holds for all cohorts, with little indication of change. For men, on the other hand, darker-skinned men experienced better status and mate-selection opportunities in more recent cohorts than in earlier ones. The higher job-mobility orientation of dark-skinned men evidently explains their improved mobility. These findings suggest a change in the evaluation of differential skin color for men within the Negro community.

Expectation fulfillment as a measure of patient satisfaction

Abstract Previous efforts to determine to what degree patients are satisfied with clinical experiences have been frustrated because of the tendency for patients to give positive, socially acceptable, and invariant answers to postexperience questioning. A new questionnaire was designed and given to 121 gynecologic clinic patients in which expectation was measured as a pretest and fulfillment as a posttest of the same six items. Of a total of 804 responses, 197 expressed increased, and 167 decreased, satisfaction with specific elements of care, a much greater variance than previously reported. Modifications are suggested to increase this tests value in service evaluation.

Diabetes Mellitus in Ataxia-Telangiectasia, Fanconi Anemia, Xeroderma Pigmentosum, Common Variable Immune Deficiency, and Severe Combined Immune Deficiency Families

The hypothesis that heterozygous carriers of genes for certain autosomal recessive syndromes may be predisposed to diabetes was tested by comparing diabetes incidence from age 20 to 69 yr in blood relatives to that in spouse controls among 7999 adult family members of patients with one of five autosomal recessive syndromes: ataxia-telangiectasia (A-T), Fanconi anemia (FA), xeroderma pigmentosum (XP), common variable immune deficiency (CVID), and severe combined immune deficiency (SCID). FA and A-T families were studied because earlier findings in family members and the frequency of diabetes in homozygotes suggested that heterozygotes might also be predisposed to diabetes. The XP, CVID, and SCID families were included to see what analysis of family data would reveal when there was no prior evidence for a gene-diabetes association. The diabetes rate ratios of 2.6 and 4.2 among FA and SCID females, respectively, were significantly elevated. For female FA heterozygotes specifically, the estimated relative risk of 5.1 for developing diabetes was also significantly elevated. Among males, the most pronounced, although not statistically significant, findings were an elevated rate ratio of 2.2 for A-T males and a low-rate ratio of 0.5 for CVID males. The results suggest that heterozygotes for some of the diabetes-associated autosomal recessive syndromes may themselves be predisposed to diabetes.

Reduction of Low Birth Weight Birth Rates by the Prevention of Unwanted Pregnancies

To determine a correlation between prevention of unwanted pregnancies and the reduction of births under 2500 grams (low birth weight: LBW) the Family Planning Evaluation Project (FPEP) of HEW monitored pregnancy wantedness in 3030 black women and 4891 white women delivering from December 1971 to May 1972. Sampling consisted of random filling of quotas by 60 major hospitals by race per week. Women whose infants died or appeared moribund in the first 24 hours were not interviewed. Overall LBW birth rates were 5% for whites and 10.6% for blacks. Among whites there was a significant difference in LBWB rates for wanted and unwanted pregnancies (4.3% compared to 6.6% p less than .05). Mathematically removing the unwanted births produced insignificant difference in LBWB rates for both races. The effects of parity marital status socioleconomic status and education on LBWB rates were compared. A striking difference appears between LBWB rates for unwanted and wanted births to women with more than 12 years of education (blacks: 11.8% vs. 2.4%; whites: 10.2% vs. 2.4%). Eliminating unwanted pregnancies on group rates for women known to be high risk for births under 2500 grams (low education and income unmarried) produced insignificant effect on data. Overall results indicate that prevention of unwanted pregnancies will insignificantly reduce overall LBW birth rates and that reduction of national LBWB rates is a poor measure of cost-effectiveness in family planning programs.

Testing the significance of risk estimates for the predisposition of heterozygotes to common diseases

A maximum‐likelihood method has been used previously to estimate, from family studies, the relative risk of common disorders for heterozygous carriers of genes for certain autosomal recessive syndromes. In this paper statistical significance of relative risk estimates was evaluated using critical values from computer‐generated sampling distributions of the test statistic. In several practical cases a significance test based on the computer‐generated distribution was more conservative than a test which assumed normality for the sampling distribution.