Daphne Morrell

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.

The effect of the quality of papanicolaou smears on the detection of cytologic abnormalities

Controversy continues regarding the relation between the quality of Papanicolaou (Pap) smears, especially the presence of endocervical cells (ECC), with the finding of cytologic abnormalities.

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.

The Quality of Cervical Cancer Screening: A Primary Care Perspective:

The bulk of cervical cancer screening is performed by primary care providers; mostly nurses and physicians. The literature regarding the quality of this screening is largely described from three perspectives; clinical, laboratory, and public health. This article describes the primary care perspective regarding issues of quality in cervical cancer screening and suggests areas for im provement. The authors discuss how effectiveness of the test, sampling methods, interpretation by the labo ratory, and reporting results impact on the quality of cervical cancer screening. Other factors which influence the quality of screening such as access to care, recall intervals, communication with the patient, costs of test ing, and organizational issues are also reviewed.