Hoda A. Guirgis

Familial association of breast/ovarian carcinoma

Twelve pedigrees which show clustering of breast/ovarian cancer among female relatives are analyzed from a medical‐genetic standpoint. The significant linear decline in estimates of cumulative breast/ovarian cancer risk to females with diminishing genetic relationship to probands and index cases, plus the lack of excessive site‐specific cancer risk to male relatives, supports a sex‐limited genetic etiology. Breast/ovarian cancer typically occurred at an early age (x̄ = 50.6 years) in these kindreds compared to the general population, which is another characteristic of hereditary cancer. Examples of apparent mother to daughter and father to daughter genetic transmission of proclivity for breast/ovarian carcinoma were prevalent in the 12 pedigrees. Excluding probands and index cases, the estimated cumulative risk of breast/ovarian cancer to female progeny of affected mothers was 46% for the age interval 20–80 years, suggesting that affected mothers in the pedigrees are transmitting a deleterious cancer‐predisposing gene to one‐half of their daughters. Eight sibships involving putative carrier males contain a total of 15 female progeny over age 20. Of these, six have manifested breast cancer and five have had ovarian cancer. These results underscore the need for physicians to be cognizant of both males and females as potential transmitters of cancer in this familial tumor association.

Genetic and pathologic findings in a kindred with hereditary sarcoma breast cancer, brain tumors, leukemia, lung, laryngeal, and adrenal cortical carcinoma

A familial cancer aggregation comprising sarcomas, brain tumors, leukemias, and carcinomas of breast, larynx, lung, adrenal cortex, and other sites has been studied from a pathologic—genetic standpoint. Based upon sibships segregating for cancer, the genetic segregation parameter is estimated to be 45.6 ± 11% which is compatible with that expected for a rare deleterious autosomal gene showing complete dominance. Pathologic review of 16 tumors by bright field microscopy revealed variable occurrences of intranuclear cytoplasmic invaginations, intranucleolar bodies, and acidophilic intracytoplasmic inclusions in eight lesions. Two tumors showed both intranuclear cytoplasmic invaginations and intranucleolar inclusions. Morphological findings coupled with the observed pattern and distribution of cancer in the subject kindred suggest that the cancer‐prone genotype interacts with one or more exogenous factors in causing this familial tumor association.

Role of heredity in multiple primary cancer

The occurrence of multiple primary malignant neoplasms characterizes virtually all varieties of hereditary cancer. This report focuses on this phenomenon in 11 families with the Cancer Family Syndrome (heritable adenocarcinomas of the colon and endometrium) and a single extended kindred with sitespecific colon cancer. Of the 316 relatives with cancer in the 12 families, 68 (21.5%) had two or more primary malignancies and 59 (86.8%) of these multiple primaries involved the colon and/or endometrium. A pooled analysis of this resource revealed a consistent 3% risk for a second primary cancer in each year of survival following first onset. If a second primary occurs, the risk for a third is extremely high (6.9% per year), but shows a nonlinear trend with increasing survival following second onset. The high risk for development of extraprimary malignancies in patients from these kindreds indicates that careful consideration should be given to total removal of their principal target organs following the initial manifestation of cancer.

Aryl-Hydrocarbon Hydroxylase Activity in Lymphocytes from Lung Cancer Patients and Normal Controls

A radiometric assay for the determination of AHH activity in lymphocytes is described. Subjects included eleven male patients with histologically verified lung cancer (nine squamous cell carcinoma and two adenocarcinoma) and eleven age- and sex-matched controls. Lung cancer patients exhibited considerably greater variation and elevated levels of both AHH activity per se and AHH activity adjusted for total cellular DNA than control individuals. Methodology for AHH determinations and implications for lung cancer epidemiology and control are discussed.

Familial cancer syndromes: A survey

Several pre‐malignant diseases are known to have a genetic etiology. This study focuses attention upon precancerous disorders wherein the mode of inheritance is either well established or wherein it remains unclear even though familial aggregation of the particular diseases has been amply documented. These conditions will be discussed as useful models for systematic investigations of the host etiologic component in carcinogenesis. Our survey of hereditary precancerous syndromes includes multiple polyposis of the coli, the multiple mucosal neuroma syndrome, the Cancer Family Syndrome, Sipples syndrome, Von Recklinghausens neurofibromatosus, the multiple nevoid basal cell carcinoma syndrome, tuberous sclerosis, familial cutaneous malignant melanoma, and carcinoma of the breast. We have emphasized the heterogeneous character of many forms of familial cancer. Familial breast cancer associations clearly show such heterogeneity, as do colon cancer syndromes. Certain of these precancerous states are characterized by phenotypes which are clinically apparent, polyposis coli being the classic example. Others, such as Sipples syndrome are amenable to routine screening for biochemical markers. The bulk of putative genetic cancer‐predisposing problems require further basic investigation of modes of inheritance. Cancer control may be enhanced through communication of useful genetic and diagnostic information to primary care physicians. Referral of cancer clusters of possible genetic etiology from clinicians to human geneticists facilitates the necessary basic research.

Multiple primary cancers and prolonged survival: familial colonic and endometrial cancers.

SummaryWe describe features of multiple cancers in a small kindred wherein a cluster of tumors affecting various anatomic sites has been observed among eight direct-line relatives. Three of these individuals have had two or more primary malignancies, and one woman showed a remarkable tolerance to invasive cancer, having had four histologically verified neoplasms (cancers of the ovary, endometrium, and colon, and myelogenous leukemia). The constellation of tumors occurring at an early age among relatives of this kindred supports a genetic etiology.

HL A in cancer family 'N'

Actual HL‐A typing has been performed on 115 members of cancer family N, a large kindred (over 1000 members ascertained) showing the findings consistent with the cancer family syndrome. In the cancer‐prone line (branches C and D) of the family, 20 of 21 members with cancer had one HL‐A haplotype, HL‐A2‐HL‐A12 (relative odds ‐ 6.30), including some deceased family members who had haplotypes assigned. Eleven of 12 family members with cancer in branches C and D, actually typed, had HL‐A2‐HL‐A12 (relative odds = 6.06). The single exception showing cancer and another haplotype in branch D is a child of a family member with haplotype HL‐A2‐HL‐A12.

Familial breast cancer in a normal population.

Family histories of cancer of all anatomical sites, with particular emphasis upon carcinoma of the breast, were evaluated in more than 4000 consecutive persons independently at medical centers in Omaha (Group I, 3261 patients) and Detroit (Group II, 1058 patients). Findings in both groups were strikingly similar. Approximately one‐half of all families did not manifest cancer; approximately one‐third had cancer in a single first‐degree relative, while slightly more than 20% had cancer in two or more first‐degree relatives. Only 7% had cancer in three or more first‐degree relatives. Approximately 9.1% of lineages in Group I and 7.4% in Group II had a single member with breast cancer, while approximately 0.7% of lineages in Groups I and II had two or more first‐degree relatives with breat cancer. Familial tumor associations with breast were observed, with statistical significance found for breast and prostate cancer (p < 0.005 in Group I, p < 0.25 in Group II, and p < 0.005 when the two groups were combined). Implications for carcinogenesis and cancer control are discussed.

Carcinoembryonic antigen (CEA) in the cancer family syndrome

We present findings on plasma CEA in relatives and spouses from six kindreds manifesting the Cancer Family syndrome. The CEA distributions per se were transformed to √CEA to correct for skewness and kurtosis. Significant effects of age and duration of smoking were adjusted for by linear regression. Relatives were classified as: 1) cancer patients, 2) individuals at high genetic cancer risk (one or more first‐degree relatives affected, and 3) individuals at low genetic cancer risk (no first‐degree relatives affected) for statistical comparisons. Unrelated spouses were also classified into corresponding groups according to their direct‐line mates status. Cancer patients and relatives at high genetic risk had significantly greater mean VCEA than relatives at low genetic risk, and, surprisingly, unrelated spouses had mean levels of √CEA which were similar to that in the corresponding cancer risk class of their direct‐line mates. Our results suggest the existence of both a genetic and connubial effect on CEA, presumably due to a common environmental agent acting in concert with the degree of genetic predisposition to oncogenesis in this syndrome.

Survival Data from a Multiphasic Mobile Cancer Detection Unit

Individuals with early cancer rarely have symptoms, through it is at this state that the best prognosis can be afforded. 22 out of 5,232-patients screened in a Mobile Cancer Detection Unit (MCDU) received cancer diagnosis (exclusive of skin cancer). These patients have enjoyed much greater survival than expected. For instance, only three have died versus and expected 7.5. Calculations show that if all cancer patients in the United States had a similar increase in survival, then the lives of at least 120,000-persons could be extended each year. These limited data must be interpreted cautiously. Nevertheless, they do hold promise since only a few percentage points increase in survival when measured against the full impact of the cancer problem will show significant patient benefit.