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We know cancer as an environmental disease primarily because of the evidence linking smoking and lung cancer. But we have also learned in the past decade that cancer arises from [...]

Background: Cancer has long been recognized to have a familial component. Elevated risks for cancers at the same site for relatives of cancer probands have been reported for both common cancers and a number of the rarer cancer sites. For a particular cancer site, however, the estimated risks to relatives have varied considerably depending on criteria for selection of probands, how cancers were determined in relatives, and overall study design. Not surprisingly, the estimated risks of other cancers in relatives of probands with cancer at a given site have been subject to even more variation. Purpose: The aim of this study was to use the Utah Population Database resource to systematically study familial clustering of 28 distinct cancer site definitions among first-degree relatives (parents, siblings, and offspring) of cancer probands. Methods: We estimated familial relative risks from the Utah Population Database by identifying all cases of cancer in these first-degree relatives. These observed values were compared with those expected based on cohort-specific internal rates calculated from 399 786 relatives of all individuals in the Utah Population Database known to have died in Utah. Results: All sites showed an excess of cancers of the same site among relatives, with thyroid and colon cancers and lymphocytic leukemia showing the highest familial risks. When the analyses were restricted to cases with early ages at diagnosis, increased familial components for most cancer sites became evident. A significant difference in familial relative risk (FRR) between male (FRR = 4.04; 95% confidence interval [CI] = 3.13-5.07) and female (FRR = 2.24; 95% CI = 1.54-3.08) probands was found for colon cancer. Highly significant familial associations (one-sided; P < .001) were found among breast, colon, and prostate cancers and between breast and thyroid cancers. Statistically significant (one-sided, P < .01) associations were also found between tobacco-associated sites (lung, larynx, lip, and cervix). Conclusions: This study represents a unique comprehensive population-based study of familial cancer. The familial associations reported here will be useful in generating hypotheses about specific genetic and environmental factors that can be tested in genetic linkage and case-control studies.

Background: Mutation of a specific, but as yet unidentified, gene BRCA1 on chromosome 17q results in increased susceptibility to breast and ovarian cancer. It is important to know the effects of this gene in terms of the age-specific risks of these cancers and the potential interaction of this gene with other known risk factors. Purpose: We performed detailed studies on a large multi-generational family, in which there is known 17q-linked breast and ovarian cancer, in order to characterize the effects of the BRCA1 mutation on development of breast and ovarian cancer. Methods: Data from the Utah Population Database were used to identify a family (identified as K2082) with a cluster of premenopausal breast cancer and ovarian cancer at any age. Blood samples from 195 members of the family were obtained and these individuals were genotyped for a series of four chromosome 17q polymorphic markers. Information on reproductive history, cancer incidence and treatment, and lifestyle factors was collected on 72 women in the family by questionnaire or through contact with living relatives. Results: Odds in favor of linkage of breast and ovarian cancer in this family to the BRCA1 region of chromosome 17q are greater than [10.sup.8] to 1. The estimated risks for breast or ovarian cancer because of the BRCA1 mutation in this family are 40% by age 50 years and 90% by age 70. No differences between affected and unaffected older BRCA1 gene carriers were observed for a number of known epidemiologic risk factors for these cancers. The gender of the parent from whom the mutant BRCA1 allele was inherited was significantly associated with phenotypic expression (P = 04). A recombinant which places BRCA1 distal to the marker Mfd191 was observed. Conclusions: Women with the BRCA1 mutation are at increased risk of developing breast and ovarian cancer. In our study population, the mutation appears to confer a lower risk of cancer at younger ages than found in previous studies. Continued interaction with family K2082 will be useful in longitudinal follow-up studies and in studies of the psychosocial implications of providing DNA diagnosis of BRCA1.

Breast cancer is the most common cancer among American women. Because metastatic breast cancer is an incurable disease, efforts to decrease breast cancer mortality have focused on early detection and improved treatment. Identification and analysis of a specific genetic susceptibility could permit detection of susceptible women and greatly increase the understanding of the initial step that eventually leads to cancer. Because susceptibility loci have been recognized as sites that often are altered during tumor progression, the identification and cloning of such loci could be important in developing cancer therapies. In this article, the progress being made in segregation analysis, linkage analysis, and cloning of breast cancer susceptibility loci is reviewed. The evidence for genetic inheritance is most consistent with dominant inheritance for at least three major susceptibility loci. Proliferative breast disease has been hypothesized to be an inherited lesion in breast cancer kindreds with both premenopausal and postmenopausal probands. Currently, there are many genetic markers for mapping the human genome. Technologic advances have progressed from restriction fragment length polymorphisms to highly polymorphic markers. Using this technology, breast cancer susceptibility in some kindreds with an early onset has been shown to be linked to chromosome 17q. Gene isolation eventually will follow with an increased understanding of the percentage of breast cancer cases that are a result of this genetic locus. Li-Fraumeni syndrome, which often is expressed as breast cancer, is due to mutations in the p53 gene. Characterization of the syndrome and its relationship to the altered gene should proceed rapidly. There is also a group of families exhibiting a genetic susceptibility that is not due to either of these loci. Together, these findings indicate that there are at least three separate major loci segregating for breast cancer susceptibility. With the current initiative to map and sequence the entire human genome and the advances that recently have been reported, a detailed molecular understanding of breast cancer predisposition can be envisaged.

Dysplastic melanocytic nevi (DMN) are nevi (moles) on the skin not present at birth that are considered to be precursors of melanoma, a form of cancer associated with pigmented moles. The risk of malignant change of these moles undoubtedly varies within populations and among patients, but the causes of malignant transformation have not been identified. It is possible that characteristic histopathological changes can be observed in people who have a personal or family history of melanoma. This was tested by examining microscopic sections of DMN removed from patients in three groups. Members of group A (17 people) had a history of melanoma; group B (79 people) members had DMN and a history of melanoma in first-degree relatives; group C members (64) were unrelated spouses of members of groups A or B. The samples were rated on a scale of 0 to 3, depending on how well they conformed to four histologic criteria considered discriminatory for DMN. Three pathologists rated the sections without knowledge of the subject's identity. Members of groups A and B were expected to have higher scores than group C members, an indication of greater cell abnormality. Results indicated that this was not the case: greater overall atypia (a measure of abnormality) in DMN did not correlate with either personal or family history of melanoma. Thus, rather than precursors to melanoma, DMN may represent an active growth phase of melanocytes, the cells that compose moles. (Consumer Summary produced by Reliance Medical Information, Inc.)

In some families, a nonpolyposis colorectal cancer is inherited as an autosomal dominant gene. In these cases, the onset is relatively early in life, and the proximal colon is the usual site. This has led to the assumption that in cases of colon cancer in general, a young age at diagnosis and a proximal location may serve as possible indicators of familial colon cancer. The Utah Population Data Base was used to determine if these factors do indeed predict familial clustering of colorectal cancer. A total of 1,800 individuals with both colon cancer and genealogical records were identified. Analysis revealed that colon cancer exhibits a familial clustering in excess of chance; this clustering is independent of age of onset or distribution of tumor. Although relatives who developed colon cancer and lived outside the state of Utah could not be identified in this study, the 1,800 cases have been shown to be statistically representative. It is worth noting that the familial clustering extended beyond close relatives, and thus is unlikely to be the result of environmental factors to which all members of a family were exposed. Recently genetic markers have become available for familial adenopolyposis; these same markers may well be applied to the study of non-polyposis familial clusters to distinguish the characteristics and possible mechanisms of inheritance of colon cancers. (Consumer Summary produced by Reliance Medical Information, Inc.)