Population-based relative risks for specific family history constellations of breast cancer.

PURPOSE: Using a large resource linking genealogy with decades of cancer data, a non-traditional approach was used to estimate individualized risk for breast cancer (BC) based on specific family history extending to first cousins, providing a clearer picture of the contribution of various aspects of both close and distant combinations of affected relatives. METHODS: RRs for BC were estimated in 640,366 females for a representative set of breast cancer family history constellations that included number of first- (FDR), second-(SDR), and third-degree relatives (TDR), maternal and paternal relatives, and age at earliest diagnosis in a relative. RESULTS: RRs for first-degree relatives of BC cases ranged from 1.61 (= 1 FDR affected, CI 1.56, 1.67) to 5.00 (≥ 4 FDRs affected, CI 3.35, 7.18). RRs for second-degree relatives of probands with 0 affected FDRs ranged from 1.04 (= 1 SDR affected, CI 1.00, 1.08) to 1.71 (≥ 4 SDRs affected, CI 1.26, 2.27) and for second-degree relatives of probands with exactly 1 FDR from 1.54 (0 SDRs affected, CI 1.47, 1.61) to 4.78 (≥ 5 SDRs; CI 2.47, 8.35). RRs for third-degree relatives with no closer relatives affected were significantly elevated over population risk for probands with ≥ 5 affected TDRs RR = 1.32, CI 1.11, 1.57). CONCLUSIONS: The majority of females in the Utah resource had a positive family history of BC in FDRs to TDRs. Presence of any number of affected FDRs or SDRs significantly increased risk for BC over population risk; and more than four TDRs, even with no affected FDRs or SDRs, significantly increased risk over population risk. Risk prediction derived from the specific and extended family history constellation of affected relatives allows identification of females at increased risk even when they do not have a conventionally defined high-risk family; these risks could be a powerful, efficient tool to individualize cancer screening and prevention.

Relative Risks for Lethal Prostate Cancer Based on Complete Family History of Prostate Cancer Death.

BACKGROUND: There are few published familial relative risks (RR) for lethal prostate cancer. This study estimates RRs for lethal prostate cancer based on comprehensive family history data, with the goal of improving identification of those men at highest risk of dying from prostate cancer. METHODS: We used a population-based genealogical resource linked to a statewide electronic SEER cancer registry and death certificates to estimate relative risks (RR) for death from prostate cancer based upon family history. Over 600,000 male probands were analyzed, representing a variety of family history constellations of lethal prostate cancer. RR estimates were based on the ratio of the observed to the expected number of lethal prostate cancer cases using internal rates. RESULTS: RRs for lethal prostate cancer based on the number of affected first-degree relatives (FDR) ranged from 2.49 (95% CI: 2.27, 2.73) for exactly 1 FDR to 5.30 (2.13, 10.93) for ≥3 affected FDRs. In an absence of affected FDRs, increased risk was also significant for increasing numbers of affected second-degree or third degree relatives. Equivalent risks were observed for similar maternal and paternal family history. CONCLUSIONS: This study provides population-based estimates of lethal prostate cancer risk based on lethal prostate cancer family history. Many family history constellations associated with two to greater than five times increased risk for lethal prostate cancer were identified. These lethal prostate cancer risk estimates hold potential for use in identification, screening, early diagnosis, and treatment of men at high risk for death from prostate cancer. Prostate77:41-48, 2017. © 2016 Wiley Periodicals, Inc.

Identification of specific Y chromosomes associated with increased prostate cancer risk.

BACKGROUND: Evidence supports the possibility of a role of the Y chromosome in prostate cancer, but controversy exists. METHODS: A novel analysis of a computerized population-based resource linking genealogy and cancer data was used to test the hypothesis of a role of the Y chromosome in prostate cancer predisposition. Using a statewide cancer registry from 1966 linked to a computerized genealogy representing over 1.2 million descendants of the Utah pioneers, 1,000 independent sets of males, each set hypothesized to share the same Y chromosome as represented in genealogy data, were tested for a significant excess of prostate cancer. RESULTS: Multiple Y chromosomes representing thousands of potentially at-risk males were identified to have a significant excess risk for prostate cancer. CONCLUSIONS: This powerful and efficient in silico test of an uncommon mode of inheritance has confirmed evidence for Y chromosome involvement in prostate cancer.

A comprehensive survey of cancer risks in extended families.

PURPOSE: Cancer is familial; yet known cancer predisposition genes, as well as recognized environmental factors, explain only a small percentage of familial cancer clusters. This population-based description of cancer clustering describes patterns of cancer coaggregation suggestive of a genetic predisposition. METHODS: Using a computerized genealogy of Utah families linked to a statewide cancer registry, we estimated the relative risks for 36 different cancer sites in first-, second-, and third-degree relatives of cancer cases, for each cancer site individually, and between cancer sites. We estimated the sex- and birth-year-specific rates for cancer using 1 million individuals in the resource. We applied these rates to groups of cases or relatives and compared the observed and expected numbers of cancers to estimate relative risks. RESULTS: Many cancer sites show significantly elevated relative risks among distant relatives for cancer of the same site, strongly supporting a heritable contribution. Multiple combinations of cancer sites were observed among first-, second-, and third-degree relatives, suggesting the existence of heritable syndromes involving more than one cancer site. CONCLUSION: This complete description of coaggregation of cancer by site in a well-defined population provides a set of observations supporting heritable cancer predispositions and may support the existence of genetic factors for many different cancers.

Evidence for an inherited predisposition contributing to the risk for rotator cuff disease.

BACKGROUND: A genetic predisposition has been suggested to contribute to the risk for development of rotator cuff disease on the basis of observed family clusters of close relatives. We used a population-based resource combining genealogical data for Utah with clinical diagnosis data from a large Utah hospital to test the hypothesis of excess familial clustering for rotator cuff disease. METHODS: The Utah Population Database contains combined health and genealogical data on over two million Utah residents. Current Procedural Terminology, Fourth Revision, codes (29827, 23412, 23410, and 23420) and International Classification of Diseases, Ninth Revision, codes (726.1, 727.61, and 840.4) entered in patient records were used to identify patients with rotator cuff disease. We tested the hypothesis of excess familial clustering using two well-established methods (the Genealogical Index of Familiality test and the estimation of relative risks in relatives) in the overall study group (3091 patients) and a subgroup of the study group diagnosed before the age of forty years (652 patients). RESULTS: The Genealogical Index of Familiality test in patients diagnosed before the age of forty years showed significant excess relatedness for individuals with rotator cuff disease in close and distant relationships (as distant as third cousins) (p = 0.001). The relative risk of rotator cuff disease in the relatives of patients diagnosed before the age of forty years was significantly elevated for second degree (relative risk = 3.66, p = 0.0076) and third degree (relative risk = 1.81, p = 0.0479) relatives. CONCLUSIONS: We analyzed a set of patients with diagnosed rotator cuff disease and a known genealogy to describe the familial clustering of affected individuals. The observations of significant excess relatedness of patients and the significantly elevated risks to both close and distant relatives of patients strongly support a heritable predisposition to rotator cuff disease.

Evidence for a heritable predisposition to death due to influenza.

Animal model studies and human epidemiological studies have shown that some infectious diseases develop primarily in individuals with an inherited predisposition. A heritable contribution to the development of severe influenza virus infection (i.e., that which results in death) has not previously been hypothesized or tested. Evidence for a heritable contribution to death due to influenza was examined using a resource consisting of a genealogy of the Utah population linked to death certificates in Utah over a period of 100 years. The relative risks of death due to influenza were estimated for the relatives of 4,855 individuals who died of influenza. Both close and distant relatives of individuals who died of influenza were shown to have a significantly increased risk of dying of influenza, consistent with a combination of shared exposure and genetic effects. These data provide strong support for a heritable contribution to predisposition to death due to influenza.