Significant evidence for a heritable contribution to cancer predisposition: a review of cancer familiality by site

<p>Abstract</p> <p>Background/Aims</p> <p>Sound and rigorous well-established, and newly extended, methods for genetic epidemiological analysis were used to analyze population evidence for genetic contributions to risk for numerous common cancer sites in Utah. The Utah Population Database (UPDB) has provided important illumination of the familial contribution to cancer risk by cancer site.</p> <p>Methods</p> <p>With over 15 years of new cancer data since the previous comprehensive familial cancer analysis, we tested for excess familial clustering using an expanded Genealogical Index of Familiality (dGIF) methodology that provides for a more informative, but conservative test for the existence of a genetic contribution to familial relatedness in cancer.</p> <p>Results</p> <p>Some new cancer sites have been analyzed for the first time, having achieved sufficiently large sample size with additions to the UPDB. This new analysis has identified 6 cancer sites with significant evidence for a heritable contribution to risk, including lip, chronic lymphocytic leukemia, thyroid, lung, prostate, and melanoma.</p> <p>Conclusions</p> <p>Both environmentally and genetically-based familial clustering have clinical significance, and these results support increased surveillance for cancer of the same sites among close relatives of affected individuals for many more cancers than are typically considered.</p

Legal Terms of Use and Public Genealogy Websites

Public genealogy websites, to which individuals upload family history, genealogy, and sometimes individual genetic data, have been used in an increasing number of public health, epidemiological, and genetic studies. Yet there is little awareness among researchers of the legal rules that govern the use of these online resources. We analyzed the online Terms of Use (TOU) applicable to 17 popular genealogy websites and found that none of them expressly permit scientific research, while at least 13 contain restrictions that may limit or prohibit scientific research using data obtained from those sites. In order to ensure that researchers who use genealogy and other data from these sites for public health and other scientific research purposes do not inadvertently breach applicable TOUs, we recommend that genealogy website operators consider revising their TOUs to permit this activity

Increased risk for other cancers in individuals with Ewing sarcoma and their relatives.

BackgroundThere are few reports of the association of other cancers with Ewing sarcoma in patients and their relatives. We use a resource combining statewide genealogy and cancer reporting to provide unbiased risks.MethodsUsing a combined genealogy of 2.3 million Utah individuals and the Utah Cancer Registry (UCR), relative risks (RRs) for cancers of other sites were estimated in 143 Ewing sarcoma patients using a Cox proportional hazards model with matched controls; however, risks in relatives were estimated using internal cohort-specific cancer rates in first-, second-, and third-degree relatives.ResultsCancers of three sites (breast, brain, complex genotype/karyotype sarcoma) were observed in excess in Ewing sarcoma patients. No Ewing sarcoma patients were identified among first-, second-, or third-degree relatives of Ewing sarcoma patients. Significantly increased risk for brain, lung/bronchus, female genital, and prostate cancer was observed in first-degree relatives. Significantly increased risks were observed in second-degree relatives for breast cancer, nonmelanoma eye cancer, malignant peripheral nerve sheath cancer, non-Hodgkin lymphoma, and translocation sarcomas. Significantly increased risks for stomach cancer, prostate cancer, and acute lymphocytic leukemia were observed in third-degree relatives.ConclusionsThis analysis of risk for cancer among Ewing sarcoma patients and their relatives indicates evidence for some increased cancer predisposition in this population which can be used to individualize consideration of potential treatment of patients and screening of patients and relatives

Evidence for a heritable predisposition to Chronic Fatigue Syndrome

<p>Abstract</p> <p>Background</p> <p>Chronic Fatigue Syndrome (CFS) came to attention in the 1980s, but initial investigations did not find organic causes. Now decades later, the etiology of CFS has yet to be understood, and the role of genetic predisposition in CFS remains controversial. Recent reports of CFS association with the retrovirus xenotropic murine leukemic virus-related virus (XMRV) or other murine leukemia related retroviruses (MLV) might also suggest underlying genetic implications within the host immune system.</p> <p>Methods</p> <p>We present analyses of familial clustering of CFS in a computerized genealogical resource linking multiple generations of genealogy data with medical diagnosis data of a large Utah health care system. We compare pair-wise relatedness among cases to expected relatedness in the Utah population, and we estimate risk for CFS for first, second, and third degree relatives of CFS cases.</p> <p>Results</p> <p>We observed significant excess relatedness of CFS cases compared to that expected in this population. Significant excess relatedness was observed for both close (p <0.001) and distant relationships (p = 0.010). We also observed significant excess CFS relative risk among first (2.70, 95% CI: 1.56-4.66), second (2.34, 95% CI: 1.31-4.19), and third degree relatives (1.93, 95% CI: 1.21-3.07).</p> <p>Conclusions</p> <p>These analyses provide strong support for a heritable contribution to predisposition to Chronic Fatigue Syndrome. A population of high-risk CFS pedigrees has been identified, the study of which may provide additional understanding.</p

Multiple primary melanomas in a CDKN2A mutation carrier exposed to ionizing radiation

Background: Recent research has shown a possible causal relationship between ionizing radiation exposure and melanoma. Individuals with mutations in CDKN2A (cyclin-dependent kinase inhibitor 2A), the major melanoma predisposition gene, have an increased susceptibility to melanoma-promoting exposures, such as UV light. We describe a patient from a familial melanoma pedigree with 7 primary melanomas on the right side of her body, the first occurring 5 years after exposure to atmospheric nuclear bomb testing in the 1950s. Observations: Physical examination revealed phototype I skin, red hair, and 26 nevi (14 on the right and 12 on the left side of her body). One nevus was larger than 5 mm, and 2 were clinically atypical. Sequence analysis demonstrated a known deleterious mutation in CDKN2A (G-34T) and homozygosity for a red hair color variant in MC1R (melanocortin 1 receptor) (R151C). Fluorescence in situ hybridization analysis of blood, fibroblasts, and melanocytes from both upper extremities ruled out mosaicism. Conclusions: Individuals such as this patient, who has CDKN2A and MC1R mutations, are likely to be more susceptible to environmental insults. A careful review of environmental exposures in these vulnerable cases may reveal cancer-promoting agents, such as ionizing radiation, that go unnoticed in less susceptible populations

Analysis of High-Risk Pedigrees Identifies 12 Candidate Variants for Alzheimer\u27s Disease

INTRODUCTION: Analysis of sequence data in high-risk pedigrees is a powerful approach to detect rare predisposition variants. METHODS: Rare, shared candidate predisposition variants were identified from exome sequencing 19 Alzheimer\u27s disease (AD)-affected cousin pairs selected from high-risk pedigrees. Variants were further prioritized by risk association in various external datasets. Candidate variants emerging from these analyses were tested for co-segregation to additional affected relatives of the original sequenced pedigree members. RESULTS: AD-affected high-risk cousin pairs contained 564 shared rare variants. Eleven variants spanning 10 genes were prioritized in external datasets: rs201665195 (ABCA7), and rs28933981 (TTR) were previously implicated in AD pathology; rs141402160 (NOTCH3) and rs140914494 (NOTCH3) were previously reported; rs200290640 (PIDD1) and rs199752248 (PIDD1) were present in more than one cousin pair; rs61729902 (SNAP91), rs140129800 (COX6A2, AC026471), and rs191804178 (MUC16) were not present in a longevity cohort; and rs148294193 (PELI3) and rs147599881 (FCHO1) approached significance from analysis of AD-related phenotypes. Three variants were validated via evidence of co-segregation to additional relatives (PELI3, ABCA7, and SNAP91). DISCUSSION: These analyses support ABCA7 and TTR as AD risk genes, expand on previously reported NOTCH3 variant identification, and prioritize seven additional candidate variants

Nutrition, lifestyle and colorectal cancer incidence: a prospective investigation of 10 998 vegetarians and non-vegetarians in the United Kingdom

In a cohort of 10998 men and women, 95 incident cases of colorectal cancer were recorded after 17 years. Risk increased in association with smoking, alcohol, and white bread consumption, and decreased with frequent consumption of fruit. The relative risk in vegetarians compared with nonvegetarians was 0.85 (95% CI: 0.55-1.32)

A Rare Variant in ERF (rs144812092) Predisposes to Prostate and Bladder Cancers in an Extended Pedigree

Simple SummaryHere we applied a powerful predisposition candidate gene identification strategy to identify rare variants shared by two related bladder cancer cases who were members of pedigrees exhibiting a significant excess of bladder cancers. We sequenced the exomes of pairs of related bladder cancer cases belonging to high-risk bladder cancer pedigrees to identify rare, shared variants shared as candidates for predisposition. A rare, shared variant in ERF was also found to show significant association with bladder cancer risk in an independent population, was present in other prostate cancer-affected members in the pedigree, and showed evidence for altering the function of the associated protein. This evidence supports ERF (ETS2 Repressor Factor) as a bladder and prostate cancer predisposition gene.Pairs of related bladder cancer cases who belong to pedigrees with an excess of bladder cancer were sequenced to identify rare, shared variants as candidate predisposition variants. Candidate variants were tested for association with bladder cancer risk. A validated variant was assayed for segregation to other related cancer cases, and the predicted protein structure of this variant was analyzed. This study of affected bladder cancer relative pairs from high-risk pedigrees identified 152 bladder cancer predisposition candidate variants. One variant in ERF (ETS Repressing Factor) was significantly associated with bladder cancer risk in an independent population, was observed to segregate with bladder and prostate cancer in relatives, and showed evidence for altering the function of the associated protein. This finding of a rare variant in ERF that is strongly associated with bladder and prostate cancer risk in an extended pedigree both validates ERF as a cancer predisposition gene and shows the continuing value of analyzing affected members of high-risk pedigrees to identify and validate rare cancer predisposition variants

Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease