Shared genomic segment analysis. Mapping disease predisposition genes in extended pedigrees using SNP genotype assays.

We examine the utility of high density genotype assays for predisposition gene localization using extended pedigrees. Results for the distribution of the number and length of genomic segments shared identical by descent among relatives previously derived in the context of genomic mismatch scanning are reviewed in the context of dense single nucleotide polymorphism maps. We use long runs of loci at which cases share a common allele identically by state to localize hypothesized predisposition genes. The distribution of such runs under the hypothesis of no genetic effect is evaluated by simulation. Methods are illustrated by analysis of an extended prostate cancer pedigree previously reported to show significant linkage to chromosome 1p23. Our analysis establishes that runs of simple single locus statistics can be powerful, tractable and robust for finding DNA shared between relatives, and that extended pedigrees offer powerful designs for gene detection based on these statistics.

Familiality of diabetes mellitus.

The aims of this study were to estimate relative risk for type 1 and type 2 diabetes in relatives of diabetic patients, and to test for excess relatedness among diabetic patients. Additionally, the difference in parental transmission of diabetes was investigated. This study used a unique Utah genealogical resource, linked to electronic medical records of the largest health provider in Utah. We identified 19,640 patients with a diagnosis of type 1 or type 2 diabetes. Relative Risks (RRs) for type 1 and type 2 diabetes were assessed for first-, second- and third-degree relatives of diabetic patients. The observed average relatedness of diabetic patients was compared to the expected relatedness using the Genealogical Index of Familiality (GIF). We observed significantly elevated RRs for type 1 diabetes in first-degree (RR=8.68; P<0.0001), second-degree (RR=1.93; P<0.0001) and third-degree relatives (RR=1.74; P<0.0001) of type 1 diabetic patients. RRs for type 2 diabetes were significantly increased in first-degree (RR=2.24; P<0.0001), second-degree (RR=1.36; P<0.0001) and third-degree relatives (RR=1.14; P<0.0001) of type 2 diabetic patients. Significantly increased RRs for type 1 diabetes were observed in the relatives of type 2 diabetic patients, and vice versa. The GIF analysis showed significant excess relatedness for type 1 diabetes cases, and independently for type 2 diabetes cases. Offspring of diabetic fathers were at significantly higher risk for type 1 diabetes than offspring of diabetic mothers (RR=9.73; P<0.0001 compared to RR=4.99; P<0.0001). No significant difference in parental transmission was observed for type 2 diabetes. Our results strongly support the existence of a genetic contribution to both type 1 and type 2 diabetes, and additionally suggest a relationship between both types of diabetes. Furthermore, our results suggest a significant difference in parental transmission of type 1 diabetes.

Genome-wide linkage analysis for aggressive prostate cancer in Utah high-risk pedigrees.

BACKGROUND: It has been proposed that studying alternative phenotypes, such as tumor aggressiveness, may be a solution for overcoming the apparent heterogeneity that has hindered the identification of prostate cancer (PC) genes. We present the results of a genome-scan for predisposition to aggressive PC using the Utah high-risk pedigree resource. METHODS: We identified 259 subjects with aggressive PC in 57 extended and nuclear families. Parametric and non-parametric multipoint linkage statistics were calculated for a genome-wide set of 401 microsatellite markers using the MCLINK software package. Stratification analyses by the number of affected subjects per pedigree (<5, >or=5) and the average age at diagnosis of affected subjects (<70 years, >or=70 years) were also performed. RESULTS: No significant results were observed at the genome-wide level, but suggestive evidence for linkage was observed on chromosomes 9q (HLOD = 2.04) and 14q (HLOD = 2.08); several pedigrees showed individual evidence for linkage at each locus (LOD > 0.58). The subset of pedigrees with earlier age at onset demonstrated nominal linkage evidence on chromosomes 3q (HLOD = 1.79), 8q (HLOD = 1.67), and 20q (HLOD=1.82). The late-onset subset showed suggestive linkage on chromosome 6p (HLOD = 2.37) and the subset of pedigrees with fewer than five affected subjects showed suggestive linkage on chromosome 10p (HLOD = 1.99). CONCLUSIONS: Linkage evidence observed on chromosomes 6p, 8q, and 20q support previously reported PC aggressiveness loci. While these results are encouraging, further research is necessary to identify the gene or genes responsible for PC aggressiveness and surmount the overarching problem of PC heterogeneity.

Identification and study of Utah pseudo-isolate populations-prospects for gene identification.

Isolate populations of varied types have proven powerful for gene identification for rare Mendelian disorders, and continue to show such promise for more complex phenotypes. Existing isolate populations are limited in the phenotypes available for study, and new population isolates are unlikely to arise. We utilize genealogical data available for the state of Utah, dating back to its European founders, to retrospectively define and examine pseudo-isolate subpopulations. These pseudo-isolate populations are defined by selection of a set of "founders" from the genealogical data, and then limitation of "immigration" by censoring of matings and offspring that do not match the isolate population design. A wide variety of pseudo isolate and other study designs are possible by varying the number and type of founders and the extent of immigration allowed. We present several different example Birth-Country pseudo-isolate populations defined within the Utah Population Database (UPDB). We utilize linked cancer phenotype data available for the Utah population to show the utility of this pseudo-isolate approach for identification of more genetically homogeneous prostate cancer pedigrees for predisposition gene identification. In conclusion, we present a unique approach to retrospective "creation" of isolate populations using existing genealogical data. We use the UPDB to exhibit the utility of this approach for the highly heterogeneous Utah population, and suggest the approach is feasible for any population for which high quality genealogy and phenotype data are available.

A simple diagnostic index for asthma.

BACKGROUND: Asthma is becoming increasingly prevalent and a number of research groups are investigating its genetic and environmental basis. OBJECTIVE: To produce a brief screening tool suitable for determining phenotype in asthma research. METHODS: The scores from eight questions on symptoms and history were obtained from 678 adults and 244 children from high asthma-incidence caucasian families. An independent physician diagnosis was also obtained with the use of a modified NHLBI-CSGA questionnaire and pulmonary function test. Stepwise logistic regression was applied to determine which of the eight questions had greatest predictive value for asthma, and the quality of the resultant models was evaluated using an independent set of 643 adults and 239 children. RESULTS: For adults, the most parsimonious model used responses from three of the eight questions. It had sensitivity and specificity of 0.94 and 0.96, respectively. For children, responses to two questions gave a model with sensitivity and specificity of 0.97. For both age groups, negative predictive values were above 0.87. Positive predictive values were 0.58 and 0.78 for adults and children respectively. The latter emphasize the need for conformation, by physician, of "affected" calls made by this initial screen. CONCLUSION: The brief questionnaires described are potentially useful in a research setting, as a preliminary screening mechanism of low cost. Their use will reduce the numbers of subjects that must undergo detailed phenotyping.

A candidate prostate cancer susceptibility gene at chromosome 17p.

It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria. The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3' end cleavage and polyadenylation specificity factor (CPSF73).

Microdissection, DOP-PCR, and comparative genomic hybridization of paraffin-embedded familial prostate cancers.

There is a clear genetic component to prostate cancer susceptibility. Regions reported to be linked to prostate cancer include 1q24-25 (HPC-1), 1q42.2-43, and Xq27-28. There is limited genetic information on familial prostate tumors. We used the Utah Population Database to identify familial prostate cancer cases and selected 35 cases from high-risk families. Tissue blocks containing discernable tumor were available from 19 cases; 13 of these yielded adequate specimens for analysis. Six cases came from families with linkage to HPC-1, 3 were known to have linkage to Xq27-28, and 4 had no linkage to a known locus; 7 cases were analyzed from patients who showed no known linkage (sporadic tumors) as controls. These paraffin-embedded tumors were laser microdissected, degenerate oligonucleotide (DOP)-amplified, and labeled for fluorescence detection by comparative genomic hybridization (CGH). Loss of 7q, 10q, and 16q and gain of 8q were common abnormalities present in both familial and sporadic tumors. Distinctive abnormalities included loss of 3p12-3p22 in 3 of 6 HPC-7-linked cases and in 2 of 3 X-linked cases and gain of 6q11-6q21 in 2 each of HPC-1 and X-linked tumors. In conclusion, laser microdissection, DOP-PCR, and CGH is a feasible method for analysis of paraffin-embedded prostate tumors. This study provides preliminary data suggesting that familial prostate cancer harbors some unique genetic changes when compared with sporadic prostate tumors.

Impact of correlated factors on bone density in individuals with a family history of osteoporosis.

Previous studies have suggested that 14-47% of the variation in bone mineral density (BMD) can be predicted using clinical risk factors. The aim of our study was to determine, for the first time, the importance of these factors in individuals with evidence of a genetic predisposition to the disease. The subjects studied were 147 female and 86 male Caucasians, all with a family history of osteoporosis. Linear regression was used to determine whether age, height, weight, and years of reduced estrogen exposure were significant predictors of BMD. Males and females were examined separately, and BMD was measured at the hip and spine. The results show that these risk factors, known to be at work in the general population, are equally important in those with a family history of osteoporosis. It is clear, therefore, that they must be taken into account, and corrected for in genetic studies of the disease.

Prostate cancer susceptibility locus HPC1 in Utah high-risk pedigrees.

A prostate cancer susceptibility locus ( HPC1 ) at 1q24-25 has been identified. Subsequent analysis showed that the majority of the evidence for localization was provided by families with relatively young (<65 years) average age at diagnosis. We examined evidence for linkage to this region in a set of 41 extended multi-case prostate cancer pedigrees containing 440 prostate cancer cases. Genotyping of five short tandem repeat markers in the region was performed on DNA from 1724 individuals, including 284 prostate cancer cases. In comparison with the families reported in the initial localization, the Utah pedigrees are generally much larger (average of 10.7 versus 5.1 cases) and have an older average age at diagnosis (69 versus 65 years). Two- and three-point linkage analyses were conducted using a previously reported model and provided replication for HPC1 (two-point: LOD = 1.73, P = 0.005 at D1S196; three-point: LOD = 2.06, P = 0.002 for the interval D1S196-D1S416 ). The youngest quartile (by median age at diagnosis) yielded a maximum LOD of 2.82, P = 0. 0003 (at D1S215-D1S222 ), compared with a maximum LOD of 0.73, P = 0. 07 for the oldest quartile pedigrees at the same locus. Further analysis with an age-dependent model, specifying higher sporadic rates for older cases, suggests that the linkage evidence may be lower than expected given the power of the resource due to a high sporadic rate in the large Utah pedigrees.

Response to radiation therapy and prognosis in breast cancer patients with BRCA1 and BRCA2 mutations.

BACKGROUND AND PURPOSE: The purpose of this study is to evaluate overall survival in BRCA1 or BRCA2 breast cancer patients, describe presenting stage, review histologic findings and evaluate response to radiotherapy. MATERIALS AND METHODS: A retrospective study was performed evaluating breast cancer patients with known mutations of BRCA1 or BRCA2. Patients from 12 different pedigrees were cross-referenced with the Utah Cancer Registry (UCR), histologic findings were verified and radiotherapy records were reviewed for acute response to treatment. Actuarial survival calculations were performed and patients were matched for age, date of diagnosis and tumor size. RESULTS: Thirty breast cancer patients with BRCA1 mutations were found to have 34 breast cancers (four had bilateral metachronous lesions) and 20 breast cancer patients with BRCA2 mutations were found to have 22 breast cancers (two had bilateral metachronous disease). The median age at diagnosis was 49 years (range 21-77 years) and 42 years (range 23-83 years), respectively, for BRCA1 and BRCA2 patients. Unusual histologic types of breast cancers were represented with 7% (4/56) medullary and 5% (3/56) lobular carcinomas. Complete staging was possible for 63% (35/56) of cancers. Stages I, II, III and IV represented 26, 63, 6 and 6% of cancers, respectively. The most severe radiation reaction was moist desquamation which was self-limiting and developed in 29% (6/21) of irradiated patients. The mean follow-up was 9.8 and 7.5 years for BRCA1 and BRCA2 cancers, respectively. Kaplan-Meier survival analysis demonstrated 5-year survival values of 75% for BRCA1 patients, 73% for BRCA2 patients, 70% for matched controls and 69% for UCR controls. No statistically significant differences were evident between the groups at 5 or 10 years. CONCLUSIONS: Despite their younger age at presentation, breast cancer patients harboring BRCAI or BRCA2 mutations present at a similar stage, display a normal acute reaction to radiotherapy and have a similar prognosis when compared with sporadic breast cancer patients.

Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13.

The penetrance of the BRCA2 gene on chromosome 13q12-13 has been estimated in two large, systematically ascertained, linked families, by use of a maximum-likelihood method to incorporate both cancer-incidence data and 13q marker typings in the families. The cumulative risk of breast cancer in female gene carriers was estimated to be 59.8% by age 50 years (95% confidence interval [95% CI] 25.9%-78.5%) and 79.5% by age 70 years (95% CI 28.9%-97.5%). The cumulative risk of breast cancer in male carriers was estimated to be 6.3% (95% CI 1.4%-25.6%) by age 70 years. There was no evidence of any risk difference between the two families. These results indicate that the lifetime breast cancer risk in BRCA2 carriers, for at least a subset of mutations, is comparable to that for BRCA1. A significant excess of ovarian cancer in gene carriers was observed (relative risk 17.69, based on three cases), but the absolute risk of ovarian cancer was less than that reported for BRCA1. Significant excesses of laryngeal cancer (relative risk 7.67, based on two possible carriers) and prostate cancer (relative risk 2.89, based on five possible carriers) were also observed. One case of ocular melanoma, as well as a second eye cancer of unspecified histology, occurred in obligate gene carriers.

A review of inherited predisposition to melanoma.

In this review, we discuss the progress of the last few years in the genetic analysis of the susceptibility to melanoma. The inclusion of dysplastic nevi in the analysis of susceptibility, although appropriate conceptually, has not greatly clarified the picture of genetic susceptibility to melanoma. One predisposing gene has clearly been linked to chromosome 9 while a second linkage to chromosome 1 is still uncertain. A gene, CDKN2, is an appealing candidate for melanoma susceptibility.

Interobserver concordance in discriminating clinical atypia of melanocytic nevi, and correlations with histologic atypia.

BACKGROUND: The clinical features attributed to atypical (formerly ¿dysplastic") nevi and to the atypical multiple mole melanoma syndrome have been used in clinical practice, as well as experimentally, to assign melanoma risk. Little information is available, however, on the interobserver reliability in assessing those features. OBJECTIVE: Our purposes were to quantify interobserver and intraobserver concordances in recognizing certain atypical characteristics of nevi and to correlate the clinical assessments with the histologic characteristics. METHODS: Three observers evaluated clinical photographs of 100 pigmented lesions (predominantly melanocytic nevi, with some lentigines and seborrheic keratoses) from 95 subjects, of whom 85 were family members of four multiple melanoma kindreds and 10 were spouses. Each lesion was rated for border irregularity, color variegation, surface contour irregularity, pigment diffusion, and macularity versus papularity. Predictions were made as to the histologic diagnoses and presence of melanocytic atypia for those lesions judged to be nevi. RESULTS: The pair-wise concordances before agreement on specific criteria were quantified by kappa statistics, which indicated slight to fair agreement in judging the atypical clinical characteristics; concordances increased to moderate levels after consensus development of criteria for color variegation and assessment of macularity, but agreement on the other features remained limited. Whereas macularity and color variegation did correlate somewhat with higher grades of histologic atypia, correlations were generally low between the clinical and histologic diagnoses. CONCLUSION: There is limited interobserver reliability in the clinical assessment of nevus atypia, although correlations do exist between some atypical characteristics and grades of histologic atypia. Because of the low concordances, the clinical discrimination of the melanoma-associated atypical nevus phenotype should rely more on quantitative aspects of the trait, such as total numbers or maximal sizes of nevi, rather than on the subjective determinations of atypia.

Genetic heterogeneity and unmapped genes for colorectal cancer.

Colorectal cancer (CRC) has a strong familial component. Candidate genes for colorectal cancer have been identified through mutations in four mismatch repair genes (hMSH2, hMLH1, hPMS1, and hPMS2) and genes that are deleted or mutated in tumors (DCC, APC, and p53). Linkage analysis of candidate loci/regions was performed in 10 kindreds ascertained for common colorectal cancer from the Utah Population Database. Evidence for linkage to candidate genes was assessed using two- or three-point logarithm of the odds ratio scores with markers spanning the region of localization. One kindred is linked to hMSH2 and also fits the criteria for hereditary nonpolyposis colorectal cancer, having early age of onset and high penetrance for CRC. The remaining nine kindreds are unlinked to the candidate genes tested. These kindreds have a later age of onset and a lower penetrance than hereditary nonpolyposis colorectal cancer kindreds. these results indicate that further unmapped susceptibility loci may be responsible for much of the familial aggregation of CRC.

THe genetics of familial breast cancer.

Because studies of breast cancer patients and their relatives provide statistical evidence for involvement of autosomal dominant genes, the identification of specific genetic effects has long been the focus of efforts to identify women at exceedingly high risk. BRCA1, a gene that confers greatly increased susceptibility to breast and ovarian cancer, was isolated in 1994, capping an intense analysis by a large number of groups of a complex phenotype. BRCA1 is a large gene and shows only limited homology to other known genes. Near the amino terminus of the predicted protein is a RING finger motif. In addition, a leucine heptad repeat appears in the interior of the sequence. Several groups have looked extensively for somatic BRCAI mutations in breast and ovarian tumors. The frequency of somatic mutations in ovarian tumors is low, and to date no somatic mutations have been found in breast tumors. More research is needed to define the role of BRCA1 in sporadic tumors. A second locus associated with predisposition to early onset breast cancer, BRCA2, has been localized to chromosome 13q. Positional cloning of this gene is well advanced and analysis of its biology and mutation spectrum is eagerly awaited. As the BRCA1 and BRCA2 genes are characterized further, a diagnostic test for breast cancer susceptibility becomes feasible.

Penetrance and expressivity of the chromosome 9p melanoma susceptibility locus (MLM).

A susceptibility locus for familial melanoma has been localized to the short arm of chromosome 9. Penetrance of melanoma was estimated by calculating the Kaplan-Meier function and fitting a log normal hazard function in 124 gene carriers in three 9p-linked kindreds. The penetrance of the gene for melanoma was estimated to be 53% by age 80. Additionally, nevus counts, skin type, and sun exposure histories were gathered for 119 individuals in two kindreds. Gene carriers were found to have higher nevus counts and nevus densities than non-gene carriers. Among gene carriers, individuals with melanoma were found to have more sun exposure within each skin type than gene carriers without melanoma. These analyses suggest that the 9p melanoma susceptibility is related to total number of nevi and that it interacts with other genetic and environmental factors to produce melanoma.

Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands.

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 off-spring) 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.

Localization of the 9p melanoma susceptibility locus (MLM) to a 2-cM region between D9S736 and D9S171.

A familial melanoma susceptibility locus (MLM) was identified on the short arm of chromosome 9 in a set of Utah and Texas kindreds. Subsequent confirmation was reported for a set of 26 Australian kindreds, a set of 7 Dutch kindreds, and a set of 13 NIH melanoma kindreds. The original localization report placed the locus near the IFNA-D9S126 interval on chromosome 9p. We report further localization using D9S171 and a newly developed marker, D9S736, both of which lie in the IFNA-D9S126 interval. Analysis of this set of kindreds places the melanoma susceptibility locus in a 2-cM region that is proximal to D9S736 and distal to D9S171.

Colonic polyps in an unselected population: prevalence, characteristics, and associations.

OBJECTIVES: To provide a proctosigmoidoscopic review of a very large set of unselected control subjects, providing an unbiased view of colonic polyps in the general population. METHODS: Sigmoidoscopic data from 406 sequentially recruited subjects were analyzed. Participation rates were over 85%, and subjects were thus free of the usual selection bias. RESULTS: Thirty-eight percent of screened individuals were found to have distal colonic polyps. Adenomas were found in 12%, and hyperplastic polyps were found in 30% of screened individuals. Adenomas were more prevalent in males and in older individuals. Hyperplastic prevalence did not differ significantly by gender or age. Synchronous adenomatous and hyperplastic polyps occurred in 3% of screened individuals, but these lesions were not associated. CONCLUSIONS: Distal colonic adenomatous and hyperplastic polyps are very common in the general population and are not associated. The high frequency of these polyps raises questions about the feasibility of biopsy for all polyps, and suggests that further study is needed to determine the appropriate indications for subsequent colonoscopy.