Search PubMed⌕ Search

Biomedical subjects

Christopher I Amos

Publications and source records attributed to Christopher I Amos.

At least 19 recordsLinked to original sources
PubMed2025

Genetic Architecture of Idiopathic Inflammatory Myopathies From Meta-Analyses.

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs, myositis) are rare systemic autoimmune disorders that lead to muscle inflammation, weakness, and extramuscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis data set to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes. METHODS: We performed association analyses on 14,903 individuals (3,206 patients and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel. Fine-mapping and expression quantitative trait locus colocalization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities. RESULTS: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-transfer RNA synthetase autoantibodies (anti-Jo-1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in Epstein-Barr virus (EBV)-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation. CONCLUSION: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.

Humans↗
PubMed2007

Identification of a novel tumor suppressor gene p34 on human chromosome 6q25.1.

In this study, we observed loss of heterozygosity (LOH) in human chromosomal fragment 6q25.1 in sporadic lung cancer patients. LOH was observed in 65% of the 26 lung tumors examined and was narrowed down to a 2.2-Mb region. Single-nucleotide polymorphism (SNP) analysis of genes located within this region identified a candidate gene, termed p34. This gene, also designated as ZC3H12D, C6orf95, FLJ46041, or dJ281H8.1, carries an A/G nonsynonymous SNP at codon 106, which alters the amino acid from lysine to arginine. Nearly 73% of heterozygous lung cancer tissues with LOH and the A/G SNP also exhibited loss of the A allele. In vitro clonogenic and in vivo nude mouse studies showed that overexpression of the A allele exerts tumor suppressor function compared with the G allele. p34 is located within a recently mapped human lung cancer susceptibility locus, and association of the p34 A/G SNP was tested among these families. No significant association between the less frequent G allele and lung cancer susceptibility was found. Our results suggest that p34 may be a novel tumor suppressor gene involved in sporadic lung cancer but it seems not to be the candidate familial lung cancer susceptibility gene linked to chromosomal region 6q23-25.

Alleles↗
PubMed2007

Dissecting the heterogeneity of rheumatoid arthritis through linkage analysis of quantitative traits.

OBJECTIVE: To dissect the heterogeneity of rheumatoid arthritis (RA) through linkage analysis of quantitative traits, specifically, IgM rheumatoid factor (IgM-RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibody titers. METHODS: Subjects, 1,002 RA patients from 491 multiplex families recruited by the North American RA Consortium, were typed for 379 microsatellite markers. Anti-CCP titers were determined based on a second-generation enzyme-linked immunosorbent assay, and IgM-RF levels were quantified by immunonephelometry. We used the Merlin statistical package to perform nonparametric quantitative trait linkage analysis. RESULTS: For each of the quantitative traits, evidence of linkage, with logarithm of odds (LOD) scores of >1.0, was found in 9 regions. For both traits, the strongest evidence of linkage was for marker D6S1629 on chromosome 6p (LOD 14.02 for anti-CCP and LOD 12.09 for RF). Six other regions with LOD scores of >1.0 overlapped between the 2 traits, on chromosomes 1p21.1, 5q15, 8p23.1, 16p12.1, 16q23.1, and 18q21.31. Evidence of linkage to anti-CCP titer but not to RF titer was found in 2 regions (chromosomes 9p21.3 and 10q21.1), and evidence of linkage to RF titer but not to anti-CCP titer was found in 2 regions (chromosomes 5p15.2 and 1q42.3). Several covariates were significantly associated with 1 or both traits, and linkage analysis exploring the covariate effects revealed striking effects of sex in modulating linkage signals for several chromosomal regions. For example, sex had a striking impact on the linkage results for both quantitative traits on chromosome 6p (P = 0.0007 for anti-CCP titer and P = 0.0012 for RF titer), suggesting a sex-HLA region interaction. CONCLUSION: Analysis of quantitative components of RA is a promising approach for dissecting the genetic heterogeneity of this complex disorder. These results highlight the potential importance of sex or other covariates that may modulate some of the genetic effects that influence the risk of specific disease manifestations.

Adult↗
PubMed2007

Association between Aurora-A kinase polymorphisms and age of onset of hereditary nonpolyposis colorectal cancer in a Caucasian population.

Aurora-A kinase is considered a potential cancer susceptibility gene that encodes a centrosome-associated, cell cycle-regulated serine/threonine kinase. We studied two single nucleotide polymorphisms (SNP) in the coding region of Aurora-A, 91T-to-A (F31I) and 169G-to-A (V57I). We studied the influence of these two polymorphisms on age of onset of hereditary nonpolyposis colorectal cancer (HNPCC). Genotyping of the Aurora-A polymorphisms was carried out on 125 Caucasian with mismatch repair (MMR) gene mutations with real-time pyrophosphate DNA sequencing. For the 91T-to-A polymorphism, we found that patients with HNPCC who were homozygous for the wild-type allele developed colorectal cancer (CRC) 7 years earlier than patients who were homozygous or heterozygous for the mutant allele. The169G-to-A polymorphism did not have a significant influence on risk for HNPCC. However, when we did haplotype analysis for these two polymorphisms, the 91A-169G haplotype was associated with protection from HNPCC at an earlier age.

Adolescent↗
PubMed2006

Polymorphisms of FAS and FAS ligand genes involved in the death pathway and risk and progression of squamous cell carcinoma of the head and neck.

PURPOSE: Alteration of the FAS/FAS ligand (FASLG) pathway regulating cell death may lead to cancer development, but the effects of functional promoter polymorphisms of the FAS and FASLG genes on risk of squamous cell carcinoma of the head and neck (SCCHN) are unknown. DESIGN: We genotyped the FAS -1377 G>A, FAS -670 A>G, FASLG -844 C>T, and FASLG IVS2nt -124 A>G polymorphisms in 721 case patients with SCCHN and 1,234 cancer-free non-Hispanic White control subjects frequency-matched by age and sex. Multivariate logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Compared with the FAS -1377 GG and -670 AA genotypes, the FAS -1377 AA and -670 (GG+AG) genotypes were associated with an increased risk of SCCHN (OR, 2.23; 95% CI, 1.07-4.64 and OR, 1.24; 95% CI, 1.01-1.52, respectively), whereas no risk of SCCHN was associated with any of the FASLG genotypes. When we used the combined FAS -1377 (GG+AG)/-670 AA genotypes as the reference, we found that the individuals carrying the FAS -1377 AA/-670 (GG+AG) had the highest risk (OR, 2.69; 95% CI, 1.24-5.83), whereas individuals carrying genotypes other than FAS -1377 (GG+AG)/-670 AA had a higher risk of SCCHN (OR, 1.24; 95% CI, 1.01-1.52). Furthermore, the elevated risk was particularly evident for pharyngeal cancer with the larger tumors without regional lymph metastasis (OR, 1.77; 95% CI, 1.07-2.94). CONCLUSIONS: The FAS (but not FASLG) polymorphisms seem to contribute to risk of developing SCCHN, particularly the pharyngeal cancer in non-Hispanic Whites. However, potential selection bias warrants future population-based studies to verify the findings.

Adolescent↗
PubMed2006

Joint effects of germ-line p53 mutation and sex on cancer risk in Li-Fraumeni syndrome.

Germ-line p53 mutations have been identified in most families with Li-Fraumeni syndrome (LFS). For germ-line p53 mutation carriers, there is considerable variability with respect to age of cancer onset and tumor type, suggesting that additional genetic effects influence the clinical severity and tumor spectrum. To identify factors that might contribute to the observed heterogeneity in time to onset, we used segregation analysis to analyze the joint effects of germ-line p53 mutations and risk modifier(s) on cancer incidence. We studied 159 kindreds, ascertained through probands who had been diagnosed with childhood soft-tissue sarcoma before 16 years of age, survived >3 years after diagnosis, and treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX) from 1944 to 1975. This unique cohort has been followed systematically for >20 years and has had germ-line p53 mutation testing in probands and extended family members. The analyses revealed that germ-line p53 mutations and sex had significant effects on cancer risk: men with p53 mutations had 151-fold higher odds of developing cancer than did those without mutations [95% confidence interval (95% CI), 60-380], and women with p53 mutations had 1,075-fold higher odds than did those without mutations (95% CI, 358-3,229) and 7.1-fold higher odds of having cancer than did men with mutations (95% CI, 2.5-20.3). These findings provide quantitative cancer risk assessments for LFS families.

Adolescent↗
PubMed2006

Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer.

PURPOSE: Understanding how specific genetic variants modify drug action pathways may provide informative blueprints for individualized chemotherapy. METHODS: We applied a pathway-based approach to examine the impact of a comprehensive panel of genetic polymorphisms on clinical outcomes in 210 esophageal cancer patients. RESULTS: In the Cox proportional hazards model, MTHFR Glu429Ala variant genotypes were associated with significantly improved survival (hazard ratio [HR] = 0.56; 95% CI, 0.35 to 0.89) in patients treated with fluorouracil (FU). The 3-year survival rates for patients with the variant genotypes and the wild genotypes were 65.26% and 46.43%, respectively. Joint analysis of five polymorphisms in three FU pathway genes showed a significant trend for reduced recurrence risk and longer recurrence-free survival as the number of adverse alleles decreased (P = .004). For patients receiving platinum drugs, the MDR1 C3435T variant allele was associated with significantly reduced recurrence risk (HR = 0.25; 95% CI, 0.10 to 0.64) and improved survival (HR = 0.44; 95% CI, 0.23 to 0.85). In nucleotide excision repair genes, there was a significant trend for a decreasing risk of death with a decreasing number of high-risk alleles (P for trend = .0008). In base excision repair genes, the variant alleles of XRCC1 Arg399Gln were significantly associated with the absence of pathologic complete response (odds ratio = 2.75; 95% CI, 1.14 to 6.12) and poor survival (HR = 1.92; 95% CI, 1.00 to 3.72). CONCLUSION: Several biologically plausible associations between individual single nucleotide polymorphisms and clinical outcomes were found. Our data also strongly suggest that combined pathway-based analysis may provide valuable prognostic markers of clinical outcomes.

Adenocarcinoma↗
PubMed2006

Mutagen sensitivity has high heritability: evidence from a twin study.

Despite numerous studies showing that mutagen sensitivity is a cancer predisposition factor, the heritability of mutagen sensitivity has not been clearly established. In this report, we used a classic twin study design to examine the role of genetic and environmental factors on the mutagen sensitivity phenotype. Mutagen sensitivity was measured in peripheral blood lymphocytes from 460 individuals [148 pairs of monozygotic (MZ) twins, 57 pairs of dizygotic (DZ) twins, and 50 siblings]. The intraclass correlation coefficients were all significantly higher in MZ twins than in dizygotes (DZ pairs and MZ-sibling pairs combined) for sensitivity to four different mutagen challenges. Applying biometric genetic modeling, we calculated a genetic heritability of 40.7%, 48.0%, 62.5%, and 58.8% for bleomycin, benzo[a]pyrene diol epoxide, gamma-radiation, and 4-nitroquinoline-1-oxide sensitivity, respectively. This study provides the strongest and most direct evidence that mutagen sensitivity is highly heritable, thereby validating the use of mutagen sensitivity as a cancer susceptibility factor.

Genetic Predisposition to Disease↗
PubMed2006

A genome-wide screen for nicotine dependence susceptibility loci.

Genome-wide model free linkage analysis was conducted for nicotine dependence and tobacco use phenotypes in 607 members of 158 nuclear families consisting of at least two ever smokers (100 or more cigarettes smoked in lifetime). DNA from whole blood was genotyped for 739 autosomal microsatellite polymorphisms with an average inter-marker distance of 4.6 cM. A peak LOD score of 2.7 was observed on chromosome 6 for scores for the Fagerström Test for Nicotine Dependence. Exploratory analyses were conducted to determine whether sequence variation at other loci affected other measures of dependence or tobacco use. Four additional loci with LOD scores of 2.7 or more were associated with alternative measures of nicotine dependence, one with current frequency of use, and one with smoking cessation. Several of the corresponding support intervals were near putative loci reported previously (on chromosomes 6, 7, and 8) while others appear to be novel (on chromosomes 5, 16, and 19).

Family Health↗
PubMed2006

An empirical Bayes method for updating inferences in analysis of quantitative trait loci using information from related genome scans.

Individual genome scans for quantitative trait loci (QTL) mapping often suffer from low statistical power and imprecise estimates of QTL location and effect. This lack of precision yields large confidence intervals for QTL location, which are problematic for subsequent fine mapping and positional cloning. In prioritizing areas for follow-up after an initial genome scan and in evaluating the credibility of apparent linkage signals, investigators typically examine the results of other genome scans of the same phenotype and informally update their beliefs about which linkage signals in their scan most merit confidence and follow-up via a subjective-intuitive integration approach. A method that acknowledges the wisdom of this general paradigm but formally borrows information from other scans to increase confidence in objectivity would be a benefit. We developed an empirical Bayes analytic method to integrate information from multiple genome scans. The linkage statistic obtained from a single genome scan study is updated by incorporating statistics from other genome scans as prior information. This technique does not require that all studies have an identical marker map or a common estimated QTL effect. The updated linkage statistic can then be used for the estimation of QTL location and effect. We evaluate the performance of our method by using extensive simulations based on actual marker spacing and allele frequencies from available data. Results indicate that the empirical Bayes method can account for between-study heterogeneity, estimate the QTL location and effect more precisely, and provide narrower confidence intervals than results from any single individual study. We also compared the empirical Bayes method with a method originally developed for meta-analysis (a closely related but distinct purpose). In the face of marked heterogeneity among studies, the empirical Bayes method outperforms the comparator.

Chromosome Mapping↗
PubMed2006

Genome-wide meta-analysis for rheumatoid arthritis.

Meta-analysis is being increasingly used as a tool for integrating data from different studies of complex phenotypes, because the power of any one study to identify causal loci is limited. We applied a novel meta-analytical approach (Loesgen et al. in Genet Epidemiol 21(Suppl 1):S142-S147, 2001) in compiling results from four studies of rheumatoid arthritis in Caucasians including two studies from NARAC (Jawaheer et al. in Am J Hum Genet 68:927-936, 2001; Jawaheer et al. in Arthritis Rheum 48:906-916, 2003), one study from the UK (MacKay et al. in Arthritis Rheum 46:632-639, 2001) and one from France (Cornelis et al. in Proc Natl Acad Sci USA 95:10746-10750, 1998). For each study, we obtained NPL scores by performing interval mapping (2 cM intervals) using GeneHunter2 (Kruglyak et al. in Am J Hum Genet 58:1347-1363, 1996; Markianos et al. in Am J Hum Genet 68:963-977, 2001). The marker maps differed among the three consortium groups, therefore, the marker maps were aligned after the interval mapping was completed and the NPL scores that were within 1 cM of each other were combined using the method of Loesgen et al. (Genet Epidemiol 21(Suppl 1):S142-S147, 2001) by calculating the weighted average of the NPL score. This approach avoids some problems in analysis encountered by using GeneHunter2 when some markers in the sample are not genotyped. This procedure provided marginal evidence (P<0.05) of linkage on chromosome 1, 2, 5 and 18, strong evidence (P<0.01) on chromosomes 8 and 16, and overwhelming evidence in the HLA region of chromosome 6.

Arthritis, Rheumatoid↗
PubMed2006

Never smokers and lung cancer risk: a case-control study of epidemiological factors.

We performed an analysis of potential epidemiological risk factors for lung cancer using data from 280 cases and 242 hospital-based controls, all lifetime never smokers (those who had smoked <100 cigarettes in their lifetimes) and frequency matched on age, gender and ethnicity. The data on demographic characteristics, medical history of respiratory diseases (asthma, emphysema, pneumonia and hay fever), weight and height, family history, female characteristics and environmental tobacco smoke (ETS) and dust exposure were derived from personal interviews. We performed a logistic regression analysis of these variables adjusting for age, gender, ethnicity, income and years of education. Exposure to ETS (OR = 2.08, 95% CI [1.25-3.43]) and dusts (OR = 2.43, 95% CI [1.53-3.88]) were associated with significantly increased risk. In the analysis for joint effects, exposure to both ETS and dusts conferred a higher risk (OR = 3.25, 95% CI [1.58-6.70]) than exposure to either alone. Family history of any cancer with onset before age 50 in at least 1 first degree relative was a significant risk predictor (OR = 1.70, 95% CI [1.10-2.64]). Individuals with a self-reported physician-diagnosed history of hay fever, but not asthma, had a decreased lung cancer risk (OR = 0.57, 95% CI [0.35-0.92]). In the multivariate analysis, exposure to ETS and dusts, and family history of cancer with onset before age 50 were significant risk factors, while a history of hay fever (occurring without asthma) was significantly protective.

Adult↗
PubMed2006

Strength of the purifying selection against different categories of the point mutations in the coding regions of the human genome.

Using available Information on the total absolute size of the coding region of the human genome, data on codon usage and pseudogene-derived mutation rates for different single nucleotide substitutions we have estimated, for the human genome, the potential numbers of mutation events capable to produce: (1) nonsense; (2) missense (radical and conservative); (3) silent; (4) splice; and (5) protein-elongating (those changing wild-type stop codon into an amino acid encoding codon) mutations. We used the NCBI dbSNP database to retrieve data on the observed number of polymorphisms of each category. The fraction of polymorphisms in each category among all potential events in the genome depends on the strength of selection: the higher the rate of polymorphism, the weaker the selection. We used nonsense mutations as a referent group. Compared with nonsense mutations, we found that the relative selection coefficient against protein-elongating mutations was 21%, and the relative selection was 12% against missense mutations. Radical missense mutations were found to be four times more deleterious compared to conservative ones. Surprisingly, we found that silent mutations on average are not neutral; with the average harmfulness of 3% of nonsense mutations. Silent mutations may be deleterious when they affect splicing by creating cryptic donor-acceptor sites or by disturbing exonic splicing enhancers (ESESs). The average selection coefficient against splice mutations was 48% of that against nonsense mutations. Converting the relative selection coefficients into absolute ones using data on loss-of-function mutations in Saccharomyces cerevisiae and Caenorhabditis elegans, or by analysis of the expected frequency of mutations in the human genome, suggested that genetic drift could play a role in population dynamics of conservative missense and silent mutations.

Computational Biology↗
PubMed2006

Characterization of BRCA1 and BRCA2 mutations in a large United States sample.

PURPOSE: An accurate evaluation of the penetrance of BRCA1 and BRCA2 mutations is essential to the identification and clinical management of families at high risk of breast and ovarian cancer. Existing studies have focused on Ashkenazi Jews (AJ) or on families from outside the United States. In this article, we consider the US population using the largest US-based cohort to date of both AJ and non-AJ families. METHODS: We collected 676 AJ families and 1,272 families of other ethnicities through the Cancer Genetics Network. Two hundred eighty-two AJ families were population based, whereas the remainder was collected through counseling clinics. We used a retrospective likelihood approach to correct for bias induced by oversampling of participants with a positive family history. Our approach takes full advantage of detailed family history information and the Mendelian transmission of mutated alleles in the family. RESULTS: In the US population, the estimated cumulative breast cancer risk at age 70 years was 0.46 (95% CI, 0.39 to 0.54) in BRCA1 carriers and 0.43 (95% CI, 0.36 to 0.51) in BRCA2 carriers, whereas ovarian cancer risk was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers. We also reported the prospective risks of developing cancer for cancer-free carriers in 10-year age intervals. We noted a rapid decrease in the relative risk of breast cancer with age and derived its implication for genetic counseling. CONCLUSION: The penetrance of BRCA mutations in the United States is largely consistent with previous studies on Western populations given the large CIs on existing estimates. However, the absolute cumulative risks are on the lower end of the spectrum.

Adult↗
PubMed2006

Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes.

The candidate-gene approach in association studies of polygenic diseases has often yielded conflicting results. In this hospital-based case-control study with 696 white patients newly diagnosed with bladder cancer and 629 unaffected white controls, we applied a multigenic approach to examine the associations with bladder cancer risk of a comprehensive panel of 44 selected polymorphisms in two pathways, DNA repair and cell-cycle control, and to evaluate higher-order gene-gene interactions, using classification and regression tree (CART) analysis. Individually, only XPD Asp312Asn, RAG1 Lys820Arg, and a p53 intronic SNP exhibited statistically significant main effects. However, we found a significant gene-dosage effect for increasing numbers of potential high-risk alleles in DNA-repair and cell-cycle pathways separately and combined. For the nucleotide-excision repair pathway, compared with the referent group (fewer than four adverse alleles), individuals with four (odds ratio [OR] = 1.52, 95% CI 1.05-2.20), five to six (OR = 1.81, 95% CI 1.31-2.50), and seven or more adverse alleles (OR = 2.50, 95% CI 1.69-3.70) had increasingly elevated risks of bladder cancer (P for trend <.001). Each additional adverse allele was associated with a 1.21-fold increase in risk (95% CI 1.12-1.29). For the combined analysis of DNA-repair and cell-cycle SNPs, compared with the referent group (<13 adverse alleles), the ORs for individuals with 13-15, 16-17, and >or=18 adverse alleles were 1.22 (95% CI 0.84-1.76), 1.57 (95% CI 1.05-2.35), and 1.77 (95% CI 1.19-2.63), respectively (P for trend = .002). Each additional high-risk allele was associated with a 1.07-fold significant increase in risk. In addition, we found that smoking had a significant multiplicative interaction with SNPs in the combined DNA-repair and cell-cycle-control pathways (P<.01). All genetic effects were evident only in "ever smokers" (persons who had smoked >or=100 cigarettes) and not in "never smokers." A cross-validation statistical method developed in this study confirmed the above observations. CART analysis revealed potential higher-order gene-gene and gene-smoking interactions and categorized a few higher-risk subgroups for bladder cancer. Moreover, subgroups identified with higher cancer risk also exhibited higher levels of induced genetic damage than did subgroups with lower risk. There was a significant trend of higher numbers of bleomycin- and benzo[a]pyrene diol-epoxide (BPDE)-induced chromatid breaks (by mutagen-sensitivity assay) and DNA damage (by comet assay) for individuals in higher-risk subgroups among cases of bladder cancer in smokers. The P for the trend was .0348 for bleomycin-induced chromosome breaks, .0036 for BPDE-induced chromosome breaks, and .0397 for BPDE-induced DNA damage, indicating that these higher-order gene-gene and gene-smoking interactions included SNPs that modulated repair and resulted in diminished DNA-repair capacity. Thus, genotype/phenotype analyses support findings from CART analyses. This is the first comprehensive study to use a multigenic analysis for bladder cancer, and the data suggest that individuals with a higher number of genetic variations in DNA-repair and cell-cycle-control genes are at an increased risk for bladder cancer, confirming the importance of taking a multigenic pathway-based approach to risk assessment.

Aged↗
PubMed2006

Assessing BRCA carrier probabilities in extended families.

PURPOSE: Carrier prediction models estimate the probability that a person has a BRCA mutation. We evaluated the accuracy of the BOADICEA model and compared its performance with that of other models (BRCAPRO, Myriad I and II, Couch, and Manchester Scoring System). We also studied the effect of extended family information on risk estimation using BOADICEA. METHODS: We compared the area under receiver operating characteristic curves generated from 472 families with one member tested for BRCA mutations. We calculated sensitivity, specificity, and predictive values at an estimated probability of 10% and explored the biases of carrier prediction. RESULTS: BOADICEA performed better than the other models in Ashkenazi Jewish (AJ) families, BRCAPRO performed slightly better in non-AJ families, and Myriad II performed comparably well in both groups. Including extended family information in BOADICEA yielded slightly better performance than did limiting the information to second-degree relatives. Using a 10% cutoff point, BOADICEA and Myriad II were most sensitive in predicting BRCA1/2 mutations in AJ families, and Myriad II was most sensitive in non-AJ families. The Manchester Scoring System was the most sensitive and least specific in a subgroup of non-AJ families. BOADICEA and BRCAPRO tended to underestimate the observed risk at low estimated probabilities and overestimate it at higher probabilities. CONCLUSION: The BOADICEA, BRCAPRO, and Myriad II models performed similarly. Including second-degree relatives slightly improved carrier prediction by BOADICEA. The Myriad II model was the easiest to implement.

Adult↗
PubMed2006

IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Insulin-like growth factor-I (IGF-I) is involved in colorectal carcinogenesis, and elevated plasma IGF-I levels are associated with sporadic colorectal cancer (CRC) risk. We investigated the relationship between IGF1 promoter cytosine-adenine (CA) dinucleotide-repeat polymorphism length and CRC risk in 121 MMR gene mutation carriers using Cox regression and Kaplan-Meier analysis. All statistical tests were two-sided. Time to onset for CRC increased for each decrease in CA-repeat number (median = 19 repeats, range = 12-22 repeats; hazard ratio [HR] = 1.17, 95% confidence interval [CI] = 1.05 to 1.31; P = .006). Patients carrying a CA(< or = 17) repeat allele had a statistically significantly higher CRC risk (HR = 2.36; 95% CI = 1.28 to 4.36; P = .006) than all others and were younger at onset (44 years versus 56.5 years; P = .023). These findings indicate a statistically significant association between shorter IGF1 CA-repeat lengths and increased risk for CRC in HNPCC. This is the first report, to our knowledge, to show that IGF1 variant genotypes modify risk of a hereditary form of cancer.

Adenine↗