Showing papers by "Alisa M. Goldstein published in 2001"
TL;DR: Age-adjusted chordoma incidence rate was age-dependent, more common in males than females, and rare among patients aged <40 years and blacks, and racial disparities in incidence for the two developmental tumors, chordoma and Ewing's sarcoma were revealed.
Abstract: Background: Chordoma, a rare tumor arising from notochordal remnants, has been described to date only by single-institution case series or small population-based surveys.
807 citations
Journal Article•
TL;DR: The multiple genetic alterations of TP53 in this population at high risk of ESCC indicate that there is a very high degree of genetic instability in these tumors, that TP53 is a primary target for inactivation, and that this tumor suppressor gene plays a critical role in the carcinogenesis process for ESCC.
Abstract: Esophageal squamous cell carcinoma (ESCC) is one of the most common fatal cancers worldwide, and north central China has some of the highest rates in the world. Previous studies from tumors in this area of China have shown high frequencies of allelic loss on chromosome 17p13-11, which includes the region where the TP53 gene is found. We examined 56 ESCC patients using single-strand conformation polymorphism and DNA sequencing to assess the frequency and spectrum of TP53 mutation and the association between allelic loss at microsatellite marker TP53 and TP53 mutations. Ninety-six % of cases were found to have at least one genetic alteration, including TP53 mutation (77%), allelic loss within the TP53 gene (73%), and/or loss of heterozygosity at the TP53 microsatellite marker (80%); 75% had two or more such alterations, including 59% with both a point mutation and an intragenic allelic loss ("two hits"). The majority of mutations observed were in exon 5, where the most common type of nucleotide substitution was a G:C-->A:T or C:G-->T:A transition, including half that occurred at CpG sites. Allelic loss was most commonly found in exon 4 but was very common in exon 5 as well. Taken together, the multiple genetic alterations of TP53 in this population at high risk for ESCC indicate that there is a very high degree of genetic instability in these tumors, that TP53 is a primary target for inactivation, and that this tumor suppressor gene plays a critical role in the carcinogenesis process for ESCC.
84 citations
TL;DR: A genomewide analysis for linkage in a family with 10 individuals affected by chordoma shows a locus for familial chordoma to 7q33, and no loss of heterozygosity was found at markers D7S1804, D 7S1824, and D7s2195 in four tumor samples from affected family members.
Abstract: Chordoma is a rare tumor originating from notochordal remnants that is usually diagnosed during midlife. We performed a genomewide analysis for linkage in a family with 10 individuals affected by chordoma. The maximum two-point LOD score based on only the affected individuals was 2.21, at recombination fraction 0, at marker D7S2195 on chromosome 7q. Combined analysis of additional members of this family (11 affected individuals) and of two unrelated families (one with 2 affected individuals and the other with 3 affected individuals), with 20 markers on 7q, showed a maximum two-point LOD score of 4.05 at marker D7S500. Multipoint analysis based on only the affected individuals gave a maximum LOD score of 4.78, with an approximate 2-LOD support interval from marker D7S512 to marker D7S684. Haplotype analysis of the three families showed a minimal disease-gene region from D7S512 to D7S684, a distance of 11.1 cM and ∼7.1 Mb. No loss of heterozygosity was found at markers D7S1804, D7S1824, and D7S2195 in four tumor samples from affected family members. These results map a locus for familial chordoma to 7q33. Further analysis of this region, to identify this gene, is ongoing.
67 citations
TL;DR: It can be concluded that de novo germline CDKN2A mutations associated with MPM are rare, and six out of 7 sporadic MPM cases displayed a recurrent missense mutation, G101W.
Abstract: Multiple primary cancers are one of the hallmarks of inherited predisposition. Outside the familial context, multiple primary tumors could be related either to germline de novo mutations or to low-penetrance mutations, in predisposing genes. We selected 100 patients who displayed multiple primary melanoma (MPM) without any known melanoma cases recorded within their families and looked for germline mutations in the two melanoma-predisposing genes identified to date, CDKN2A and CDK4 exon 2. Nine patients (9%) had germline mutations in CDKN2A, whereas none carried germline mutations in exon 2 of CDK4. Seven cases displayed a recurrent missense mutation, G101W, already described in more than 20 melanoma-prone families; one case carried a missense mutation never reported to date (P114S), and the last case was a carrier of a 6 bp insertion at nucleotide 57 resulting in a duplication of codons 18 and 19. To ascertain whether the G101W was a mutational hot spot for de novo mutations or a common founder mutation, we genotyped eight microsatellite markers flanking the CDKN2A gene. After allowing for recombination over time, haplotype sharing provided evidence for an original G101W mutation common to 6 out of 7 sporadic MPM cases. Therefore, it can be concluded that de novo germline CDKN2A mutations associated with MPM are rare.
55 citations
TL;DR: Although the efficiency of counter-matching is greatest when the risk factors are very rare, the study of such rare factors is not realistic unless one is interested in very strong interaction effects, and counter- matching appears to be more appropriate than most traditional epidemiologic methods for theStudy of interactions involving rare factors.
Abstract: The interest in studying gene-environment interaction is increasing for complex diseases. However, most methods of detecting gene-environment interactions may not be appropriate for the study of interactions involving rare genes (G:) or uncommon environmental exposures (E:), because of poor statistical power. To increase this power, the authors propose the counter-matching design. This design increases the number of subjects with the rare factor without increasing the number of measurements that must be performed. In this paper, the efficiency and feasibility (required sample sizes) of counter-matching designs are evaluated and discussed. Counter-matching on both G: and E: appears to be the most efficient design for detecting gene-environment interaction. The sensitivity and specificity of the surrogate measures, the frequencies of G: and E:, and, to a lesser extent, the value of the interaction effect are the most important parameters for determining efficiency. Feasibility is also more dependent on the exposure frequencies and the interaction effect than on the main effects of G: and E: Although the efficiency of counter-matching is greatest when the risk factors are very rare, the study of such rare factors is not realistic unless one is interested in very strong interaction effects. Nevertheless, counter-matching appears to be more appropriate than most traditional epidemiologic methods for the study of interactions involving rare factors.
36 citations
TL;DR: This study suggests that one or more unidentified tumor suppressor genes are located on chromosome arm 13q that play a role in the development of esophageal squamous cell carcinoma.
Abstract: Allelic loss on chromosome 13 occurs frequently in esophageal squamous cell carcinoma. However, studies of the two known tumor suppressor genes located on 13q, RB1 and BRCA2, have shown few mutations, suggesting that other genes are likely to be involved in the development of this tumor type. To identify a minimal deletion interval, we first analyzed 42 microsatellite markers spanning chromosome bands 13q11-q13 in 56 esophageal squamous cell carcinoma patients, including 34 with a family history of upper gastrointestinal cancer and 22 without a family history of cancer. Lifestyle risk factors and clinical/pathologic characteristics were also collected. Two commonly deleted regions were identified: one was located on band 13q12.11, between markers D13S787 and D13S221; the other was located on bands 13q12.3-q13.1 from markers D13S267 to D13S219. We observed higher allelic loss frequencies for eight of the microsatellite markers in those patients with a family history of upper gastrointestinal cancer compared to patients without such a history. This study suggests that one or more unidentified tumor suppressor genes are located on chromosome arm 13q that play a role in the development of esophageal squamous cell carcinoma.
32 citations
TL;DR: Nine markers surrounding CDKN2A in three American and four Canadian families carrying the V126D mutation found that the mutation appears to have originated 34–52 generations ago (1-LOD-unit support interval 13–98 generations).
Abstract: One of the most common melanoma-related CDKN2A mutations reported in North America is the V126D mutation. We examined nine markers surrounding CDKN2A in three American and four Canadian families carrying the V126D mutation. All seven families had a haplotype consistent with a common ancestor/founder for this mutation. In addition, the mutation appears to have originated 34-52 generations ago (1-LOD-unit support interval 13-98 generations).
28 citations
TL;DR: The results suggest that L1 is a more powerful approach than L2 to detect major gene and covariatc effects as well as to identify accurately gene×covariate interaction effects in a common and complex disease such as the Genetic Analysis Workshop 12 MG6 simulated trait.
Abstract: We compared two joint likelihood approaches, with complete (L1) or without (L2) linkage disequilibrium, under different ascertainment schemes, for the genetic analysis of the disease trait and marker gene 1 in replicate 42. Joint likelihoods were computed without a correction for the selection scheme. For the different sampling schemes we have explored, our results suggest that L1 is a more powerful approach than L2 to detect major gene and covariate effects as well as to identify accurately gene x covariate interaction effects in a common and complex disease such as the Genetic Analysis Workshop 12 MG6 simulated trait.
4 citations
TL;DR: It is found that the moving average test was more powerful than a test based on single p‐values, and in some cases, the weighting procedure increased the power further and was similar to that of multipoint analysis, but this was not consistently found.
Abstract: Our previous studies have demonstrated that the power to detect linkage was improved by calculating a moving average of consecutive p-values in a small region as compared with testing all single p-values. The goal of this study was to test whether the power can be improved further with an alternative method whereby the middle p-values in the sequence were given more weight than the others. We also wanted to compare the moving average tests with multipoint linkage tests. The simulated extended pedigree data from the general population was analyzed to identify two major genes (MG1 and MG5) underlying two quantitative traits (Q1 and Q5). We used the variance components method implemented in the GENEHUNTER program to test for linkage of 14-marker regions each on chromosome 19 and chromosome 1 to the adjusted quantitative traits Q1 and Q5, respectively, in all 50 replicates. As before, we found that the moving average test was more powerful than a test based on single p-values. In some cases, the weighting procedure increased the power further and was similar to that of multipoint analysis, but this was not consistently found. In addition, all methods had low power and it is not possible to make a general conclusion that some weighting schemes are better than others.
3 citations