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Hope Northrup - One of the best experts on this subject based on the ideXlab platform.
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Mutations and polymorphisms in the tuberous sclerosis complex gene on Chromosome 16
Human mutation, 1997Co-Authors: Joseph A. Rodriguez, Estanislado Rodriguez, William B. Dobyns, Mauricio R. Delgado, Hope NorthrupAbstract:Tuberous sclerosis complex (TSC) is an autosomal dominant disorder of benign tumor formation, hamartomata, and hamartias. TSC has been shown to be genetically heterogeneous, with one causative gene mapping to Chromosome 9q (denoted TSC1) and at least one other gene on Chromosome 16p (denoted TSC2). The TSC2 gene was recently cloned. We have tested 88 TSC probands with the TSC2 cDNA by Southern blotting searching for gross deletions/rearrangements/insertions. We detected two deletions and a rare intragenic polymorphic variant. This is a similar rate of mutation detection (2/88; 2.3%) to that in the orignial report (10/260/;3.8%). The rare polymorphic variant was initially detected in the proband of a Chromosome 9-linked multiplex TSC family. The polymorphism segregated with previously tested markers on Chromosome 16 independently of the disease gene, verifying that the variation was unrelated to TSC status. We have also begun searching for subtle mutations by SSCA and direct sequencing. After screening three exons, we found two intragenic polymorphic variants. Both polymorphisms are common, making them useful for linkage studies in known affected families. © 1997 Wiley-Liss, Inc.
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Report of a critical recombination further narrowing the TSC1 region.
Journal of medical genetics, 1996Co-Authors: Jill R. Murrell, Alan Buckler, Susan H. Blanton, Hope NorthrupAbstract:A large tuberous sclerosis multigenerational family segregating with markers on Chromosome 9q from the TSC1 region was studied with a new highly polymorphic marker (designated A6) from the region. A critical affected person showed recombination with the marker, eliminating approximately 100 kilobases from the telomeric end of the critical region, which contains three genes and three to four additional exons for which the associated genes have not been delineated. This information serves to further the search for the TSC1 gene.
Allen E. Bale - One of the best experts on this subject based on the ideXlab platform.
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The Nevoid Basal Cell Carcinoma Syndrome: Genetics and Mechanism of Carcinogenesis
Cancer investigation, 1997Co-Authors: Allen E. BaleAbstract:The nevoid basal cell carcinoma syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin, ovarian fibroma, and medulloblastoma. Unlike many other hereditary disorders associated with cancer, if features widespread birth defects. Laboratory studies of radiation sensitivity and Chromosome instability over the past 20 years have generally yielded negative or inconclusive results. Screening for allelic loss in sporadic and hereditary basal cell carcinomas, hereditary ovarian fibromas, and sporadic medulloblastomas provided evidence for a tumor suppressor gene on Chromosome 9q important in all three tumor types. Demonstration of a constitutional Chromosome 9q deletion in an unusual patient with this syndrome and genetic linkage studies in large kindreds indicated that the nevoid basal cell carcinoma syndrome gene maps to the same location lost in tumors. These data indicate that tumors arise with homozygous inactivation of the gene and imply that it normally functions as a tumor suppressor. In contrast, hemizygous germline mutations lead to multiple congenital anomalies.
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Relationship Between Sunlight Exposure and a Key Genetic Alteration in Basal Cell Carcinoma
Journal of the National Cancer Institute, 1996Co-Authors: Mae R. Gailani, David J. Leffell, Annemarie Ziegler, Earl G. Gross, Douglas E. Brash, Allen E. BaleAbstract:Basal cell carcinoma (BCC) of the skin is the most common cancer in humans. Epidemiologic studies implicate sunlight exposure as one risk factor, but the limited association between BCCs and UVB radiation (i.e., UV radiation of a wavelength of 280-320 nm) suggests that additional factors must be involved. At the molecular level, not much is known about the role of specific environmental agents in the pathogenesis of BCCs. Point mutations of the types produced by UVB radiation are seen in the p53 gene (also known as TP53; Chromosome 17p) of 40%-56% of BCCs. Loss of heterozygosity (LOH) on Chromosome 9q22, however, is the most frequent genetic alteration in these tumors, and its causative agent is unknown. We investigated whether the genetic alteration in Chromosome 9 is common to all clinical subtypes of BCCs and whether inactivation of this putative tumor suppressor is related to sunlight exposure. The presence of UVB radiation-related point mutations in the p53 gene was used as an internal control for sunlight exposure to the precursor cells. Tumor and blood samples were obtained from skin cancer patients by a surgeon who used Mohs' micrographic surgical technique. Clinical information on each tumor included location, size, histologic, subtype and whether it was primary or recurrent and sporadic or hereditary. Sixty BCCs from 58 patients were evaluated for LOH with 12 polymorphic markers that span Chromosome 9. A subset of 18 tumors was evaluated for point mutations in exons 2-11 of the p53 gene, and a subset of 26 tumors was evaluated for LOH by use of a polymorphism in exon 4 of the p53 gene. Associations between tumor characteristics and molecular alterations were tested by a two-tailed chi-squared analysis or a two-tailed Fisher's exact test, depending on sample size. In a clinically diverse series of 47 informative tumors, 32 (68%) showed LOH for Chromosome 9q markers, irrespective of histologic characteristics or clinical behavior. Forty-four (94%) of the 47 tumors were from sun-exposed areas of the body, defined as the head and neck in both sexes, shoulders or chest in males, and legs in females. No association was found between Chromosome 9q LOH and sunlight exposure, as assessed by either the location of tumors on the body or the presence of UVB radiation-related p53 mutations. Of note, there was a striking difference between the frequency of LOH on Chromosome 17p (two [12.5%] of 16 informative tumors) and on Chromosome 9q (32 [68%] of 47 informative tumors; P < .001). Inactivation of a gene on Chromosome 9q22 may be a necessary event for basal cell carcinogenesis. The pathogenesis of mutations in this gene may involve factors other than sunlight in a large proportion of tumors. The limited association between sunlight exposure and BCC incidence may reflect an etiologic contribution of additional environmental agents.
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Molecular analysis of Chromosome 9q deletions in two Gorlin syndrome patients.
American journal of human genetics, 1996Co-Authors: R. Shimkets, Michael Dean, Alisa M. Goldstein, Mae R. Gailani, V. M. Siu, T. Yang-feng, C. Pressman, Sonja Levanat, Allen E. BaleAbstract:Gorlin syndrome is an autosomal dominant disorder characterized by multiple basal cell carcinomas, medulloblastomas, ovarian fibromas, and a variety of developmental defects. All affected individuals share certain key features, but there is significant phenotypic variability within and among kindreds with respect to malformations. The gene (NBCCS) maps to Chromosome 9q22, and allelic loss at this location is common in tumors from Gorlin syndrome patients. Two recessive cancer-predisposition syndromes, xeroderma pigmentosum group A (XPAC) and Fanconi anemia group C (FACC), map to the NBCCS region; and unusual, dominant mutations in these genes have been proposed as the cause of Gorlin syndrome. This study presents cytogenetic and molecular characterization of germ-line deletions in one patient with a Chromosome 9q22 deletion and in a second patient with a deletion of 9q22-q3l. Both have typical features of Gorlin syndrome plus additional findings, including mental retardation, conductive hearing loss, and failure to thrive. That Gorlin syndrome can be caused by null mutations (deletions) rather than by activating mutations has several implications. First, in conjunction with previous analyses of allelic loss in tumors, this study provides evidence that associated neoplasms arise with homozygous inactivation of the gene. In addition, dominant mutations of the XPAC and FACC1 genes can be ruled out as the cause of Gorlin syndrome, since the two patients described have null mutations. Finally, phenotypic features that show variable expression must be influenced by genetic background, epigenetic effects, somatic mutations, or environmental factors, since these two patients with identical alterations (deletions) of the Gorlin syndrome gene have somewhat different manifestations of Gorlin syndrome.
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Fine Mapping of the Locus for Nevoid Basal Cell Carcinoma Syndrome on Chromosome 9q
The Journal of investigative dermatology, 1994Co-Authors: John G. Compton, Alisa M. Goldstein, Maria L. Turner, Allen E. Bale, Kathleen S. Kearns, O. Wesley Mcbride, Sherri J. BaleAbstract:The nevoid basal cell carcinoma syndrome is an autosomal dominant disorder characterized primarily by multiple basal cell carcinomas, odontogenic keratocysts, and pits of the palms and soles. Tumor deletion studies and linkage analysis in Caucasians have revealed that the gene is on Chromosome 9q. To further refine the location of the nevoid basal cell carcinoma syndrome locus, we tested linkage to this region in three families. Evaluation of recombinants suggested that the nevoid basal cell carcinoma syndrome locus lies in the interval defined distally by D9S127. Our data, together with existing published data defining D9S12 as a proximal flanking marker, refine the location of nevoid basal cell carcinoma syndrome to an 8.3-cM interval. Two of the families studied were African-American and show a notable variation in phenotypic expression in which affected individuals developed few skin cancers. However, despite clinical heterogeneity, our data are consistent with the hypothesis that the same locus is involved in these African-American families.
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Nevoid Basal Cell Carcinoma Syndrome
Journal of Investigative Dermatology, 1994Co-Authors: Allen E. Bale, Mae R. Gailani, David J. LeffellAbstract:The nevoid basal cell carcinoma syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin, ovarian fibromas, and medulloblastomas. Unlike other hereditary disorders associated with cancer, it features widespread developmental defects. Laboratory studies of radiation sensitivity and Chromosome instability over the past 20 years have generally yielded negative or inconclusive results. Recently, screening for allelic loss in sporadic and hereditary basal cell carcinomas, hereditary ovarian fibromas, and sporadic medulloblastomas provided evidence for a tumor suppressor gene on Chromosome 9q, important in all three tumor types. Demonstration of a Chromosome 9q deletion in an unusual patient with this syndrome and genetic linkage studies in large kindreds indicated that the nevoid basal cell carcinoma syndrome gene maps to the exact same location lost in tumors. These data show that tumors arise with homozygous inactivation of the gene and imply that it normally functions as a tumor suppressor. In contrast, hemizygous germ-line mutations lead to multiple congenital anomalies. J Invest Dermatol 103:126S-130S, 1994
Margaret A Knowles - One of the best experts on this subject based on the ideXlab platform.
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Destabilization of Chromosome 9 in transitional cell carcinoma of the urinary bladder.
British journal of cancer, 2001Co-Authors: Fumihiro Kimura, Margaret A Knowles, Andrea R. Florl, Hans-helge Seifert, Jari Louhelainen, Simone Maas, Wolfgang A. SchulzAbstract:The most frequent genetic alteration in transitional cell carcinoma of the urinary bladder (TCC) is loss of Chromosome 9 which targets CDKN2A on 9p. The targets on 9q are not confirmed. Here, 81 advanced TCC specimens were investigated for loss of heterozygosity (LOH) and homozygous deletions (HD) on Chromosome 9q using multiplex analysis of microsatellite markers. 41/81 tumours (51%) showed LOH on 9q, with LOH at all markers in 33 cases. Eight partial losses involved three regions in 9q12, 9q22.3, and 9q33- 9q34. No mutations were identified in the candidate tumour suppressor gene DBCCR1 in three tumours showing restricted LOH at 9q32-33. 22% of the specimens had HD at CDKN2A, but no HD was found on 9q. Two tumours had lost 9p only and five 9q only. 9q LOH was not related to tumour grade or stage and present or absent with equal frequency in recurrent TCC. LOH on 9q correlated with the extent of genome-wide hypomethylation (P < 0.0001) which extended into satellite sequences located in 9q12 juxtacentromeric heterochromatin. While the high frequency of Chromosome 9q loss in TCC may reflect destabilization of the Chromosome related to hypomethylation of repetitive DNA, the data are compatible with the existence of tumour suppressor genes on this Chromosome arm.
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detailed deletion mapping of Chromosome 9q in bladder cancer evidence for two tumour suppressor loci
Oncogene, 1995Co-Authors: Tomonori Habuchi, Jayne Devlin, Patricia A Elder, Margaret A KnowlesAbstract:Abstract Loss of heterozygosity (LOH) at loci on Chromosome 9p and/or 9q is the most frequent genetic alteration in transitional cell carcinoma (TCC) of the bladder. However, localisation of the tumour suppressor locus or loci on 9q has been hampered by the relative infrequency of tumours with subchromosomal deletions. We have used 24 microsatellite markers to examine LOH in 70 new cases of TCC of the bladder and upper urinary tract. Forty tumours (57%) showed LOH at one or more loci on 9q and partial deletions were detected in five tumours (7%). Combined data from the five cases with partial deletions place one tumour suppressor locus at 9q34 between D9S61 and D9S66 (an estimated distance of 13-14 cM). This region is frequently deleted in other sporadic tumours and encompasses one of the loci for tuberous sclerosis (TSC1). One tumour contained a distinct deletion between D9S153 and D9S109 (9q13-q31), which encompasses the locus for the familial nevoid basal cell carcinoma syndrome (Gorlin syndrome). This may indicate the presence of another tumour suppressor locus on 9q for TCC. Our findings significantly reduce the regions of 9q within which suppressor genes for TCC may reside. The possible involvement of two deletion targets on 9q in addition to the locus at 9p21 implicated in TCC may explain why LOH at all loci on Chromosome 9 is frequent in TCC.
Ellen C. Zwarthoff - One of the best experts on this subject based on the ideXlab platform.
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The random development of LOH on Chromosome 9q in superficial bladder cancers
The Journal of pathology, 2002Co-Authors: Angela A.g. Van Tilborg, L E Groenfeld, Annie De Vries, Maarten De Bont, Ellen C. ZwarthoffAbstract:Allelic loss on Chromosome 9q is a very frequent event in bladder carcinogenesis. In recent years, efforts have been directed towards identifying the postulated tumour suppressor genes on this Chromosome arm by deletion mapping and mutation analysis. However, no convincing candidate genes have been identified. This paper describes the development of Chromosome 9q alterations in multiple recurrent superficial bladder cancers of ten patients and shows that loss of heterozygosity (LOH) on this Chromosome is almost never the characteristic first step. The regions of loss are multiple and variable in different tumours from the same patient and expand in subsequent tumours. Moreover, the regions of loss vary from patient to patient. It is concluded that even if 9q harbours a bladder cancer gatekeeper gene, it is unlikely that the gene will be identified through LOH analysis alone.
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The Chromosome 9q genes TGFBR1, TSC1, and ZNF189 are rarely mutated in bladder cancer
The Journal of pathology, 2001Co-Authors: Angela A.g. Van Tilborg, Annie De Vries, Ellen C. ZwarthoffAbstract:This study assessed a series of bladder tumours and bladder tumour cell lines for sequence variation in the Krüppel-like zinc finger gene ZNF189, the tuberous sclerosis complex gene 1 (TSC1), and the TGF beta receptor type I (TGFBR1). All three genes have been mapped to 9q regions commonly deleted in transitional cell carcinoma of the bladder. Mutation analysis of the coding sequence of these genes revealed several variant bands that were shown to represent polymorphisms. Mutation analysis of the ZNF189 gene in bladder cancer cell lines identified one amino acid substitution (lysine-->isoleucine) at position 323 in exon 4. For the TSC1 gene, two mutations were identified in two out of 27 independent cell lines. Both mutations result in a truncated protein. Furthermore, one out of 36 bladder tumours had a frameshift mutation in exon 7 of the TSC1 gene. No tumour-specific mutations were found in the TGFBR1 gene. The length of the polyalanine tract present in exon 1 of the TGFBR1 gene was also investigated. It has been suggested that the allele with six alanines (6A) is more frequent in patients with bladder and other cancers, so bladder cancer patients were compared with normal controls. In both groups, the percentage of heterozygotes was 17%. These data do not support a role for the 6A allele in bladder cancer susceptibility.
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Evidence for two candidate tumour suppressor loci on Chromosome 9q in transitional cell carcinoma (TCC) of the bladder but no homozygous deletions in bladder tumour cell lines.
British journal of cancer, 1999Co-Authors: Angela A.g. Van Tilborg, L E Groenfeld, Theodorus H Van Der Kwast, Ellen C. ZwarthoffAbstract:The most frequent genetic alterations in transitional cell carcinoma (TCC) of the bladder involve loss of heterozygosity (LOH) on Chromosome 9p and 9q. The LOH on Chromosome 9p most likely targets the CDKN2 locus, which is inactivated in about 50% of TCCs. Candidate genes that are the target for LOH on Chromosome 9q have yet to be identified. To narrow the localization of one or more putative tumour suppressor genes on this Chromosome that play a role in TCC of the bladder, we examined 59 tumours with a panel of microsatellite markers along the Chromosome. LOH was observed in 26 (44%) tumours. We present evidence for two different loci on the long arm of Chromosome 9 where potential tumour suppressor genes are expected. These loci are delineated by interstitial deletions in two bladder tumours. Our results confirm the results of others and contribute to a further reduction of the size of these regions, which we called TCC1 and TCC2. These regions were examined for homozygous deletions with EST and STS markers. No homozygous deletions were observed in 17 different bladder tumour cell lines.
L Grossman - One of the best experts on this subject based on the ideXlab platform.
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Epidemiology of ultraviolet-DNA repair capacity and human cancer.
Environmental health perspectives, 1997Co-Authors: L GrossmanAbstract:The following conclusions are derived from an epidemiological study. Reduced repair of ultraviolet (UV)-induced DNA damage contributes directly to basal cell carcinoma (BCC) in individuals with prior sunlight overexposure. A family history of BCC is a predictor of low DNA repair. Repair of UV-damaged DNA declines at a fixed rate of approximately 1% per annum in noncancerous controls. The DNA repair differences between young BCC cases and their controls disappear as they age. Hence, BCC, in terms of DNA repair, is a premature aging disease. The persistence of photochemical damage because of reduced repair results in point mutations in the p53 gene and allelic loss of the nevoid BCC gene (Gorlin's syndrome) located on Chromosome 9q. The fact that environmental vulnerability is gender oriented implicates hormones in regulating DNA repair. Xeroderma pigmentosum appears to be a valid paradigm for the role of DNA repair in BCC in the general population.
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DNA repair and epidemiology of basal cell carcinoma.
Clinical Chemistry, 1995Co-Authors: L Grossman, Qingyi WeiAbstract:Abstract In a molecular epidemiological study of DNA repair, host reactivation assay was used to measure the DNA repair capacity of cryopreserved lymphocytes from 88 primary basal cell carcinoma (BCC) patients and 135 cancer-free controls. In this study population, reduced repair of ultraviolet radiation-induced DNA damage contributed to the risk of sunlight-induced BCC. A family history of BCC is associated with low DNA repair. Repair of ultraviolet radiation-damaged DNA declines at a rate of approximately 1%/year in noncancerous controls. Reduced DNA repair is more likely seen in young BCC patients, indicating that BCC is a premature aging disease of the skin. The persistence of photochemical damage because of reduced repair results in point mutations in the p53 gene and allelic loss of the nevoid BCC gene located on Chromosome 9q. Xeroderma pigmentosum appears to be a valid paradigm for the role of DNA repair in BCC in the general population.
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Progression of Basal Cell Carcinoma through Loss of Chromosome 9q and Inactivation of a Single p53 Allele
Cancer research, 1994Co-Authors: Peter Van Der Riet, L Grossman, Qingyi Wei, Debra Karp, Evan R. Farmer, Kaori Tokino, J. Michael Ruppert, David SidranskyAbstract:Basal cell carcinoma (BCC) of the skin represents a unique group of tumors strongly associated with exposure to UV light. Unlike squamous carcinoma of the skin, BCC is generally indolent, noninvasive, and rarely metastatic. To study the involvement of tumor suppressor genes in these neoplasms, we analyzed 36 BCCs for p53 mutations and a subset of these tumors for loss of Chromosomes 17p and 9q. Sixty-nine % of sporadic BCCs had lost a 9q allele, with the common area of loss surrounding the putative gene for nevoid BCC or Gorlin's syndrome. Forty-four % (16 of 36) of BCCs had a mutated p53 allele, usually opposite pyrimidine tracts, which is consistent with UV-induced mutations. Surprisingly, only one tumor had lost a 17p allele, and in all BCCs only one p53 allele was inactivated. This is in direct contrast to other epithelial tumors, which usually progress by the inactivation of both p53 alleles.