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Ghulam Nabi - One of the best experts on this subject based on the ideXlab platform.
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tumour suppressor gene cdkna2 status on Chromosome 9p in resected renal tissue improves prognosis of localised kidney cancer
Oncotarget, 2016Co-Authors: Ismail Elmokadem, Stewart Fleming, Thomas Kidd, Norman Pratt, Ghulam NabiAbstract:// Ismail El-Mokadem 1 , Thomas Kidd 3 , Norman Pratt 2 , Stewart Fleming 3 , Ghulam Nabi 1 1 Academic Section of Urology, Division of Cancer Research, University of Dundee, Ninewells Hospital, DD1 9SY, Dundee, Scotland 2 Department of Cytogenetic, University of Dundee, Ninewells Hospital, DD1 9SY, Dundee, Scotland 3 Department of Pathology, University of Dundee, Ninewells Hospital, DD1 9SY, Dundee, Scotland Correspondence to: Ghulam Nabi, email: g.nabi@dundee.ac.uk Keywords: kidney cancer, genetics, microsatellite analysis, Chromosome 9p Received: May 16, 2016 Accepted: September 15, 2016 Published: September 22, 2016 ABSTRACT Background: Genetic alterations on Chromosome 9p, including inactivation of the tumour suppressor gene, CDKN2A, result in cellular proliferation and growth of tumours. Our aim was to use microsatellite analysis and fluorescence in situ hybridization (FISH) to characterise the architecture of this region. Results: Seventy-five out of 77 clear cell renal cell cancers (tumour/normal pairs) were interpretable for LOH analysis on Chromosome 9p (two tumours were excluded, as all five primers were uninformative). Twenty out of 75 (26.6%) tumours showed LOH in at least one of the five primers employed. Most allelic deletions were detected, telomeric to the CDKN2A region at D9S916, with 11 out of 52 informative tumours (21%) displaying LOH. The LOH in the coding region of CDKN2A, at D9S974 and D9S942, was associated with a higher pT-stage ( p = 0.004) and metastasis ( p = 0.006, both markers). The rate of Chromosome 9p deletion in ccRCC was 44% (35/80 cases) according to FISH. Somatic copy number loss of Chromosome 9p was associated with a larger tumour size ( p = 0.002), higher pathological tumour stage ( p = 0.021), presence of tumour necrosis ( p = 0.019) and microvascular invasion ( p = 0.032). The cases with copy number loss, loss of heterozygosity and copy number neutral ( n = 42) were at a higher risk of cancer-specific death when compared to tumours in category D ( n = 32) (Log-rank: p = 0.001). Seventeen patients with localised ccRCC developed recurrence, and fourteen of those showed either LOH or somatic copy number loss at CDKN2A (Log-rank: p = 0.005). Multivariate analysis showed that LOH or copy number loss at CDKN2A retained its independent prognostic effect, improving the predictive accuracy of stage and SSIGN score by concordance Index C from 0.823 to 0.878 ( p = 0.001). Materials and Methods: Cytogenetics data, microsatellite analysis and FISH were acquired for a cohort of patients undergoing resection for clinically localised renal cancer between January 2001 and December 2005. Five microsatellite markers (D9S916, D9S1814, D9S974, D9S942 and D9S171) assessed loss of heterogeneity (LOH) using DNA samples and in the same cohort FISH analysis was accomplished on tissue microarray slides. The FISH data were scored by two observers blinded to the histological data of the patients. Cytogenetic aberrations were correlated with histological and clinical outcomes by univariate and multivariate analyses using different prognostic models. Disease specific and recurrence free survival based on cytogenetic changes were assessed by Kaplan Meier methods. Conclusions: A comprehensive cytogenetic analysis using microsatellite analysis and FISH of the CDKN2A region on Chromosome 9p improves the predictive accuracy of known prognostic factors in clinically localised renal cell carcinoma undergoing surgical resection.
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Microsatellite alteration and immunohistochemical expression profile of Chromosome 9p21 in patients with sporadic renal cell carcinoma following surgical resection.
BMC Cancer, 2016Co-Authors: Ismail El-mokadem, Stewart Fleming, Thomas Kidd, Norman Pratt, Katherine Garret, David Batty, Ghulam NabiAbstract:Background Long-term prognostic significance of loss of heterozygosity on Chromosome 9p21 for localized renal cell carcinoma following surgery remains unreported. The study assessed the frequency of deletions of different loci of Chromosome 9p along with immunohistochemical profile of proteins in surgically resected renal cancer tissue and correlated this with long-term outcomes.
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Chromosome 9p deletion in clear cell renal cell carcinoma predicts recurrence and survival following surgery
British Journal of Cancer, 2014Co-Authors: Ismail Elmokadem, John Fitzpatrick, J Bondad, Petra Rauchhaus, J Cunningham, N Pratt, Stewart Fleming, Ghulam NabiAbstract:Chromosome 9p deletion in clear cell renal cell carcinoma predicts recurrence and survival following surgery
David Sidransky - One of the best experts on this subject based on the ideXlab platform.
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identification of a novel region of homozygous deletion on Chromosome 9p in squamous cell carcinoma of the lung the location of a putative tumor suppressor gene
Cancer Research, 1997Co-Authors: Jonathan Wiest, Wilbur A Franklin, John T Otstot, Kristian Forbey, Marileila Varellagarcia, Harry A Drabkin, Robert M Gemmill, Steve Ahrent, David Sidransky, Geno SaccomannoAbstract:Abstract Cytogenetic and molecular studies have implied the presence of tumor suppressor genes (TSGs) on Chromosome 9p that are critical in the development of lung and other cancers. The p16/CDKN2 gene, a cyclin dependent kinase inhibitor, is a well-defined TSG on 9p21. Although the frequency of mutations in the p16/CDKN2 gene has been detected in approximately 30% of non-small cell lung cancer, loss of heterozygosity on 9p has been observed in greater than 70% of non-small cell lung cancers. These and other deletion mapping studies have suggested the existence of additional TSGs on 9p. This study examined Chromosome 9p for TSG loci by analyzing 23 squamous cell carcinomas of the lung with 21 microsatellite markers. Loss of heterozygosity was detected in all of the tumors, and homozygous deletions of the p16/CDKN2 locus were observed in 6 of the 23 tumors (26%). In addition, a novel region of homozygous deletion was detected in six tumors (26%) at D9S126, approximately 2.5 cM proximal to p16/CDKN2. A single tumor contained a homozygous deletion at both the p16/CDKN2 locus and the D9S126 locus. The possibility of homozygous loss was confirmed by multiplex PCR using both the D9S126 marker and a Chromosome 9p control marker. Fluorescence in situ hybridization analysis with P1 and cosmid probes containing D9S126 also confirmed these data. The minimum region of homozygous deletion was determined by testing markers immediately proximal and distal to the D9S126 region. The data identify a homozygous loss on the short arm of Chromosome 9 suggesting the presence of a novel TSG locus, proximal to p16/CDKN2 and located between D9S265 and D9S259.
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homozygous deletion on Chromosome 9p and loss of heterozygosity on 9q 6p and 6q in primary human small cell lung cancer
Cancer Research, 1994Co-Authors: Adrian Merlo, Edward Gabrielson, Mack Mabry, Robin T Vollmer, Stephen B Baylin, David SidranskyAbstract:We analyzed the pattern of allelic loss in 33 primary human small cell lung cancers (SCLCs) using highly informative microsatellite markers on Chromosomes 2p, 3p, 5q, 6, 9, 13q, and 17p. Nineteen of these tumors (58%) displayed loss of heterozygosity on Chromosome 9. Fourteen SCLCs demonstrated loss of heterozygosity for all informative markers on both chromosomal arms; two tumors demonstrated partial loss on Chromosome 9p. In one tumor, a multiplex polymerase chain reaction assay disclosed a homozygous deletion at 9p21–22 including the markers IFN-α, D9S126 , and D9S171 . Two SCLCs retained all informative markers on 9p but showed allelic loss of the entire 9q arm, while one case had a partial loss of proximal 9q extending into all of 9p. Analysis of other chromosomal arms showed loss of heterozygosity on 3p (93%), 5q (75%), 6p (46%), 6q (47%), 13q (75%), and 17p (93%). It was necessary to test multiple markers at several loci because of the frequent expression of microsatellite instability that confounded our mapping efforts in SCLCs with replication errors. This study demonstrates the frequent loss of a suppressor gene locus on Chromosome 9p21–22 and identifies novel suppressor loci on 6p, 6q, and 9q in primary SCLC.
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Frequent loss of Chromosome 9p21-22 early in head and neck cancer progression.
Cancer Research, 1994Co-Authors: Peter Van Der Riet, Homaira Nawroz, Ralph H. Hruban, Russell L. Corio, Kaori Tokino, Wayne M. Koch, David SidranskyAbstract:Abstract In order to define more clearly the role of Chromosome 9 loss in head and neck squamous cell carcinoma (HNSCC), 29 invasive carcinomas and 17 preinvasive lesions were analyzed for loss of heterozygosity (LOH) on Chromosome 9. We found LOH in 21 of 29 (72%) HNSCC tumors using highly polymorphic microsatellite markers. In 17 of 21, LOH was found at all informative sites on the p arm with no LOH of the q arm. Further mapping in tumors, with partial LOH of the 9p arm, localized a common region of loss between markers D9S165 and D9S156 . Deletion of this region on Chromosome 9 has been found in several other tumor types implying the presence of a tumor suppressor gene at this locus. The inactivation of a tumor suppressor gene on Chromosome 9p may represent the most commonly described genetic alteration in HNSCC. A similar incidence of allelic loss on Chromosome 9p was identified in 12 of 17 (71%) preinvasive lesions. The identical frequency of loss in preinvasive and invasive lesions suggests that loss of 9p is an early event in HNSCC progression.
John N Eble - One of the best experts on this subject based on the ideXlab platform.
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Loss of Chromosome 9p is an independent prognostic factor in patients with clear cell renal cell carcinoma
Modern Pathology, 2008Co-Authors: Matteo Brunelli, Albino Eccher, Stefano Gobbo, Vincenzo Ficarra, Giacomo Novara, Paolo Cossu-rocca, Franco Bonetti, Fabio Menestrina, Liang Cheng, John N EbleAbstract:Loss of Chromosome 9p has been implicated in the progression of renal cell carcinoma. We evaluated the clinical utility of fluorescence in situ hybridization analysis of loss of Chromosome 9p in 73 patients with clear cell renal cell carcinomas with varied stage, size, grade, necrosis (SSIGN) scores. Loss of Chromosome 9p was observed in 13 tumors (18%). The 5-year cancer-specific survival of patients without loss of Chromosome 9p was 88% and was 43% in those with loss of Chromosome 9p ( P
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loss of Chromosome 9p is an independent prognostic factor in patients with clear cell renal cell carcinoma
Modern Pathology, 2008Co-Authors: Matteo Brunelli, Albino Eccher, Stefano Gobbo, Vincenzo Ficarra, Giacomo Novara, Franco Bonetti, Fabio Menestrina, Liang Cheng, Paolo Cossurocca, John N EbleAbstract:Loss of Chromosome 9p has been implicated in the progression of renal cell carcinoma. We evaluated the clinical utility of fluorescence in situ hybridization analysis of loss of Chromosome 9p in 73 patients with clear cell renal cell carcinomas with varied stage, size, grade, necrosis (SSIGN) scores. Loss of Chromosome 9p was observed in 13 tumors (18%). The 5-year cancer-specific survival of patients without loss of Chromosome 9p was 88% and was 43% in those with loss of Chromosome 9p (P<0.001). Local extension of the primary tumor according to the 2002 TNM staging system, lymph node involvement, the presence of distant metastases, and the SSIGN score were the other variables that predicted cancer-specific survival in univariate analysis. Loss of Chromosome 9p was an independent prognostic factor in multivariate analysis. Our data indicate that the detection of Chromosome 9p loss by fluorescence in situ hybridization analysis of clear cell renal cell carcinoma adds prognostic information beyond the pathological factors included in the current predictive models for renal cell carcinoma, such as SSIGN score.
Ismail Elmokadem - One of the best experts on this subject based on the ideXlab platform.
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tumour suppressor gene cdkna2 status on Chromosome 9p in resected renal tissue improves prognosis of localised kidney cancer
Oncotarget, 2016Co-Authors: Ismail Elmokadem, Stewart Fleming, Thomas Kidd, Norman Pratt, Ghulam NabiAbstract:// Ismail El-Mokadem 1 , Thomas Kidd 3 , Norman Pratt 2 , Stewart Fleming 3 , Ghulam Nabi 1 1 Academic Section of Urology, Division of Cancer Research, University of Dundee, Ninewells Hospital, DD1 9SY, Dundee, Scotland 2 Department of Cytogenetic, University of Dundee, Ninewells Hospital, DD1 9SY, Dundee, Scotland 3 Department of Pathology, University of Dundee, Ninewells Hospital, DD1 9SY, Dundee, Scotland Correspondence to: Ghulam Nabi, email: g.nabi@dundee.ac.uk Keywords: kidney cancer, genetics, microsatellite analysis, Chromosome 9p Received: May 16, 2016 Accepted: September 15, 2016 Published: September 22, 2016 ABSTRACT Background: Genetic alterations on Chromosome 9p, including inactivation of the tumour suppressor gene, CDKN2A, result in cellular proliferation and growth of tumours. Our aim was to use microsatellite analysis and fluorescence in situ hybridization (FISH) to characterise the architecture of this region. Results: Seventy-five out of 77 clear cell renal cell cancers (tumour/normal pairs) were interpretable for LOH analysis on Chromosome 9p (two tumours were excluded, as all five primers were uninformative). Twenty out of 75 (26.6%) tumours showed LOH in at least one of the five primers employed. Most allelic deletions were detected, telomeric to the CDKN2A region at D9S916, with 11 out of 52 informative tumours (21%) displaying LOH. The LOH in the coding region of CDKN2A, at D9S974 and D9S942, was associated with a higher pT-stage ( p = 0.004) and metastasis ( p = 0.006, both markers). The rate of Chromosome 9p deletion in ccRCC was 44% (35/80 cases) according to FISH. Somatic copy number loss of Chromosome 9p was associated with a larger tumour size ( p = 0.002), higher pathological tumour stage ( p = 0.021), presence of tumour necrosis ( p = 0.019) and microvascular invasion ( p = 0.032). The cases with copy number loss, loss of heterozygosity and copy number neutral ( n = 42) were at a higher risk of cancer-specific death when compared to tumours in category D ( n = 32) (Log-rank: p = 0.001). Seventeen patients with localised ccRCC developed recurrence, and fourteen of those showed either LOH or somatic copy number loss at CDKN2A (Log-rank: p = 0.005). Multivariate analysis showed that LOH or copy number loss at CDKN2A retained its independent prognostic effect, improving the predictive accuracy of stage and SSIGN score by concordance Index C from 0.823 to 0.878 ( p = 0.001). Materials and Methods: Cytogenetics data, microsatellite analysis and FISH were acquired for a cohort of patients undergoing resection for clinically localised renal cancer between January 2001 and December 2005. Five microsatellite markers (D9S916, D9S1814, D9S974, D9S942 and D9S171) assessed loss of heterogeneity (LOH) using DNA samples and in the same cohort FISH analysis was accomplished on tissue microarray slides. The FISH data were scored by two observers blinded to the histological data of the patients. Cytogenetic aberrations were correlated with histological and clinical outcomes by univariate and multivariate analyses using different prognostic models. Disease specific and recurrence free survival based on cytogenetic changes were assessed by Kaplan Meier methods. Conclusions: A comprehensive cytogenetic analysis using microsatellite analysis and FISH of the CDKN2A region on Chromosome 9p improves the predictive accuracy of known prognostic factors in clinically localised renal cell carcinoma undergoing surgical resection.
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Chromosome 9p deletion in clear cell renal cell carcinoma predicts recurrence and survival following surgery
British Journal of Cancer, 2014Co-Authors: Ismail Elmokadem, John Fitzpatrick, J Bondad, Petra Rauchhaus, J Cunningham, N Pratt, Stewart Fleming, Ghulam NabiAbstract:Chromosome 9p deletion in clear cell renal cell carcinoma predicts recurrence and survival following surgery
P L Kramer - One of the best experts on this subject based on the ideXlab platform.
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evidence for linkage of restless legs syndrome to Chromosome 9p are there two distinct loci
Neurology, 2008Co-Authors: Katja Lohmannhedrich, A Neumann, Andre Kleensang, Thora Lohnau, H Muhle, Ana Djarmati, Inke R Konig, Peter P Pramstaller, Eberhard Schwinger, P L KramerAbstract:Background: Restless legs syndrome (RLS) is a common sensory-motor disorder characterized by paresthesias and an intense urge to move the legs with a considerable familial aggregation. To date, no gene mutation has been found, but five gene loci have been mapped in primary RLS to Chromosomes 12q, 14q, 9p, 2q, and 20p (RLS1 through 5). Patients/Methods: We identified a four-generational German RLS family with 37 family members including 15 affected cases. We performed linkage analysis using microsatellite markers at the five known loci. Prompted by the identification of a potentially shared haplotype near the RLS3 locus, we expanded the investigated linkage region on Chromosome 9p using additional DNA markers. Results: Mode of inheritance in our RLS family was compatible with an autosomal dominant pattern, and disease onset was mainly in childhood or adolescence. We excluded linkage to the RLS1, RLS2, RLS4, and RLS5 loci. However, we identified a likely new RLS gene locus (RLS3*) on Chromosome 9p with a maximum lod score of 3.60 generated by model-based multipoint linkage analysis. A haplotype flanked by D9S974 and D9S1118 in a 9.9-Mb region, centromeric to RLS3, was shared by all 12 investigated patients. In addition, 11 of them carried a common haplotype extending telomeric to D9S2189 that is located within RLS3. Conclusions: We demonstrate linkage to a locus on Chromosome 9p that is probably distinct from RLS3. Our family with a rather homogeneous phenotype and very early disease onset represents a unique opportunity to further elucidate the genetic causes of the frequent restless leg syndrome.