PMID- 27682877
OWN - NLM
STAT- MEDLINE
DCOM- 20180226
LR  - 20191210
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 7
IP  - 45
DP  - 2016 Nov 8
TI  - Tumour suppressor gene (CDKNA2) status on chromosome 9p in resected renal tissue 
      improves prognosis of localised kidney cancer.
PG  - 73045-73054
LID - 10.18632/oncotarget.12196 [doi]
AB  - 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.
FAU - El-Mokadem, Ismail
AU  - El-Mokadem I
AD  - Academic Section of Urology, Division of Cancer Research, University of Dundee, 
      Ninewells Hospital, DD1 9SY, Dundee, Scotland.
FAU - Kidd, Thomas
AU  - Kidd T
AD  - Department of Pathology, University of Dundee, Ninewells Hospital, DD1 9SY, 
      Dundee, Scotland.
FAU - Pratt, Norman
AU  - Pratt N
AD  - Department of Cytogenetic, University of Dundee, Ninewells Hospital, DD1 9SY, 
      Dundee, Scotland.
FAU - Fleming, Stewart
AU  - Fleming S
AD  - Department of Pathology, University of Dundee, Ninewells Hospital, DD1 9SY, 
      Dundee, Scotland.
FAU - Nabi, Ghulam
AU  - Nabi G
AD  - Academic Section of Urology, Division of Cancer Research, University of Dundee, 
      Ninewells Hospital, DD1 9SY, Dundee, Scotland.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (CDKN2A protein, human)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p18)
SB  - IM
MH  - Alleles
MH  - *Chromosomes, Human, Pair 9
MH  - Cyclin-Dependent Kinase Inhibitor p16
MH  - Cyclin-Dependent Kinase Inhibitor p18/*genetics
MH  - DNA Copy Number Variations
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Kaplan-Meier Estimate
MH  - Kidney Neoplasms/*genetics/*mortality/pathology/surgery
MH  - Loss of Heterozygosity
MH  - Microsatellite Repeats
MH  - Neoplasm Staging
MH  - Prognosis
MH  - Proportional Hazards Models
MH  - Sequence Deletion
PMC - PMC5341962
OTO - NOTNLM
OT  - chromosome 9p
OT  - genetics
OT  - kidney cancer
OT  - microsatellite analysis
COIS- CONFLICTS OF INTEREST None.
EDAT- 2016/09/30 06:00
MHDA- 2018/02/27 06:00
PMCR- 2016/11/08
CRDT- 2016/09/30 06:00
PHST- 2016/05/16 00:00 [received]
PHST- 2016/09/15 00:00 [accepted]
PHST- 2016/09/30 06:00 [pubmed]
PHST- 2018/02/27 06:00 [medline]
PHST- 2016/09/30 06:00 [entrez]
PHST- 2016/11/08 00:00 [pmc-release]
AID - 12196 [pii]
AID - 10.18632/oncotarget.12196 [doi]
PST - ppublish
SO  - Oncotarget. 2016 Nov 8;7(45):73045-73054. doi: 10.18632/oncotarget.12196.