title: Chromosome 14q loss defines a molecular subtype of clear-cell renal cell carcinoma associated with poor prognosis.
abstract: Loss of chromosome 14 has been associated with poor outcomes in clear-cell renal cell carcinoma. Expression of HIFα isoforms has been linked to distinct molecular phenotypes of clear-cell renal cell carcinoma. We hypothesized that chromosome 14 loss could lead to a decrease in HIF1α levels, as its gene (HIF1A) resides in this chromosome. We analyzed 112 archival clear-cell renal cell carcinoma tumor specimens with 250K SNP microarrays. We also evaluated expression of HIFα isoforms by qPCR and immunohistochemistry in a subset of 30 patients. Loss of chromosome 14q was associated with high stage (III-IV, P=0.001), high risk for recurrence (P=0.002, RR 2.78 (1.506-5.153)) and with decreased overall survival (P=0.030) in non-metastatic clear-cell renal cell carcinoma. HIF1α mRNA and protein expression was reduced in specimens with loss of 14q (P=0.014) whereas HIF2α was not. Gain of 8q was associated with decreased overall survival (P<0.0001). Our studies confirm an association between 14q loss and clinical outcome in non-metastatic clear-cell renal cell carcinoma patients and that 8q gain is a candidate prognostic marker for decreased overall survival and appears to further decrease survival in patients with 14q loss. We have also identified that differential expression of HIF1α is associated with 14q loss. Further exploration of 8q gain, 14q loss, MYC, HIF1A and EPAS1 (HIF2α) as molecular markers of tumor behavior and prognosis could aid in personalizing medicine for patients with clear-cell renal cell carcinoma.
authors: Department of Pathology, The Methodist Hospital Research Institute, Houston, TX, USA. famonzon@tmhs.org
authors: Federico A
authors: FA
authors: Monzon
authors: Karla
authors: K
authors: Alvarez
authors: Lief
authors: L
authors: Peterson
authors: Luan
authors: L
authors: Truong
authors: Robert J
authors: RJ
authors: Amato
authors: Joan
authors: J
authors: Hernandez-McClain
authors: Nizar
authors: N
authors: Tannir
authors: Anil V
authors: AV
authors: Parwani
authors: Eric
authors: E
authors: Jonasch
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D002872:Chromosome Deletion; D002883:Chromosomes, Human, Pair 14; D020869:Gene Expression Profiling; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000235:genetics; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D013997:Time Factors; D014481:United States; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human