Mutations of 3p21 Epigenetic Regulators in Clear Cell Renal Cell Carcinoma: Sequencing and Clinicopathologic Analysis of 188 Cases
Hongying Huang, AA Hakimi, Irina Ostrovnaya, Hikmat A Al-Ahmadie, Anuradha Gopalan, Samson W Fine, James J Hsieh, Victor E Reuter, Satish K Tickoo, Ying-Bei Chen. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: Clear cell renal cell carcinoma (ccRCC), the most common subtype of RCC, is characterized by inactivation of the VHL gene on 3p25 in the majority of cases. Large scale genomic analyses have recently discovered frequent mutations of several epigenetic regulators on 3p21 in ccRCC, including PBRM1 (41%), SETD2 (3-12%) and BAP1 (8-11%). The clinical significance of these mutations is largely unknown.
Design: We studied 188 patients who underwent radical or partial nephrectomy for ccRCC during 2001-2011 at our institution. All H&E slides were reviewed for staging and various histologic features. DNA extracted from frozen tissue of the tumor and matched normal was sequenced for VHL, PBRM1, SETD2 and BAP1. Immunohistochemical study for BAP1 was performed on 116 cases.
Results: Our cohort included 132 (70%) men and 56 (30%) women. Median age was 61 yr (36-86). Tumor size ranged from 1.0 to 16.7 cm (median 5.1). At resection, 106 of 188 (56%) were pT3 or higher, and 111 (59%) tumors were Fuhrman nuclear grade 3 or 4. Thirteen patients died from kidney cancer (mean time to death: 20 months). Median follow-up for survivors was 35 months. Of the 188 tumors, VHL was mutated in 96 (51.1%), PBRM1 in 57 (30.3%), SETD2 in 14 (7.4%), and BAP1 in 11(6.4%) cases. Truncating mutations accounted for 77%, 89%, 79% and 50% of all mutations for VHL, PBRM1, SETD2 and BAP1, respectively. The remaining were missense mutations. VHL and PBRM1 were frequently co-mutated (p=0.007). Tumors with mutations of either PBRM1 or BAP1 were more likely to present with higher tumor stage 3-4 (p=0.01 and p=0.04 respectively). BAP1 mutations were associated with high nuclear grade (3 and 4) (p=0.03), while mutations of other genes were not associated with nuclear grade. BAP1 mutations were also associated with worse cancer specific survival (p=0.002). Of the 116 cases stained for BAP1, 3 of the 4 tumors with BAP1 mutations showed a complete loss of BAP1 nuclear staining. One discordant case retained BAP1 expression. The nuclear stain of BAP1 in the majority of tumors (80%) with wild-type BAP1 was strong and diffuse. However, the staining was weaker in about 20% cases and one case was equivocal.
Conclusions: Chromosome 3p21 locus harbors three frequently mutated ccRCC tumor suppressor genes. BAP1 mutations are associated with worse cancer specific survival, suggesting a role in disease progression. Studies are on-going to explore other histologic features that may associate with mutation status, and to assess the clinical utility of BAP1, SETD2 and PBRM1 immunostains.
Category: Genitourinary (including renal tumors)
Monday, March 4, 2013 11:00 AM
Proffered Papers: Section A, Monday Morning