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Translational Science Survey Section: Kidney Cancer
Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎
Basic/Translational Science Survey Section: Kidney Cancer Comprehensive molecular characterization of papillary renal cell carcinoma. Cancer Genome Atlas Research Network. Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, Wheeler DA, Murray BA, Schmidt L, Zuna R. N Engl J Med 2016 Jan 14;374(2):135–45. Commentary Papillary renal cancers account for 10% to 15% of all renal cell carcinoma and have been divided pathologically into 2 distinct subtypes. Type 1 papillary tumors typically present at early stage and follow an indolent course. In contrast type 2 papillary tumors present more often at advanced stage and demonstrate inferior overall survival in several reports. Despite observed differences in stage of presentation, outcomes appear to be similar at comparable stages [1,2]. Linehan and colleagues of the Cancer Genome Atlas Research Network reported on the TCGA profiling of 161 primary papillary renal cell carcinoma including 75 type 1, 60 type 2, and 26 unclassifiable tumors. Notably, the type 1 cohort was made up of predominantly (480%) stage I/ II tumors, whereas fewer than half of the type 2 cohort were stage I/II—a distribution markedly skewed from what is reported clinically [3] and potentially introducing substantial bias to any comparison analysis. Copy number analysis separated the entire cohort into 3 distinct subgroups with group I containing most of the type 1 and early-stage type 2 tumors, and showing universal gains of chromosomes 7 and 17. Group II was predominantly type 2, showing few copy number alterations. In contrast, group III was characterized by high aneuploidy and frequent loss of 9p. Mutations of MET, SETD2, NF2, KDM6A, and SMARCB1 were detected in 24% of the entire cohort. Altered MET status was present in 81% of type 1, largely driven by trisomy of chromosome 7. Both type 1 and type 2 had a comparably high number of mutations in the SWI/ SNF complex (SMARCB1 and PBRM1), the chromatin modifier pathways (SETD2, KDM6A, and BAP1), and Hippo signaling (NF2). Notably, alterations of CDKN2A, resulting in increased Rb phosphorylation, were seen in 25% of the clinical type 2 tumors and were associated with significantly lower survival relative to the remainder of the type 2 cohort. Analysis by DNA methylation, messenger RNA and microRNA expression pattern identified 4 discrete clusters. The largest (C1) was predominantly histologic type 1, showing gain of chromosome 7 and high rate of MET alterations. However, histologic type 2 tumors strikingly divided into 3 separate groups. The majority fell roughly into 2 clusters based on pathologic tumor stage with C2a containing early stage I/II and C2b predominantly stage III and IV. However, a fourth tight cluster (n ¼ 9) of type 2 tumors was clearly delineated, carrying a unique global hypermethylation profile or CpG Island Methylator Phenotype (CIMP). Of these 9 CIMP tumors, more than half carried germline or somatic mutations of fumarate hydratase (FH) and all showed loss of FH messengesr RNA expression and silencing of CDKN2A. This distinct subgroup represented 5% of the entire cohort and included all of the known germline FH specimens. Not surprisingly, the CIMP cohort corresponded to younger age at presentation and dismal survival. However, Kaplan-Meier curves for C1 and C2a were closely approximated, consistent with multiple reports of comparable outcome for early-stage tumors of both papillary subtypes [1]. C2b tumors demonstrated intermediate survival, likely attributable to their enrichment for higher tumor stage. These findings have implications for tumor risk assessment protocols based on small renal mass biopsy. The risk that has been to date attributed to type 2 histologic status is limited to a minority of papillary tumors with the CIMP profile. Thus, protocols designed to aggressively resect all type 2 papillary tumors regardless of size likely represent overtreatment. Screening for the CIMP phenotype will better tailor surveillance and treatment strategies.
Jodi K. Maranchie, M.D., F.A.C.S. http://dx.doi.org/10.1016/j.urolonc.2017.01.010
References [1] Ledezma RA, Negron E, Paner GP, Rjepaj C, Lascano D, Haseebuddin M, et al. Clinically localized type 1 and 2 papillary renal cell carcinomas have similar survival outcomes following surgery. World J Urol 2016;34:687–93. [2] Klatte T, Pantuck AJ, Said JW, Seligson DB, Rao NP, LaRochelle JC, et al. Cytogenetic and molecular tumor profiling for type 1 and type 2 papillary renal cell carcinoma. Clin Cancer Res 2009;15:1162–9. [3] Alomari AK, Nettey OS, Singh D, Kluger H, Adeniran AJ. Clinicopathological and immunohistochemical characteristics of papillary renal cell carcinoma with emphasis on subtyping. Hum Pathol 2015;46:1418–26.
1078-1439/r 2017 Elsevier Inc. All rights reserved.
Basic/Translational Science Survey Section: Kidney Cancer Comprehensive molecular characterization of papillary renal cell carcinoma. Cancer Genome Atlas Research Network. Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, Wheeler DA, Murray BA, Schmidt L, Zuna R. N Engl J Med 2016 Jan 14;374(2):135–45. Commentary Papillary renal cancers account for 10% to 15% of all renal cell carcinoma and have been divided pathologically into 2 distinct subtypes. Type 1 papillary tumors typically present at early stage and follow an indolent course. In contrast type 2 papillary tumors present more often at advanced stage and demonstrate inferior overall survival in several reports. Despite observed differences in stage of presentation, outcomes appear to be similar at comparable stages [1,2]. Linehan and colleagues of the Cancer Genome Atlas Research Network reported on the TCGA profiling of 161 primary papillary renal cell carcinoma including 75 type 1, 60 type 2, and 26 unclassifiable tumors. Notably, the type 1 cohort was made up of predominantly (480%) stage I/ II tumors, whereas fewer than half of the type 2 cohort were stage I/II—a distribution markedly skewed from what is reported clinically [3] and potentially introducing substantial bias to any comparison analysis. Copy number analysis separated the entire cohort into 3 distinct subgroups with group I containing most of the type 1 and early-stage type 2 tumors, and showing universal gains of chromosomes 7 and 17. Group II was predominantly type 2, showing few copy number alterations. In contrast, group III was characterized by high aneuploidy and frequent loss of 9p. Mutations of MET, SETD2, NF2, KDM6A, and SMARCB1 were detected in 24% of the entire cohort. Altered MET status was present in 81% of type 1, largely driven by trisomy of chromosome 7. Both type 1 and type 2 had a comparably high number of mutations in the SWI/ SNF complex (SMARCB1 and PBRM1), the chromatin modifier pathways (SETD2, KDM6A, and BAP1), and Hippo signaling (NF2). Notably, alterations of CDKN2A, resulting in increased Rb phosphorylation, were seen in 25% of the clinical type 2 tumors and were associated with significantly lower survival relative to the remainder of the type 2 cohort. Analysis by DNA methylation, messenger RNA and microRNA expression pattern identified 4 discrete clusters. The largest (C1) was predominantly histologic type 1, showing gain of chromosome 7 and high rate of MET alterations. However, histologic type 2 tumors strikingly divided into 3 separate groups. The majority fell roughly into 2 clusters based on pathologic tumor stage with C2a containing early stage I/II and C2b predominantly stage III and IV. However, a fourth tight cluster (n ¼ 9) of type 2 tumors was clearly delineated, carrying a unique global hypermethylation profile or CpG Island Methylator Phenotype (CIMP). Of these 9 CIMP tumors, more than half carried germline or somatic mutations of fumarate hydratase (FH) and all showed loss of FH messengesr RNA expression and silencing of CDKN2A. This distinct subgroup represented 5% of the entire cohort and included all of the known germline FH specimens. Not surprisingly, the CIMP cohort corresponded to younger age at presentation and dismal survival. However, Kaplan-Meier curves for C1 and C2a were closely approximated, consistent with multiple reports of comparable outcome for early-stage tumors of both papillary subtypes [1]. C2b tumors demonstrated intermediate survival, likely attributable to their enrichment for higher tumor stage. These findings have implications for tumor risk assessment protocols based on small renal mass biopsy. The risk that has been to date attributed to type 2 histologic status is limited to a minority of papillary tumors with the CIMP profile. Thus, protocols designed to aggressively resect all type 2 papillary tumors regardless of size likely represent overtreatment. Screening for the CIMP phenotype will better tailor surveillance and treatment strategies.
Jodi K. Maranchie, M.D., F.A.C.S. http://dx.doi.org/10.1016/j.urolonc.2017.01.010
References [1] Ledezma RA, Negron E, Paner GP, Rjepaj C, Lascano D, Haseebuddin M, et al. Clinically localized type 1 and 2 papillary renal cell carcinomas have similar survival outcomes following surgery. World J Urol 2016;34:687–93. [2] Klatte T, Pantuck AJ, Said JW, Seligson DB, Rao NP, LaRochelle JC, et al. Cytogenetic and molecular tumor profiling for type 1 and type 2 papillary renal cell carcinoma. Clin Cancer Res 2009;15:1162–9. [3] Alomari AK, Nettey OS, Singh D, Kluger H, Adeniran AJ. Clinicopathological and immunohistochemical characteristics of papillary renal cell carcinoma with emphasis on subtyping. Hum Pathol 2015;46:1418–26.
1078-1439/r 2017 Elsevier Inc. All rights reserved.