Clear cell RCC is molecularly characterized by the sequence of VHL loss‒inappropriate stabilization of HIFs‒proangiogenic gene expression signature; mutations in genes involved with the PI3K/AKT pathway; and mutations in SETD2, BAP1, and MTOR. Aggressive clear cell RCC demonstrates a metabolic shift. Type 1 papillary RCC (scanty cytoplasm; better prognosis than that of type 2) is characterized by MET alteration. Type 2 papillary RCC (abundant eosinophilic cytoplasm) is characterized by CDKN2A (p16) silencing and SETD2 mutation. A subset of papillary RCC is characterized by aggressive behavior, CIMP-positive, and FH mutation. Chromophobe RCC is characterized by somatic mutation in mitochondrial DNA, mutations of TP53 and PTEN, and imbalanced chromosome duplication. MiT family translocation RCC is characterized by TFE3/TFEB rearrangement. SDH-deficient RCC is characterized by SDHB inactivation. HLRCC-associated RCC is characterized by germline mutation in FH. Emerging/provisional entities of RCCs in the 2016 WHO classification include ALK rearrangement-associated RCC, which is potentially responsive to ALK inhibitors.
Although we have obtained the knowledge of molecular pathological epidemiology of renal cell tumors and classified these tumors into a number of subtypes, the subclassification of renal cell tumors is currently less useful for clinicians to offer meaningful therapeutic suggestions to patients. In fact, we continue to use mostly traditional approaches for treating patients. Using the subclassification of renal cell tumors based on their molecular pathological epidemiology, we must thoroughly progress toward the use of clinical translation and precision medicine for treating patients.
Written by: Kentaro Inamura
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- Moch H, Humphrey PA, Ulbright TM, Reuter VE. WHO Classification of Tumours of the Urinary System and Male Genital Organs, 4th ed. Lyon: IARC Press; 2016.
- The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013;499:43-9.
- Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, et al. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N Engl J Med 2016;374:135-45.
- Davis CF, Ricketts CJ, Wang M, Yang L, Cherniack AD, Shen H, et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 2014;26:319-30.
- Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D, et al. The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia. Am J Surg Pathol 2013;37:1469-89.
- Inamura K. Translocation Renal Cell Carcinoma: An Update on Clinicopathological and Molecular Features. Cancers (Basel) 2017;9.
- Haake SM, Rathmell WK. Renal cancer subtypes: Should we be lumping or splitting for therapeutic decision making? Cancer 2017;123:200-209.
- Giles RH, Choueiri TK, Heng DY, Albiges L, Hsieh JJ, Linehan WM, et al. Recommendations for the Management of Rare Kidney Cancers. Eur Urol 2017:doi: 10.1016/j.eururo.2017.06.040. [Epub ahead of print].