Urologic Oncology: Seminars and Original Investigations
Seminar ArticlesMutations in renal cell carcinoma
Introduction
Renal cell carcinoma (RCC) comprises 80% to 85% of all renal neoplasms and is estimated to represent 3.8% of all new cancer diagnoses in the United States; in 2017, there were 63,990 new cases of RCC with 14,400 deaths [1]. RCC is classified by histology, with over 15 subtypes identified in 2016 by the World Health Organization; clear cell RCC (ccRCC) accounts for ∼75% of these malignant tumors followed by papillary (types 1 and 2; 15%) and chromophobe subtypes (5%) [2], [3].
Although approximately two-thirds of patients with RCC present with localized disease, 30% of patients presenting with localized ccRCC will eventually develop metastasis and require systemic treatment [4]. Currently, the only established risk factors for development of RCC are obesity, hypertension, tobacco, and NSAID use [3]. Hereditary forms of RCC are estimated to represent 3% to 5% of all kidney cancers and there are 9 known inherited syndromes that carry an increased risk of RCC including Von Hippel Lindau (VHL) disease, BAP1 mutant disease, Birt–Hogg–Dube syndrome, Familial clear cell kidney cancer with chromosome 3 translocation, hereditary leiomyomatosis and kidney cell cancer, Hereditary papillary kidney cancer, Phosphatase and tension homolog (PTEN) hamartoma syndrome, SDH-associated kidney cancer, and Tuberous sclerosis complex [5]. Additional disease causing genes have been identified such as BAP1, PBRM1, and CDKN2B, and as genome sequencing expands more will likely be annotated [6], [7], [8].
In RCC patients with localized disease, treatment options include partial or radical nephrectomy, ablation, or active surveillance [3], [9]. Patients with high-risk localized disease after surgery may be treated with adjuvant targeted therapy with sunitinib which in the S-TRAC trial has shown an improvement in disease-free recurrence at 5 years (6.8 vs. 5.6 years), but not overall survival with 3 other trials utilizing sunitinib, sorafenib, pazopanib, or axitinib all not meeting their primary endpoint [10], [11], [12]. The standard treatment for metastatic disease is systemic therapy, with a minority of highly selected patients undergoing metastasectomy or active surveillance [9].
Prior to the last 15 years, the mainstay of treatment for advanced RCC was cytokine-based therapy (interferon alpha and interleukin-2); however, given an unfavorable toxicity profile, low response rates, and multiple newer and more effective targeted and immunotherapy options, these modalities are no longer frequently utilized [13]. Since the mid-2000s, due to an increased understanding of the molecular basis of RCC, drastic advances in systemic therapy have occurred, most notably first with the approval of molecular-targeted therapy in the form of multiple antiangiogenic and mammalian target of rapamycin (mTOR) inhibitor drugs and more recently with the approval of immune checkpoint inhibitors [4], [13]. For example, sunitinib or pazopanib, both vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs), have been for a decade the standard first-line treatment of advanced ccRCC based on an objective response rate of 25% to 30% and median progression-free survival (PFS) of 8.5 to 9.5 months [14]. Even more recently, novel immunotherapy with checkpoint inhibitor nivolumab, an antibody against the programmed cell death 1 receptor, was approved as second-line treatment of advanced RCC, and the combination of nivolumab and ipilimumab, an anti-cytotoxic T-lymphocyte-associated antigen 4 antibody, was approved as front-line treatment for patients with intermediate and poor risk ccRCC [15], [16]. Finally, combinations of immunotherapy with targeted therapy are also in rapid development and likely to become standards-of-care in the near future [17], [18].
The expansion of treatment options for patients with advanced RCC over the past 15 years is a testament to enhanced understanding of the genetics and genomics of RCC and the ability to apply this knowledge to drug development. However, much work remains to be done as there are still no validated biomarkers to select patient treatment, and in only rare cases, the knowledge of particular mutations in RCC can lead to rational treatment selection. Below we will review the mutational landscape and its potential application to treatment in the most common RCC subtypes. Table 1 summarizes some of these findings.
Section snippets
Molecular genetics of RCC
The study of 1 heritable form of RCC, (VHL), led to the discovery of the importance of chromosome 3p in renal cancer, in particular in ccRCC, the subtype in which the most investigation and drug development has occurred [19], [20]. This chromosome is now known to contain many genes, which have known associations with RCC such as VHL, PBRM1, BAP1, and SETD2 [21]. A key early discovery was the recognition of VHL alterations in both hereditary and sporadic RCC [19], [20], [22]. Functional loss of
Clear cell carcinoma: mutations
While inactivation of VHL is considered a seminal discovery in ccRCC, other key genetic mutations have been identified with the advancement of molecular sequencing technology. The Cancer Genome Atlas Consortium analyzed the genomic profiles of 446 primary nephrectomy samples in patients with pathologically confirmed ccRCC. The majority of sequenced tumors were from patients with localized disease (372 tumors with stage 1–3 disease) while 74 samples were from patients with metastatic disease.
Clear cell carcinoma: therapeutic implications
The development of TKIs have revolutionized the treatment paradigm for RCC; however, response is limited and patients ultimately develop resistance. The role that genetic mutations play in resistance is yet unknown and is of high interest as a potential target for further treatment. A 2011 study sequenced tumors from 397 patients with advanced RCC who were enrolled in a clinical trial to receive pazopanib vs. placebo. The study found specific genetic polymorphisms that were associated with
Papillary RCC
Papillary RCC (PRCC) represents around 15% to 20% of all kidney cancers and is categorized into 2 main types. Type 1 tumors tend to be multifocal and are associated with hereditary papillary renal cancer. In contrast, type 2 tumors tend to be more heterogeneous and are associated with another familial disorder called hereditary leiomyomatosis and renal cell cancer [5], [75], [76], [77].
PRCCs are typically unresponsive to cytokine therapy and have a modest response to TKIs [76]. In patients with
Sarcomatoid differentiation
Sarcomatoid RCC (SRCC) describes morphologic changes in RCC that are characterized by biphasic epithelioid and sarcomatous components. These changes can be found in any given RCC histology although clear cell is most common. Once believed to be an independent subtype, sarcomatoid features no longer have this classification. These tumors are found in approximately 5% to 10 % of RCC and 15% of stage IV disease. When sarcomatoid features are present, tumors tend to be large, invasive, and
Future directions
Significant strides in elucidating the genetic basis of RCC have dramatically advanced treatment options for this disease. In the past, systemic therapy for RCC was associated with poor response and toxicity, but we can now offer patients more effective and tolerable treatment options. Future studies should explore linking genetics to prognosis, resistance to targeted therapies, and the identification of future therapeutic targets.
References (89)
- et al.
Hereditary kidney cancer syndromes
Adv Chronic Kidney Dis
(2014) - et al.
Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial
Lancet
(2016) - et al.
Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial
Lancet Oncol
(2018) - et al.
Evolution of circulating tumor DNA Profile from first-line to subsequent therapy in metastatic renal cell carcinoma
Eur Urol
(2017) - et al.
Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations
Cell
(2012) - et al.
Massive genomic rearrangement acquired in a single catastrophic event during cancer development
Cell
(2011) - et al.
The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1
J Biol Chem
(2009) - et al.
Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation
Lancet Oncol
(2013) - et al.
Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma
Eur Urol
(2017) - et al.
Clinical usefulness of PI3K/Akt/mTOR genotyping in companion with other clinical variables in metastatic renal cell carcinoma patients treated with everolimus in the second and subsequent lines
Ann Oncol
(2015)
Characterization of clinical cases of advanced papillary renal cell carcinoma via comprehensive genomic profiling
Eur Urol
Anti-programmed cell death protein 1 (PD-1) antibody nivolumab leads to a dramatic and rapid response in papillary renal cell carcinoma with sarcomatoid and rhabdoid features
Eur Urol
Genomic characterization of renal cell carcinoma with sarcomatoid dedifferentiation pinpoints recurrent genomic alterations
Eur Urol
Renal cell carcinoma
Nat Rev Dis Primers
Systemic therapy for metastatic renal-cell carcinoma
N Engl J Med
Germline mutations in the CDKN2B tumor suppressor gene predispose to renal cell carcinoma
Cancer Discov
A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma
Mol Cancer Res
A germline mutation in PBRM1 predisposes to renal cell carcinoma
J Med Genet
Kidney cancer, version 2.2017, NCCN clinical practice guidelines in oncology
J Natl Compr Cancer Netw
Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy
N Engl J Med
Randomized phase III trial of adjuvant pazopanib vs. placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma
J Clin Oncol
Pazopanib vs. Sunitinib in metastatic renal-cell carcinoma
N Engl J Med
Nivolumab vs. everolimus in advanced renal-cell carcinoma
N Engl J Med
Nivolumab plus ipilimumab vs. sunitinib in advanced renal-cell carcinoma
N Engl J Med
IMmotion151: a randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma (mRCC)
J Clin Oncol
Identification of the von Hippel-Lindau disease tumor suppressor gene
Science
Molecular genetics of clear-cell renal cell carcinoma
J Clin Oncol
Molecular biology of renal cell cancer and the identification of therapeutic targets
J Clin Oncol Off J Am Soc Clin Oncol
Phase I Dose-Escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2α antagonist in patients with previously treated advanced clear cell renal cell carcinoma
J Clin Oncol Off J Am Soc Clin Oncol
Targeting renal cell carcinoma with a HIF-2 antagonist
Nature
Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing
Nat Genet
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing
N Engl J Med
Comprehensive molecular characterization of clear cell renal cell carcinoma
Nature
Molecular and metabolic basis of clear cell carcinoma of the kidney
Adv Anat Pathol
Comprehensive molecular characterization of clear cell renal cell carcinoma
Nature
PTEN/MMAC1/TEP1 mutations in human primary renal-cell carcinomas and renal carcinoma cell lines
Int J Cancer
Integrated molecular analysis of clear-cell renal cell carcinoma
Nat Genet
Cited by (59)
Semantic Computed Tomography Features for Predicting BRCA1-associated Protein 1 and/or Tumor Protein p53 Gene Mutation Status in Clear Cell Renal Cell Carcinoma
2023, International Journal of Radiation Oncology Biology PhysicsDownregulation of praja2 restrains endocytosis and boosts tyrosine kinase receptors in kidney cancer
2024, Communications Biology
- 1
Contributed equally to the manuscript.