Review article
Heterogeneity in renal cell carcinoma

https://doi.org/10.1016/j.urolonc.2017.05.006Get rights and content

Highlights

  • A comprehensive review of tumor heterogeneity in RCC.

  • Carcinogenesis starts with a single mutation, over time new subclones occur.

  • Clonal evolution changes the genomic profile over time, contributing to ITH.

  • Intertumor heterogeneity contributes to differential response to treatment.

  • ITH poses a significant challenge in identifying biomarkers and targeted therapy.

Abstract

Introduction

In recent years, molecular characterization of renal cell carcinoma has facilitated the identification of driver genes, specific molecular pathways, and characterization of the tumor microenvironment, which has led to a better understanding of the disease. This comprehension has revolutionized the treatment for patients with metastatic disease, but despite these advancements many patients will develop resistance leading to treatment failure. A primary cause of this resistance and subsequent treatment failure is tumor heterogeneity. We reviewed the literature on the mechanisms of tumor heterogeneity and its clinical implications.

Methods

A comprehensive literature search was performed using the MEDLINE/PubMed Index.

Results

Intertumor and intratumor heterogeneity is possibly a reason for treatment failure and development of resistance. Specifically, the genetic profile of a renal tumor differs spatially within a tumor as well as among patients. Genomic mutations can change temporally with resistant subclones becoming dominant over time.

Conclusions

Accounting for intratumor and intertumor heterogeneity with better sampling of cancer tissue is needed. This will hopefully lead to improved identification of driver mutations and actionable targets. Only then, we can move past the one-size-fits-all approach toward personalized treatment based on each individual׳s molecular profile.

Introduction

Renal cell carcinoma (RCC) accounts for approximately 4% of all new cancer cases worldwide, accounting for more than 90% of primary kidney tumors [1]. Despite the increased rate of incidental renal masses, 15% to 20% of cases are discovered at an advanced stage [2]. Targeted therapy based on common molecular alterations has become first-line therapy for patients with advanced RCC [1], [3]. However, most patients will eventually develop resistance [3].

Intratumor heterogeneity (ITH) at the genetic level is defined as the presence of genetically different clones in different subpopulations of the same tumor [4]. RCC is known to be a heterogeneous tumor, and ITH in RCC had been demonstrated over two decades ago [5]. Several studies have shown the existence of ITH among primary and metastatic lesions by identifying the differences in the rates of von Hippel-Lindau gene (VHL) mutations and copy number changes of other chromosomes [6], [7]. These differences at the genomic level is a key mechanism in the differential response to pharmacotherapy and treatment resistance.

Section snippets

Methods

A comprehensive search of MEDLINE/PubMed was performed to find basic science, review, and original articles in English language until November 2016. No other limit was placed on dates of publication. The keywords to identify articles of interest included but were not limited to RCC, kidney cancer, heterogeneity, ITH, intertumor heterogeneity, renal mass biopsy, and targeted therapy. Articles were identified by searching the title of the article using “and” statements such as “renal cell

Genomic mutations and tumorigenesis in RCC

There are well-established genetic mutations that cause the various subtypes of RCC. These include mutations of the VHL gene, which occurs in most patients with clear cell RCC (ccRCC) [8]. MET and fumarate hydratase mutations have been associated with papillary RCC (pRCC). Mutations in folliculin are associated with chromophobe RCC (chRCC), whereas TFEB/TFE3 genes translocation mediates translocation RCC (tRCC). Hereditary cases make up only 4% of patients with RCC. This low incidence means

Conclusion

RCC is a highly heterogeneous tumor. Therefore, a single treatment option cannot be the preferred treatment for all patients. Current evidence suggests that treatment resistance and failure is caused by resistant subclones that are not targeted by the initial treatment. This could be addressed by combination therapies. However, a one-size-fits-all approach is not optimal for treating advanced RCC and treatments need to be personalized. Better sampling of tumor specimens and identification of

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