Login to Access Video or Poster Abstract: MP39-04
Sources of Funding: Funded in part by the Sidney Kimmel Center for Prostate and Urologic Cancers and the National Cancer Institute Training Grant T32 CA082088 (BM, GM)

Introduction

Unclassified renal cell carcinoma (uRCC) is a rare, aggressive non-clear cell variant recognized by the World Health Organization (WHO) and which has no standard therapy. Currently, there is no consensus on further stratifying uRCC subtypes based on histological findings. We recently reported the findings of a molecular analysis of 62 high-grade primary uRCC from our institution ("discovery cohort") in which we identified recurrent somatic mutations in 29 genes (Chen et al, Nat Comm 2016). In this study we aim to report the clinical characteristics of the largest series of patients with uRCC and to validate the molecular features using an independent clinical cohort.

Methods

Tumor samples from primary renal (n=39) and metastatic sites (n=20) from 59 patients ("validation cohort") diagnosed with advanced uRCC by expert pathologists were analyzed using targeted next-generation sequencing for somatic alterations. Molecular and clinical characteristics of these samples were compared to the previously reported discovery cohort.

Results

Clinical patient and tumor characteristics of the discovery cohort (n=62) and the validation cohort (n=59) are depicted in table 1. The frequently mutated genes in the validation cohort were NF2 (27%), SETD2 (12%), FH (12%), TP53 (10%), TERT (8%), and PIK3CA (8%). NF2 and SETD2 were the two most frequently mutated genes, consistent with the discovery cohort. Systemic therapy was given to 42 patients. The median follow-up was 19.9 months. Seventeen patients died secondary to disease and one from other causes. Inactivating mutations of NF2 or other member of Hippo pathway (27%) accounted for 41% of cancer-specific death, with median survival of 21 months, representing the largest molecular subset of uRCC demonstrating poor outcomes.

Conclusions

URCC is an aggressive subtype of RCC, with data suggesting loss of NF2 to have the worst outcomes. Molecular analysis of our current uRCC validation cohort with more advanced disease reveals similar molecular subsets as in the discovery cohort of primary RCC. These findings open a new opportunity for precision medicine.

Funding

Funded in part by the Sidney Kimmel Center for Prostate and Urologic Cancers and the National Cancer Institute Training Grant T32 CA082088 (BM, GM)