Login to Access Video or Poster Abstract: MP39-02
Sources of Funding: This study was supported in part by the Sidney Kimmel Center for Prostate and Urologic Cancers and by the National Cancer Institute T32 CA082088 (MG, BM)._x000D_ NIH Ruth L. Kirschstein National Research Service Award T32CA082088 _x000D_ German Research Foundation (DFG) Grant CA1403/1-1

Introduction

Evaluation of genetic divergence among primary (P) and metastatic (M) tumors in renal cell carcinoma (RCC) is limited to small or unmatched P-M cohorts. We aim to better characterize somatic mutation (SM) disparities in a cohort of matched P-M tumors.

Methods

We prospectively sequenced 47 clear cell RCC (ccRCC) and 12 non-clear cell RCC (nccRCC) P-M matched pairs using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a custom 410-gene (previously 341) next-generation sequencing assay.

Results

We detected 527 SM, with a mean (SD) of 4.5 (3.13) per sample. Overall concordance rate (shared mutations/total mutations) was 49% (46% for ccRCC vs 78% for nccRCC). Private mutations in the P tumors were present in 32 (68%) and 3 (25%) of the ccRCC and nccRCC cohorts, respectively. Private mutations in the M tumors were present in 32 (68%) of the ccRCC and in 3 (25%) of nccRCC patients (Figure 1a). Strikingly, SETD2 mutations were private to the M or the P in 70% (16/23), and PTEN alterations were private to the M in 66% (4/6). There were no shared ROS1 mutations, and 83% (5/6) of these were private to the M._x000D_ In a patient-by-patient analysis, 17% (10) of the pairs shared all SM; 15% (9) shared all of the SM in the M, with only private SM in the P; 25% (15) shared all SM in the P, with private SM only in the M; 42% (25) shared SM in the P-M; and some SM were private to either the P or the M. Only 14 pairs showed two SM in the same gene (Figure 1b); in 57% (8) the M presented a mutation in the same gene as the P but on a different location (convergent evolution), in 28% (4) the M presented both the mutation observed in the P and an additional mutation in the same gene (evolution of metastasis), and in 14% (2) the M showed a subclone of the SM observed in the P (sub-clonal seeding). _x000D_

Conclusions

Our data suggest that both linear and parallel progression of metastases is observed in RCC. Although the absence of shared SM in matched pairs may be explained by tumor heterogeneity, metastasis-specific SM may represent cells of the P tumor with advantages to develop metastatic disease giving growth advantages in the studied samples. The extent to which the identified mutations contribute to the development of characteristics of metastatic spread needs to be analyzed further.

Funding

This study was supported in part by the Sidney Kimmel Center for Prostate and Urologic Cancers and by the National Cancer Institute T32 CA082088 (MG, BM)._x000D_ NIH Ruth L. Kirschstein National Research Service Award T32CA082088 _x000D_ German Research Foundation (DFG) Grant CA1403/1-1