Abstract 52: Identification of genomic alterations associated with metastasis in clear cell renal cell carcinoma
Authors: Thodima Venkata J. , Gowrishankar Banumathy , Molina Ana , Georges Murielle , Chaganti RSK , Motzer Robert J. , Houldsworth Jane 
Published: May 2015

Abstract
Clear cell renal cell carcinoma (ccRCC) is the most abundant and lethal form of RCC and about one third of patients exhibit metastasis with poor prognosis. At the molecular level, metastasis is accompanied by multiple genetic and epigenetic alterations including genomic copy number changes. Identification of novel genomic markers and underlying mechanisms associated with metastasis could result in better therapeutic management of ccRCC patients. In this study, aCGH was performed using Agilent 244K arrays on DNA from 83 primary and 64 metastatic unmatched ccRCC fresh-frozen specimens and profiles were compared using Fisher's Exact test (FDR, p-value ≤ 0.05), with a minimum threshold difference of 15%. Significant copy number changes were found at 15 loci between primary and metastatic lesions, after excluding loci enriched in normal CNVs. Loss of 2p16.1-p15, 2q33.1-q33.3, 3q11.1-q13.2, 3q22.3, 10q21.3-q22.1 and 11p15.4 were more frequent in primary lesions, while nine aberrations (gain of 5q23.3-q31.1, 7q21.3-q22.1, 16p11.2, 20q11.1-q13.12, 21p11.2-q11.1 and loss of 4p15.2-p14, 4q, 9p24.3-p13.3 and 18q21.2-q21.31) were more frequent in metastatic lesions. While some of these aberrations have previously been implicated in metastasis, nine were novel. In order to further examine the association of these aberrations with metastasis, the frequencies of the 15 aberrations were determined in primary ccRCCs publicly available from TCGA, stratified into low (stages I and II, n=287) and high stage groups (III and IV, n=202). Eight of the nine aberrations that were more frequent in metastatic lesions, were also observed at a higher frequency in high stage TCGA primary ccRCC (four were significantly higher between Stages I and IV). Little or no trend was observed for the six aberrations more frequent in primary lesions.
In order to identify alterations associated with specific metastatic sites, aCGH profiles were compared across metastatic lesions at sites represented by at least 6 specimens: 15 lung, 7 bone, 6 lymph node, 6 pancreas and 6 brain metastatic ccRCC specimens. Gain of 7q11 and 8p12-p11, and loss of 6q14-q22 and 10q were specifically observed in lung metastases. Gain of chr12 and loss of chr22 were frequent in bone, loss of 1q32-q41 and gain of 22q11 in lymph node, and loss of 2p22.3, 8p12, 8q12-q13 and 8q24 in pancreatic lesions. No specific aberrations were found in brain lesions.
In conclusion, this study has confirmed known and identified novel genomic loci associated with metastasis in ccRCC. Determination of candidate genes of the aberrations will further our understanding of metastatic progression of ccRCC and together with examination of metastatic site-specific alterations, may assist in selecting patients with metastatic disease for appropriate targeted therapy and lead to improved overall survival.
Citation Format: Venkata J. Thodima, Banumathy Gowrishankar, Ana Molina, Murielle Georges, RSK Chaganti, Robert J. Motzer, Jane Houldsworth. Identification of genomic alterations associated with metastasis in clear cell renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 52. doi:10.1158/1538-7445.AM2014-52