Abstract 2233: Rearrangement of ERG and CHD1 genes in prostate cancer as a marker of tumor heterogeneity

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-10, Vol.74 (19_Supplement), p.2233-2233
• Main Authors: Tereshchenko, Irina V., Zhong, Hua, Chekmareva, Marina, Santanam, Urmila, Petrosky, Whitney, Kane-Goldsmith, Noriko, Tischfield, Jay A., DiPaola, Robert
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-2233

Efforts to develop targeted therapy based on genomic findings are complicated by the polygenic nature of drug resistance and genetic heterogeneity between separate biopsy cores. These findings have led to the conclusion that analysis of multiple biopsy cores and consideration of multiple targeted agents will be important. Because of our concern that these assessments may be missing an additional layer of heterogeneity within even a single biopsy core, which sequencing alone may not identify, we studied the genetic heterogeneity of cells in focal areas using TMA. Using confocal microscopy, we analyzed the most common and prostate cancer specific gene rearrangement (TMPRSS2-ERG fusion and CHD1 deletion) in neighboring single cells in a tumor focus without changing the stromal microenvironment. We evaluated 56 patients that underwent radical prostatectomy at CINJ with pathological assessment, grading, and ERG rearrangement status. Overall, ERG rearrangements occurred in 24/56 (42.9%) patients. The most frequent mechanism of rearrangements was deletion (58%), while a split event was confirmed in 25% of the ERG-rearranged cases. In 88% of cases the ERG rearrangement was associated with TMPRSS2-ERG gene fusion. A copy number gain of the non-rearranged ERG gene occurred in 10/56 (17.6%) cases. A heterogeneous mix of ERG deletions, translocations, and copy number changes occurred in 8/24 (33%) patients, with a combination of deletions and translocations alone occurring in 3/24 (12.5%) cases. 20/21 (95%) of analyzed cases with ERG-rearrangement were negative for CHD1 gene rearrangement (p< 0.01). Overall, 14/45 (31.1%) of patients had CHD1 deletion, and 13/14 (93%) CHD1- cases correlate with ERG-rearrangement negative status (p< 0.01). 10/45 (22.2%) cases represent CHD1 gene copy number gain. These results support the notion that additional heterogeneity may be present even in a focus of a single biopsy core. These data are extremely important and urgently require further study to understand heterogeneity of genetic changes, because clinical studies have already been launched using genetic changes such as TMPRSS2-ERG fusions found in a single core biopsy to direct a specific therapy, including a trial using ABT-888 only in patients with this fusion now ongoing at CINJ. Citation Format: Irina V. Tereshchenko, Hua Zhong, Marina Chekmareva, Urmila Santanam, Whitney Petrosky, Noriko Kane-Goldsmith, Jay A. Tischfield, Robert DiPaola. Rearrangement of ERG and CHD1 genes