Ateeq Bushra, Kunju Lakshmi P, Carskadon Shannon L, Pandey Swaroop K, Singh Geetika, Pradeep Immanuel, Tandon Vini, Singhai Atin, Goel Apul, Amit Sonal, Agarwal Asha, Dinda Amit K, Seth Amlesh, Tsodikov Alexander, Chinnaiyan Arul M, Palanisamy Nallasivam
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
Prostate. 2015 Jul 1;75(10):1051-62. doi: 10.1002/pros.22989. Epub 2015 Mar 23.
Molecular stratification of prostate cancer (PCa) based on genetic aberrations including ETS or RAF gene-rearrangements, PTEN deletion, and SPINK1 over-expression show clear prognostic and diagnostic utility. Gene rearrangements involving ETS transcription factors are frequent pathogenetic somatic events observed in PCa. Incidence of ETS rearrangements in Caucasian PCa patients has been reported, however, occurrence in Indian population is largely unknown. The aim of this study was to determine the prevalence of the ETS and RAF kinase gene rearrangements, SPINK1 over-expression, and PTEN deletion in this cohort.
In this multi-center study, formalin-fixed paraffin embedded (FFPE) PCa specimens (n = 121) were procured from four major medical institutions in India. The tissues were sectioned and molecular profiling was done using immunohistochemistry (IHC), RNA in situ hybridization (RNA-ISH) and/or fluorescence in situ hybridization (FISH).
ERG over-expression was detected in 48.9% (46/94) PCa specimens by IHC, which was confirmed in a subset of cases by FISH. Among other ETS family members, while ETV1 transcript was detected in one case by RNA-ISH, no alteration in ETV4 was observed. SPINK1 over-expression was observed in 12.5% (12/96) and PTEN deletion in 21.52% (17/79) of the total PCa cases. Interestingly, PTEN deletion was found in 30% of the ERG-positive cases (P = 0.017) but in only one case with SPINK1 over-expression (P = 0.67). BRAF and RAF1 gene rearrangements were detected in ∼1% and ∼4.5% of the PCa cases, respectively.
This is the first report on comprehensive molecular profiling of the major spectrum of the causal aberrations in Indian men with PCa. Our findings suggest that ETS gene rearrangement and SPINK1 over-expression patterns in North Indian population largely resembled those observed in Caucasian population but differed from Japanese and Chinese PCa patients. The molecular profiling data presented in this study could help in clinical decision-making for the pursuit of surgery, diagnosis, and in selection of therapeutic intervention.
基于包括ETS或RAF基因重排、PTEN缺失以及SPINK1过表达等基因异常的前列腺癌（PCa）分子分层显示出明确的预后和诊断价值。涉及ETS转录因子的基因重排是在PCa中观察到的常见致病体细胞事件。白种人PCa患者中ETS重排的发生率已有报道，然而，在印度人群中的发生情况在很大程度上尚不清楚。本研究的目的是确定该队列中ETS和RAF激酶基因重排、SPINK1过表达以及PTEN缺失的患病率。
在这项多中心研究中，从印度的四个主要医疗机构获取了福尔马林固定石蜡包埋（FFPE）的PCa标本（n = 121）。将组织切片并使用免疫组织化学（IHC）、RNA原位杂交（RNA-ISH）和/或荧光原位杂交（FISH）进行分子谱分析。
通过IHC在48.9%（46/94）的PCa标本中检测到ERG过表达，在一部分病例中通过FISH得到了证实。在其他ETS家族成员中，虽然通过RNA-ISH在1例中检测到ETV1转录本，但未观察到ETV4的改变。在所有PCa病例中，12.5%（12/96）观察到SPINK1过表达，21.52%（17/79）观察到PTEN缺失。有趣的是，在30%的ERG阳性病例中发现了PTEN缺失（P = 0.017），但在只有1例SPINK1过表达的病例中发现了PTEN缺失（P = 0.67）。在约1%和约4.5%的PCa病例中分别检测到BRAF和RAF1基因重排。
这是关于印度男性PCa主要病因异常综合分子谱分析的首份报告。我们的研究结果表明，北印度人群中的ETS基因重排和SPINK1过表达模式在很大程度上与白种人人群中观察到的相似，但与日本和中国的PCa患者不同。本研究中呈现的分子谱分析数据有助于在手术、诊断以及治疗干预选择方面的临床决策。
