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Analysis of ALK gene in 133 patients with breast cancer revealed polysomy of chromosome 2 and no ALK amplification

2015-08-21 00:01:10

SPRINGER OPEN; 21 August 2015: DOI:10.1186/s40064-015-1235-9


Matthew G. Hanna, Vesna Najfeld, Hanna Y. Irie, Joseph Tripodi, Anupma Nayak



Abstract


ALK has emerged as a novel tumorigenic factor in several epithelial human cancers. Crizotinib, an ALK tyrosine kinase inhibitor, is currently approved to treat lung cancer patients exhibiting ALK gene rearrangements. Our goal was to determine the incidence of ALK aberrations in relation to different breast cancer types. Tissue micro-arrays were constructed of ER+/PR±/HER2– (n = 37), ER–/PR–/HER2+ (n = 15), ER–/PR–/HER2– (n = 61) and ER+/PR+/HER2+ (n = 20) breast cancers; including 13 inflammatory breast carcinomas. FISH was performed using ALK break-apart and chromosome 2 centromere enumeration probes (CEP2). Neither ALK rearrangements nor amplification were identified in the 133 breast cancer cases evaluated. However, copy number gains (CNG) of ALK were identified in 82 of 133 patients (62 %). The CEP2 analysis revealed polysomy of chromosome 2 in all HCNG and LCNG cases, indicating the CNG of ALK are due to polysomy of chromosome 2, rather than true amplification of ALK. To conclude, we observed CNG of ALK secondary to chromosome 2 polysomy in a significant percentage of breast cancer cases, a phenomenon similar to polysomy 17. This study is one of the largest studies to have investigated ALK aberrations in breast cancer and the only study to include all subtypes.

Background


The anaplastic lymphoma kinase (ALK), a gene located on the short arm of chromosome 2 (2p23), encodes a transmembrane tyrosine kinase receptor capable of activating downstream STAT3, AKT/PI3K and RAS/ERK signaling pathways responsible for cell proliferation, migration and survival. Alterations in the ALK gene are known to play role in genesis and biology of many tumors including anaplastic large cell lymphoma, neuroblastoma, inflammatory myofibroblastic tumors, diffuse large B cell lymphoma, renal carcinoma, serous carcinoma of the ovary, esophageal squamous cell carcinoma, colon carcinoma and more recently non-small cell lung carcinoma. These alterations embrace various rearrangements/translocations, somatic mutations, copy number gains or amplifications. The discovery of the EML4-ALK fusion gene in a subset of non-small cell lung carcinoma (3–7 %) has steered the development of a therapeutic drug crizotinib (a tyrosine kinase inhibitor that inhibits the activity of the ALK fusion proteins, cMET, ROS1, and RON) that is FDA approved for treating lung cancer patients exhibiting ALK gene rearrangements.



A few recent studies have investigated the role of ALK aberrations in breast cancer, particularly in the context of inflammatory breast cancer and triple negative breast cancers, however, the results have been conflicting. Inflammatory breast cancer and triple negative breast cancers have the worst prognosis amongst all the subtypes of breast cancer. Inflammatory breast carcinoma is a rare but aggressive type of locally advanced breast cancer characterized by a clinical diagnosis of rapid onset erythema and/or edema of the breast skin (peau d’orange appearance) secondary to blockade of dermal lymphatics by tumor emboli. Most inflammatory breast cancers are hormone receptor (estrogen and progesterone receptors) negative and human epidermal growth factor receptor (HER2) positive, and are treated by multidisciplinary approaches involving systemic chemotherapy, surgery, and radiation. Despite multimodality therapy, overall survival is only 35–40 % at 5-years as compared to 80 % for non-inflammatory breast cancers. Triple negative breast cancer is defined by lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2). Due to lack of hormone receptors and HER2 overexpression, there is no effective targeted therapy so far for this particular subset of patients. Therefore, identification of aberrations in genes such as ALK will be clinically useful for breast cancers, given the availability of various ALK inhibitors.



The purpose of this study was to determine the incidence and frequency of ALK amplification and rearrangements in different breast cancer subtypes including triple negative and inflammatory breast cancers.



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