Certain patients with non-small cell lung cancer develop constitutive tumor kinase activity due to the production of echinoderm microtubule-associated protein-like 4 - anaplastic lymphoma kinase (EML4-ALK), a fusion protein that contributes to carcinogenesis. This is most similar to the molecular pathophysiology of which of the following disorders?

Question

Certain patients with non-small cell lung cancer develop constitutive tumor kinase activity due to the production of echinoderm microtubule-associated protein-like 4 - anaplastic lymphoma kinase (EML4-ALK), a fusion protein that contributes to carcinogenesis.  This is most similar to the molecular pathophysiology of which of the following disorders?

Quizplus · Accepted Answer

11ec160b_3973_4686_9249_db14d481e05c_MD0001_00 Approximately four percent of patients with non-small cell lung carcinoma (NSCLC) have an inversion of the short arm of chromosome 2 that creates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase). This results in a constitutively active tyrosine kinase that causes malignancy. Interestingly, patients who harbor this gene fusion are usually young non-smokers, often with adenocarcinoma, who lack mutations in either the epidermal growth factor receptor gene or the K-ras gene. The kinase activity of this fusion protein is a target of the protein kinase inhibitor, crizotinib. The pathophysiology of EML4-ALK NSCLC is most similar to the pathophysiology of chronic myelogenous leukemia (CML). In CML, the classic and most common cause is a translocation between chromosomes 9 and 22. The ABL proto-oncogene is transported from chromosome 9 to chromosome 22 where it is placed adjacent to the BCR gene. The resulting oncogene, BCR-ABL, codes for a fusion protein with constitutive tyrosine kinase activity. This protein stimulates the proliferation of granulocytic precursors and leads to the development of CML. The kinase activity of this fusion protein is a target of the protein kinase inhibitor, imatinib. (Choice A) Burkitt lymphoma is characterized by a translocation of the c-myc oncogene on the long arm of chromosome 8 to the Ig heavy chain region on chromosome 14. This causes constitutive overproduction of c-myc, a nuclear phosphoprotein that functions as a transcription activator. (Choice C) Patients with follicular lymphoma have a t(14;18) translocation that causes overexpression of the antiapoptotic BCL2 gene product. (Choice D) Li-Fraumeni syndrome is an autosomal dominant predisposition to a variety of cancers, particularly sarcomas and tumors of the breast, brain, and adrenal cortex. This syndrome is associated with a mutation of the tumor suppressor gene, p53. (Choice E) Translocation between the cyclin D1 locus on chromosome 11 and the immunoglobulin heavy chain locus on chromosome 14 is characteristic of mantle cell lymphoma. This abnormality results in increased production of cyclin D1, a promoter of the G1 to S-phase transition during the cell cycle. Educational objective: Some patients with non-small cell lung carcinoma (NSCLC) harbor a chromosomal rearrangement that creates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase). This results in a constitutive active tyrosine kinase that causes malignancy. __________ References: Recurrent EML4-ALK-associated lung adenocarcinoma with a slow clinical course. (http://www.ncbi.nlm.nih.gov/pubmed/20659620)

Certain Patients with Non-Small Cell Lung Cancer Develop Constitutive Tumor