A 50-year-old man comes to the office due to a lump in his neck that has fluctuated in size over the past several months. The mass is nonpainful, and the patient has no associated dysphagia, chest pain, weight loss, or fever. He has no chronic medical conditions. Social history is significant for smoking a pack of cigarettes per day and occasional alcohol use. Vital signs are normal. Physical examination shows a firm, enlarged, movable, left-sided cervical lymph node. Biopsy of the mass reveals abnormal cells with a t(14;18) chromosomal translocation. This chromosomal change is most likely to cause which of the following abnormalities?
Chromosomal translocations associated with hematologic malignancies | |
Malignancy | Pathogenesis |
Acute promyelocytic | t(15;17) involving PML & RARA → PML-RARα oncoprotein → myeloid differentiation inhibited
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Burkitt | t(8;14) involving MYC & IGH → MYC overexpression → cell growth
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Chronic myeloid | t(9;22) involving ABL1 & BCR → BCR-ABL1 oncoprotein → cell proliferation
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Follicular | t(14;18) involving IGH & BCL2 → BCL2 overexpression → apoptosis evasion
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Mantle cell | t(11;14) involving CCND1 & IGH → cyclin D1 overexpression → cell cycle progression
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Follicular lymphoma is a common, indolent, non-Hodgkin lymphoma derived from germinal center B cells. It often presents as a painless, slow-growing, waxing-and-waning, peripheral (eg, cervical) lymphadenopathy in middle-aged or elderly adults.
The classic cytogenetic abnormality detected in follicular lymphoma is the t(14;18) translocation, in which the BCL2 (B-cell leukemia/lymphoma-2) gene on chromosome 18 is positioned near the site of the immunoglobulin heavy-chain enhancer element on chromosome 14. This leads to increased BCL2 transcription and overexpression of BCL2 protein. The BCL2 protein exerts antiapoptotic effects by preventing the release of proapoptotic factors from the mitochondria. Overexpression of BCL2 allows the neoplastic cells to evade apoptosis.
(Choice B) The BCR-ABL1 fusion gene is the characteristic abnormality seen in chronic myeloid leukemia. It is formed through a reciprocal translocation between chromosomes 9 and 22 (the Philadelphia chromosome). The BCR-ABL1 protein is a constitutively active tyrosine kinase, which results in uncontrolled proliferation of granulocytes.
(Choice C) HER2 (ie, ERBB2) is a receptor tyrosine kinase. In some cases of breast cancer, the HER2 gene on chromosome 17 is amplified, causing HER2 receptor overexpression.
(Choice D) MYC protein is a transcription factor that is a critical component of cell growth regulation. MYC is overexpressed in a variety of malignancies, including Burkitt lymphoma, which is characterized by translocations involving the MYC gene located on chromosome 8, most frequently with the immunoglobulin heavy-chain gene.
(Choice E) Tumor suppressor protein p53, encoded by TP53 on chromosome 17, stops the cell cycle when DNA damage is identified. Inactivation of p53 is seen in many malignancies. Li-Fraumeni cancer syndrome is an autosomal dominant syndrome caused by an inherited TP53 mutation, resulting in an increased risk of malignancy (eg, sarcoma, breast).
Educational objective:
Follicular lymphoma is a common, indolent non-Hodgkin lymphoma. It is characterized by a translocation involving BCL2 on chromosome 18, which becomes positioned near the immunoglobulin heavy-chain gene on chromosome 14, resulting in overexpression of BCL2 (an antiapoptotic protein).