chromosomal translocation

**Definition and types** - **Reciprocal translocation:** Two nonhomologous chromosomes exchange segments. It is usually balanced, so carriers are typically phenotypically normal. Carriers have a higher risk of infertility, recurrent miscarriage, and offspring with unbalanced gametes (partial trisomy or monosomy) because of abnormal segregation at meiosis. - **Robertsonian translocation:** Two acrocentric chromosomes (13, 14, 15, 21, 22) fuse at the centromere. The short arms are lost, and this is generally harmless because the p arms carry redundant rRNA genes. Carriers have 45 chromosomes. Examples: - Familial Down syndrome: t(14;21) or t(21;21). About 4% of Down syndrome cases are caused by Robertsonian translocation. Recurrence risk is higher when the parent is a carrier. A t(21;21) carrier has a ~100% risk of an affected child. - Patau syndrome (trisomy 13) can also result from Robertsonian translocation. - **Balanced vs. unbalanced:** Balanced means no net gain or loss of genetic material. Unbalanced means net gain or loss, which usually causes congenital anomalies or intellectual disability.

**Pathophysiology in cancer** Somatic translocations cause cancer through two main mechanisms: 1. **Fusion gene formation.** Two genes join to produce a chimeric protein with constitutive activity. 2. **Promoter or enhancer swapping.** A proto-oncogene is placed next to a strong promoter, such as the immunoglobulin gene loci, and is overexpressed.

**High-yield cancer translocations** - **t(9;22) BCR-ABL (Philadelphia chromosome):** CML, and some ALL (poor prognosis). It produces a constitutively active tyrosine kinase. Treat with imatinib, dasatinib, or nilotinib. - **t(8;14) c-MYC–IgH:** Burkitt lymphoma. It is associated with EBV and shows a "starry sky" histology. - **t(14;18) IgH–BCL2:** Follicular lymphoma. BCL2 overexpression blocks apoptosis. - **t(11;14) cyclin D1 (BCL1)–IgH:** Mantle cell lymphoma (CD5+). - **t(15;17) PML-RARα:** AML M3 (acute promyelocytic leukemia). It is associated with DIC and Auer rods. Treat with all-trans retinoic acid (ATRA) and arsenic trioxide. - **t(12;21) ETV6-RUNX1:** Pediatric B-ALL, with a good prognosis. - **t(8;21) RUNX1-RUNX1T1:** AML with a good prognosis. - **inv(16) / t(16;16) CBFB-MYH11:** AML M4Eo. - **t(11;22) EWS-FLI1:** Ewing sarcoma (small round blue cells, "onion skin" periosteal reaction). - **t(X;18) SYT-SSX:** Synovial sarcoma. - **t(12;16) FUS-DDIT3:** Myxoid liposarcoma. - **t(2;13) PAX3-FOXO1:** Alveolar rhabdomyosarcoma. - **t(X;11) / t(11;X):** Seen in some translocation renal cell carcinomas (TFE3). - **t(2;5) NPM-ALK:** Anaplastic large cell lymphoma. - **EML4-ALK (inversion on 2p):** A subset of lung adenocarcinomas, treated with ALK inhibitors such as crizotinib. - **t(4;14) / t(11;14):** Multiple myeloma. - **t(X;1), t(X;17):** Papillary renal cell carcinoma (TFE3). - **t(1;13):** Alveolar rhabdomyosarcoma variant.

**Other inherited or syndromic translocations** - **Cri-du-chat** (5p deletion) can be caused by parental translocation. - **Chronic translocation-related infertility:** Balanced carriers can have recurrent pregnancy loss.

**Diagnosis** - **Karyotyping** (G-banding) detects large translocations. - **FISH** detects specific translocations, such as BCR-ABL, in interphase cells. - **PCR / RT-PCR** detects fusion transcripts and is used to monitor minimal residual disease (e.g., BCR-ABL in CML). - **Chromosomal microarray** does not detect balanced translocations because it detects copy number changes only.

**Clinical pearls for boards** - A history of recurrent miscarriages should prompt parental karyotyping to look for a balanced translocation. - Translocation Down syndrome is not associated with advanced maternal age, unlike the nondisjunction form (~95% of cases). - The Philadelphia chromosome is the classic example of a targetable fusion product (tyrosine kinase inhibitors). - Nomenclature: t(A;B)(p;q) lists the chromosomes involved, with the lower number first.