Chapter 079. Cancer Genetics (Part 8)

Table 79-3 Representative Oncogenes at Chromosomal TranslocationsGene (Chromosome)TranslocationMalignancyABL BCR (22q11)(9q34.1)–(9;22)(q34;q11)Chronic myelogenous leukemiaATF1 EWS (22q12)(12q13)–(12;22)(q13;q12)Malignant melanoma of soft parts (MMSP)BCL1 IgH (14q32)(11q13.3)–(11;14)(q13;q32)Mantle lymphomacellBCL2 IgH (14q32)(18q21.3)–(14;18)(q32;q21)Follicular lymphomaFLI1 EWS (22q12)(11q24)–(11;22)(q24;q12)Ewings sarcomaLCK TCRB (7q35)(1p34)–(1;7)(p34;q35)T lymphocytic (ALL)cellacute leukemiaMYC (14q32)(8q24)–IgH(8;14)(q24;q32)Burkitts B cell ALLlymphoma,WT1 EWS (22q12)(11p13)–(11;22)(p13;q12)Desmoplasticsmallround cell tumor (DSRCT)PAX3(2q35)–(2;13)(q35;q14)AlveolarFKHR/ALV(13q14)rhabdomyosarcomaPAX7(1p36)–(1;13)(p36;q14)Alveolar rhabdomyosarcomaKHR/ALV(13q14)RET (10q11.2) ...
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Chapter 079. Cancer Genetics (Part 8) Chapter 079. Cancer Genetics (Part 8) Table 79-3 Representative Oncogenes at Chromosomal Translocations Gene Translocation Malignancy(Chromosome) ABL (9q34.1)– (9;22)(q34;q11) Chronic myelogenousBCR (22q11) leukemia ATF1 (12q13)– (12;22)(q13;q12) Malignant melanomaEWS (22q12) of soft parts (MMSP) BCL1 (11q13.3)– (11;14)(q13;q32) Mantle cellIgH (14q32) lymphoma BCL2 (18q21.3)– (14;18)(q32;q21) Follicular lymphomaIgH (14q32) FLI1 (11q24)– (11;22)(q24;q12) Ewings sarcomaEWS (22q12) LCK (1p34)– (1;7)(p34;q35) T cell acuteTCRB (7q35) lymphocytic leukemia (ALL) MYC (8q24)–IgH (8;14)(q24;q32) Burkitts lymphoma,(14q32) B cell ALL WT1 (11p13)– (11;22)(p13;q12) Desmoplastic smallEWS (22q12) round cell tumor (DSRCT) PAX3 (2q35)– (2;13)(q35;q14) AlveolarFKHR/ALV(13q14) rhabdomyosarcoma PAX7 (1p36)– (1;13)(p36;q14) AlveolarKHR/ALV(13q14) rhabdomyosarcoma RET (10q11.2) (10;17)(q11.2;q23) Papillary thyroid carcinomas Source: From R Hesketh: The Oncogene and Tumour Suppressor GeneFacts Book, 2d ed. San Diego, Academic Press, 1997; with permission. The first reproducible chromosome abnormality detected in humanmalignancy was the Philadelphia chromosome detected in CML. This cytogeneticabnormality is generated by reciprocal translocation involving the ABL oncogene,a tyrosine kinase on chromosome 9, being placed in proximity to the BCR(breakpoint cluster region) on chromosome 22. Figure 79-7 illustrates thegeneration of the translocation and its protein product. The consequence ofexpression of the BCR-ABL gene product is the activation of signal transductionpathways leading to cell growth independent of normal external signals. Imatinib,a drug that specifically blocks the activity of BCR-ABL has shown remarkableefficacy with little toxicity in patients with CML. Knowledge of genetic alterationsin cancer can lead to mechanism-based design and development of cancer drugs. Figure 79-7 Specific translocation seen in chronic myelogenous leukemia (CML) . The Philadelphia chromosome (Ph) is derived from a reciprocaltranslocation between chromosomes 9 and 22 with the breakpoint joining thesequences of the ABL oncogene with the BCR gene. The fusion of these DNAsequences allows the generation of an entirely novel fusion protein with modifiedfunction. (Courtesy of ER Fearon and KR Cho.)