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上皮肿瘤和融合基因 Epithelial Neoplasms and Fusion Genes

上皮肿瘤和融合基因 Epithelial Neoplasms and Fusion Genes. Hongying Zhang ( 张红英 ) 1 , Andre M. Oliveira 2 1 Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China （ 中国四川省成都市四川大学华西医院病理科 ） ;

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上皮肿瘤和融合基因 Epithelial Neoplasms and Fusion Genes

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  1. 上皮肿瘤和融合基因Epithelial Neoplasms and Fusion Genes Hongying Zhang (张红英)1, Andre M. Oliveira2 1Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China（中国四川省成都市四川大学华西医院病理科）; 2Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

  2. Introduction • Recurrent chromosomal rearrangements with the formation of fusion genes（融合基因）have been traditionally associated with hematologic and mesenchymal tumors （血液肿瘤和间叶肿瘤）but only rarely in epithelial neoplasms（上皮肿瘤） • This view has cultivated the erroneous impression that the oncogenic mechanisms present in these tumors are fundamentally different from those found in epithelial neoplasms

  3. Nat Genet 2004;36:331-4. • One of the reasons more fusion genes have been found in hematologic malignancies is because these tumors are more often karyotyped • There may not be any fundamental tissue-specific differences in the genetic mechanisms by which neoplasia is initiated

  4. Introduction • Review and discuss the chromosomal rearrangements and fusion genes in epithelial neoplasms • Head and neck • Thyroid • Kidney • Breast • Prostate • Lung

  5. Pleomorphic Adenoma • PLAG1 fusion genes (8q12) (40%) • CTNNB1-PLAG1-most common • t(3;8)(p21;q12) • HMGA2 fusion genes (12q13-15)(8%) • HMGA2-FHIT • HMGA2-NFIB • HMGA2-WIF1 HAS2–PLAG1 and COL1A2–PLAG1 have been seen in lipoblastoma HMGA2 is involved in a variety of neoplasms The PLAG1 or HMGA2 gene fusions have been identified only in pleomorphic adenomas (among salivary gland neoplams).

  6. Mucoepidermoid Carcinoma • MECT1-MAML2 fusion gene(55%) • Associated with a better clinical outcome • Also been identified in Warthin tumor • EWSR1-POU5F1 fusion gene-less common • Associated with the less well-differentiated tumors SKY and IHC analysis Genes Chromosomes Cancer 2006;45:470–81.

  7. Papillary Thyroid Carcinoma • RET fusion genes(35%) • CCDC6-RET-associated with classic histology • NCOA4-RET-associated with previous radiation therapy • NTRK1 fusion genes (5%) • TPM3-NTRK1, TPR-NTRK1, TFG-NTRK1 • BRAF fusion genes (1%) • AKAP9-BRAF

  8. PPARG1 fusion genes PAX8-PPARG1 fusion* (30%) CREB3L2-PPARG1 fusion (3%) Follicular Thyroid Carcinoma

  9. Science 2000;289:1357-60. t(2;3)(q13;p25) rearrangement of the PPARG1 locus (3p25) rearrangement of the PAX8 locus (2q13) NH2 COOH

  10. The fusion gene is not specific for carcinomas • Some follicular adenomas may be early follicular carcinomas without capsular or vascular invasion • Some reported adenomas were actually poorly sampled carcinomas • Some follicular adenomas can evolve into carcinomas • The PAX8-PPARG1 fusion was significantly associated with vascular invasion • FVPTCs with PAX8-PPARG1 fusion should be classified in the group of FTC rather than as a variant of PTC

  11. Midline Carcinoma of Children and Young Adults (NUT Midline Carcinoma) Am J Surg Pathol 2008;32:828–834.

  12. rearrangement of the BRD4 locus immunoreactivity with antibody to NUT t(15;19)(q13;p13) BRD4-NUT fusion Images were kindly provided by Dr French, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

  13. Renal Cell Carcinoma (RCC) • TFE3 fusion genes (25-35% of paediatric RCC) • ASPL-TFE3 fusion gene • Also been described in alveolar soft part sarcoma • PRCC-TFE3 fusion gene • Alpha-TFEB fusion gene Xp11.2 rearrangement F/28 yrs rearrangement of the TFE3 locus

  14. Breast Carcinoma • ETV6-NTRK3 fusion gene in secretary breast carcinoma (SBC) (12/13 cases) Cancer Cell 2002;2:367-76.

  15. F/6 yrs secretary breast carcinoma (SBC) t(12;15)(p13;q25) ETV6-NTRK3 fusion ETV6 rearrangement Cancer Cell 2002;2:367-76. • a relative higher incidence in children and young adults • low histological grade • a more favourable prognosis Also encountered in cellular mesoblastic nephroma and infantile fibrosarcoma

  16. Thisfusion is a hallmark of ACC Proc Natl Acad Sci U S A 2009;106:18740-4. • t(6;9)(q22–23;p23–24) in adenoid cystic carcinomas (ACC) of the breast and head and neck • MYB-NFIB fusion (11 of 11 cases)

  17. TMPRSS2 fusion genes TMPRSS2-ERG fusion gene (55%) TMPRSS2-ETV1 fusion gene (25%) Prostate Carcinoma Science 2005;310:644-8.

  18. EML4-ALK in non-small-cell lung carcinomas (NSCLCs) (<7%) The majority of them belong to adenocarcinomas This fusion appears to be associated with young age Predominantly seen in non- or light-smokers Two additional alternate ALK fusion genes TFG-ALK KIF5B-ALK Lung Carcinoma

  19. ALK immunoreactivity chimeric protein Provided by Drs Boland and Yi, Mayo Clinic, Rochester, MN, USA rearrangement of the ALK locus

  20. Conclusions • The formation of fusion genes is a universal oncogenic mechanism observed in a variety of human neoplasms • The use of traditional gene mapping techniques and novel bioinformatic approaches have led to the identification of several novel fusion genes in epithelial neoplasms • The identification of fusion genes in epithelial neoplasia has open new avenues for the diagnosis, prognosis and therapy of epithelial neoplasms

  21. Thank you for your attention

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