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Cytogenetic Insights in Mesenchymal Tumors Jonathan A. Fletcher, M.D. Pathology & Pediatrics Brigham & Women’s Hospital Dana-Farber Cancer Institute Harvard Medical School Boston, MA How it is done! Mince, then disaggregate cells by overnight treatment with collagenase Disaggregated cells are plated as monolayer cultures on glass slides or in plastic flasks All cultures are inspected daily, to determine whether tumor cells are growing, and when metaphase harvests should be performed Leiomyoma: simple karyotype with t(12;14) HMGA2 (HMGIC) Leiomyosarcoma: G-banded karyotype Complex! Clonal (arrows) and nonclonal aberrations Example 1 Novel biologic mechanisms revealed through indentification of recurrent cytogenetic abnormalities in mesenchymal tumors Aneurysmal Bone Cyst and the fusion fusion oncogene Aneurysmal Bone Cyst and the fusion fusion oncogene Aneurysmal Bone Cyst • Patients are generally < 20 years old • Can recur locally, but do not become malignant • “Primary ABC” have been generally regarded as nonneoplastic • “Secondary ABC” associated with – – – – osteoblastoma chondroblastoma giant cell tumor osteosarcoma Aneurysmal Bone Cyst • 1999: Panoutsakopoulos et al. reported translocation t(16;17) in two ABC – neoplastic basis – recurrent oncogenic mechanism Aneurysmal Bone Cyst • 17p13 rearrangements in: – “solid variants” of ABC – soft-tissue ABC • 25% of ABC have t(16;17) • >25% of ABC have alternate translocations, involving 17p13, but not 16q22 Aneurysmal Bone Cyst • t(16;17) – 17p13 gene = USP6 (Ewing’s oncogene) – 16q22 gene = CDH11 (aka “osteoblastic cadherin”) – promoter swapping between CDH11 and USP6 • fusion of highly active CDH11 promoter to the 5’ UTR of USP6 Aneurysmal Bone Cyst Corroboration of “promoter swapping” mechanism in USP6 fusions Translocation Gene Promoter Swapping? t(9;17) osteomodulin YES t(17;17) COL1A1 YES t(1;17) TRAP150 YES t(3;17) ZNF9 YES Aneurysmal Bone Cyst What is the neoplastic cell? Mechanisms in secondary ABC? USP6 oncogene in ABC spindle-cells USP6 oncogene is not found in “secondary ABC” Secondary ABC Associated Chondroblastoma USP6 or CDH11 Rearrangement in ABC • 36 of 52 (69%) primary ABC • 0 of 17 secondary ABC – giant cell tumor – osteoblastoma – chondroblastoma – fibrous dysplasia USP6 is an evolutionarily-recent fusion of the PRC17 and USP32 genes (hominoid specific) PRC17 USP32 TBC (rabGAP) UBP >95% identity TBC (rabGAP) USP6 UBP USP6 Function: regulates endocytosis/destruction of activated proteins CDH 11 TBC (rabGAP) UBP - inactivates rab family members -UBP protease reverses ubiquitination -rab function required for endocytosis of activated EGFR - ?synergize with rabGAP function to inhibit endocytosis/proteolysis USP6 Expression • Normal expression restricted to embryonic tissues and testis • Neoplastic expression restricted to mesenchymal tumors: – 2 of 2 osteoblastomas – 1 of 4 myofibromas – 1 of 3 Ewing’s sarcomas Conclusions • USP6 is overexpressed due to promoter swapping mechanisms in most primary ABC • USP6 overexpression may stabilize oncogenic proteins • USP6 is an evolutionarily recent gene, with likely relevance in sarcoma • Useful models of mesenchymal tumor biology can come from unlikely places Example 2 Smooth Muscle Tumors • Use of cytogenetic clues to identify clinically-relevant biologic pathways in a genetically complex disease Leiomyoma: simple karyotype with t(12;14) HMGA2 (HMGIC) Leiomyosarcoma: G-banded karyotype How do leiomyomas progress to malignancy? ??? Intravenous Leiomyomatosis t(12;14) with: partial trisomy 12q partial deletion 14q Typical uterine leiomyoma Balanced t(12;14) Intravenous leiomyomatosis Unbalanced t(12;14) Partial trisomy 12q Paola Dal Cin Brad Quade Cynthia Morton Cytogenetic correlates for leiomyoma progression • Vascular invasion – intravenous leiomyomatosis – unbalanced t(12;14) • Increased proliferation – cellular leiomyoma – deletion 1p (also common in lms) • Distant metastases – “benign metastasizing leiomyoma” – deletions of 19q and 22q Pulmonary Chondroid Hamartoma (HMAG2 & HMGA1 oncogenes) PCH: primitive mesenchymal, fat, chondroid PCH: primitive mesenchymal, fat, chondroid, smooth muscle Leiomyosarcoma/Leiomyoma: where do they start? Is there proof that any sarcoma arises from a differentiated mesenchymal cell? • • • • • • • osteo – bone chondro – cartilage lipo – fat leiomyo – smooth muscle rhabdo – skeletal muscle fibro – myofibroblast “GIST” – interstitial cell of Cajal NO Andre Oliveira George Demetri Antonio Perez-Atayde Paola Dal Cin Christopher Fletcher Mark Gebhardt Cynthia Morton Sam Singer Andrew Rosenberg Marisa Nucci Anette Duensing Chang-Jie Chen Nora Joseph Bryna Mcconarty Felicity Smith Lynn Yu Christopher Hubert Maureen Thyne Vicki Derr Stana Weremowicz Julia Bridge THANK YOU!!!
