GLI1-amplifications expand the spectrum of soft tissue neoplasms defined by GLI1 gene fusions Journal Article
| Authors: | Agaram, N. P.; Zhang, L.; Sung, Y. S.; Singer, S.; Stevens, T.; Prieto-Granada, C. N.; Bishop, J. A.; Wood, B. A.; Swanson, D.; Dickson, B. C.; Antonescu, C. R. |
| Article Title: | GLI1-amplifications expand the spectrum of soft tissue neoplasms defined by GLI1 gene fusions |
| Abstract: | GLI1 fusions involving ACTB, MALAT1, and PTCH1 genes have been recently reported in a subset of malignant soft tissue tumors with characteristic monomorphic nested epithelioid morphology and frequent S100 positivity. However, we encountered a group of morphologically similar soft tissue tumors lacking the canonical GLI1 gene fusions and sought to investigate their genetic abnormalities. A combined approach including RNA sequencing, targeted exome sequencing and FISH methodologies were used to identify potential novel genetic abnormalities. Ten patients (five females, five males) with an age range of 4–65 years (median 32.5) were identified. Tumors were located in the soft tissues of the limbs, trunk and head and neck, with one each in the tongue and lung. Histologically, tumors revealed ovoid to epithelioid cells arranged in a distinctive nested-trabecular pattern, separated by thin septa and a delicate vascular network. Two cases showed areas of increased nuclear pleomorphism and focal fascicular spindle cell growth. Four tumors showed a high mitotic count (≥15/10 HPFs), with necrosis seen in three of them. Lymphovascular invasion was noted in two cases. No consistent immunoprofile was detected, with positivity for CD56 (six cases), S100 (four cases), SMA (two cases), and pan-CK (one case). FISH showed GLI1 (12q13.3) gene amplification in all 10 cases, with co-amplification of CDK4 (12q14.1) in nine (90%) and MDM2 (12q15) in eight (80%) cases. Targeted exome sequencing performed in three cases confirmed the GLI1, CDK4, and MDM2 co-amplification. Only one case showed the presence of both GLI1 break-apart and amplification, although no gene partner was detected. Our findings suggest that GLI1 amplification, often associated with co-amplifications of CDK4 and MDM2 genes, may represent an alternative genetic mechanism of GLI1 oncogenic activation akin to GLI1 fusions, defining the pathogenesis of an emerging group of malignant soft tissue tumors with a distinctive nested growth pattern and variable immunoprofile. © 2019, United States & Canadian Academy of Pathology. |
| Keywords: | adolescent; adult; child; clinical article; human tissue; preschool child; school child; aged; middle aged; young adult; unclassified drug; histopathology; mitosis; gene amplification; cell growth; cohort analysis; retrospective study; tumor marker; soft tissue; fluorescence in situ hybridization; limb; gene fusion; lung; spindle cell; protein s 100; neck; upregulation; cytokeratin; epithelioid cell; transcription factor gli1; tongue; cancer morphology; soft tissue tumor; cyclin dependent kinase 4; protein mdm2; rna sequence; smooth muscle actin; head; tumor necrosis; trunk; cd56 antigen; dedifferentiated liposarcoma; next generation sequencing; lymph vessel metastasis; human; male; female; priority journal; article; whole exome sequencing; pan cytokeratin |
| Journal Title: | Modern Pathology |
| Volume: | 32 |
| Issue: | 11 |
| ISSN: | 0893-3952 |
| Publisher: | Nature Research |
| Date Published: | 2019-11-01 |
| Start Page: | 1617 |
| End Page: | 1626 |
| Language: | English |
| DOI: | 10.1038/s41379-019-0293-x |
| PUBMED: | 31189998 |
| PROVIDER: | scopus |
| PMCID: | PMC6821565 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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