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 (5 females, 5 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 3 of them. Lymphovascular invasion was noted in 2 cases. No consistent immunoprofile was detected, with positivity for CD56 (6 cases), S100 (4 cases), SMA (2 cases) and pan-CK (1 case). FISH showed GLI1 (12q13.3) gene amplification in all 10 cases, with co-amplification of CDK4 (12q14.1) in 9 (90%) and MDM2 (12q15) in 8 (80%) cases. Targeted exome sequencing performed in 3 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.

Primary myxoid and epithelioid mesenchymal tumor of the kidney with a novel GLI1‐FOXO4 fusion

“…GLI1 rearrangements have been identified in several malignant soft tissue tumors including pericytoma‐like tumors, 19,20 gastric plexiform fibromyxoma, 21 gastroblastoma, 22 and a group of malignant epithelioid neoplasms with frequent S100 protein expression. The latter group of tumors has been shown to harbor either GLI1 fusions or GLI1 amplifications 17,23 …”

Gene of the month: GLI-1

“…These tumours were composed of oval epithelioid cells arranged in nests and trabeculae invested by a delicate vasculature. Additionally, some of the tumours showed nuclear pleomorphism, high mitotic rate (>15 mitoses per 10 high-power fields), more spindled morphology and areas of necrosis 5. Together with GLI-1 amplification, CDK4 and MDM2 were coamplified in 90% and 80% of cases, respectively 5…”

“…Recently, Agaram and colleagues described 10 tumours from the soft tissues of the limbs, trunk and head and neck that all showed GLI-1 (12q13.3) amplification 5. These tumours were composed of oval epithelioid cells arranged in nests and trabeculae invested by a delicate vasculature.…”

A Malignant Neoplasm From the Jejunum With aMALAT1-GLI1Fusion and 26-Year Survival History

“…11,[13][14][15][16][17][18] MALAT1-GLI1, ACTB-GLI1, and PTCH1-GLI1 gene fusions, or GLI1 amplifications, have also been reported in epithelioid tumors from diverse sites including soft tissue, skeletal muscle, bone, and retroperitoneum with variable S100 protein, cytokeratin, and CD56 expression and the potential for metastatic behavior. 19,20 In this article, we describe a case of a MALAT1-GLI1associated malignancy arising in the jejunum, an origin not previously reported for a GLI1 fusion-associated tumor. The patient had multiple recurrences over a 26-year period.…”