Ahmad Abdel-Azim

He/Him/His
Research Trainee/Undergraduate Student
Medicine
Pulmonary and Critical Care Medicine
Comprehensive genomic and clinicopathologic characterization of advanced PEComa tumors with metastatic potential

Principal Investigator: David J. Kwiatkowski

Authors: Krinio Giannikou1,2, Ahmad Abdel-Azim1, Junko Tsuji2, Elio Adib1, Zachary Zhu1, Chin-Lee Wu4, Guido Martignetti5, Elizabeth P. Henske6, Gavin Ha3, Gad Getz2, Jason Hornick4, Andrew J. Wagner5*, David J. Kwiatkowski1,2* 1 Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA 2 Broad Institute of Harvard and MIT, Cancer Genome Program, Cambridge, MA, USA 3 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA 4 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA 5 Center for Sarcoma and Bone Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Lay Abstract

PEComa (Perivascular Epithelioid cell tumor) is a rare tumor, predominantly seen in females that affects multiple organs with high risk of developing secondary malignant growths at a distance from a primary site of cancer. PEComa commonly have mutations in either TSC1 or TSC2 genes that cause Tuberous Sclerosis Complex, a rare genetic disorder. In this study, we searched for mutations in all known 20,000 genes in 74 resected malignant PEComa tumors from 59 patients; this is the largest study ever conducted and compared to Leiomyosarcoma (LMS), a similar tumor entity with overlapping characteristics. We found that genetic alterations in just three genes were common in PEComa: TP53, TSC2 and TSC1, the two latest of which are not seen in LMS. Overall, we observed that PEComa and LMS share many similarities in genomic level. Because mutations in TSC1/TSC2 in tumors are associated with response to treatment with mTORC1 inhibitors, many (75%) of these PEComa had been treated with rapamycin or other mTORC1 inhibitors. We found that patients respond to rapalog therapy with favorable disease outcome and such responses are often durable (> 1 year) and strongly correlate with alterations in TSC2.

Scientific Abstract

Background: Malignant PEComa (Perivascular Epithelioid cell tumor) is a rare neoplasm that demonstrates local invasion and/or distant metastases with poor prognosis. Approximately 35-40% of PEComa have TSC1/TSC2 mutations.

Aim: To identify other events beyond TSC1/TSC2 alterations that might contribute to tumor development and to compare to The Cancer Genome Atlas (TCGA) Leiomyosarcoma (LMS), a similar sarcoma subtype.

Material-Methods: Exome sequencing was performed in 74 malignant PEComa from 59 patients (median age 52).

Results: We found that mutations in TP53 (27%), TSC2 (24%) and TSC1 (18%) were the most frequent alterations, whereas other somatic events were mainly non-recurrent missense alterations of uncertain clinical significance. C>T at CpG was the most common substitution, consistent with the aging mutation signature, similar to LMS. Copy number analysis showed that PEComa have multiple focal amplifications and deletions (e.g. RB1, TP53), also similar to LMS. 73% of patients were treated with mTOR inhibitors (mTORi) with median progression-free survival 1.4 years, and median overall survival 2.9 years. Patients with TSC2 mutations had sustained benefit in response to mTORi (median survival not reached).

Conclusions: PEComa have a low somatic mutation rate, similar to LMS, but also substantial TSC1/TSC2 mutations in contrast to LMS.

Clinical Implications
We performed the first exome analysis in malignant PEComa, and we found that they have a very low somatic mutation rate, similar to LMS. mTOR inhibitors provide clinical benefit for patients with TSC2 mutations.

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