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PTEN – Leiomyosarcoma

Leiomyosarcoma (LMS) is a malignant smooth muscle neoplasm characterized by frequent somatic inactivation of the tumor suppressor PTEN. A 42-year-old male with mismatch repair–deficient unresectable iliopsoas LMS exhibited biallelic PTEN loss (copy number loss and p.Asn323fs) and achieved pathologic complete response following combined antiangiogenic therapy and pembrolizumab (PMID:35237514). In a molecular analysis of 38 uterine LMS cases, PTEN deletions were significantly more frequent compared with other uterine smooth muscle tumor variants (P < .01) (PMID:24986214). No germline segregation or familial cases have been reported in LMS, consistent with a somatic mode of alteration.

Functional studies across multiple tumor types demonstrate that loss of PTEN lipid phosphatase activity drives oncogenesis via upregulation of PI3K/Akt signaling. Lipid phosphatase–deficient mutants such as p.Cys124Ser fail to inhibit Akt phosphorylation, enhance cell proliferation and motility, and promote angiogenesis in vivo and in vitro models (PMID:10051603). Concordant findings from animal and cellular assays support haploinsufficiency as the primary mechanism of PTEN-mediated tumor suppression in LMS. To date, no reports have refuted the role of PTEN loss in high-grade smooth muscle tumors.

Key Take-home: Somatic PTEN inactivation via deletions or loss-of-function mutations contributes to leiomyosarcoma pathogenesis and may inform molecular diagnostics and targeted therapy strategies.

References

  • Frontiers in Oncology • 2022 • Case Report: Complete Response to Antiangiogenesis and Immune Checkpoint Blockade in an Unresectable MMR-Deficient Leiomyosarcoma Harboring Biallelic Loss of PTEN PMID:35237514
  • Cancer • 2014 • Molecular analyses of 6 different types of uterine smooth muscle tumors: Emphasis in atypical leiomyoma PMID:24986214
  • Proceedings of the National Academy of Sciences of the United States of America • 1999 • Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway PMID:10051603

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Somatic PTEN deletions in 38 LMS cases (P < .01) and a single case with biallelic loss ([PMID:24986214]; [PMID:35237514])

Genetic Evidence

Limited

One LMS proband with biallelic PTEN loss and enrichment of PTEN deletions in a 38-case cohort

Functional Evidence

Moderate

In vitro and in vivo models show loss of PTEN lipid phosphatase activity (e.g., p.Cys124Ser) drives PI3K/Akt activation and tumor phenotypes ([PMID:10051603])