Inactivating Mutations of RB1 and TP53 Correlate With Sarcomatous Histomorphology and Metastasis/Recurrence in...

Area of Science:

• Oncology
• Genetics
• Gastrointestinal Stromal Tumors (GISTs)

Background:

• Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms.
• Loss-of-function mutations in TP53 and CDKN2A are known in GISTs.
• RB1 mutations have not been previously reported in GISTs.

Purpose of the Study:

• To determine the mutation frequency of TP53, RB1, and CDKN2A in GISTs.
• To investigate the clinical significance of these mutations in GIST pathogenesis.

Main Methods:

• Massive parallel sequencing of TP53, RB1, and CDKN2A in 83 primary untreated GISTs.
• Fluorescence in situ hybridization (FISH) for gene loci in tumors with identified mutations.

Main Results:

• Inactivating mutations in RB1 were found in two GISTs.
• Inactivating mutations in TP53 were identified in two GISTs.
• All four mutated tumors were high-risk, KIT-mutant GISTs with aggressive histomorphology and high mitotic activity. Three patients developed recurrent/metastatic disease, and one had intraoperative tumor rupture. The combined frequency of TP53 and RB1 mutations in high-risk GISTs was 13%.

Conclusions:

• TP53 and RB1 mutations are associated with high-risk/malignant GISTs.
• These mutations occur at a similar, relatively low frequency.
• The findings suggest TP53 and RB1 mutations may serve as biomarkers for aggressive GIST subtypes.