PanNET mutations affect DNA damage repair, chromatin remodeling, telomere maintenance, and mTOR signaling.
Major finding: PanNET mutations affect DNA damage repair, chromatin remodeling, telomere maintenance, and mTOR signaling.
Concept: Comprehensive molecular analysis of 102 clinically sporadic PanNETs uncovers essential PanNET pathways.
Impact: The comprehensive identification of PanNET genetic alterations may aid risk stratification and treatment.
Pancreatic neuroendocrine tumors (PanNET) are classified into three groups: low grade (G1), intermediate grade (G2), and high grade (G3). G3 PanNETs have a universally poor prognosis, whereas G1 and G2 tumors have an unpredictable clinical course. A better understanding of the molecular underpinnings of the disease may enable better risk stratification and the identification of patients who might benefit from early aggressive therapy. Scarpa and colleagues performed comprehensive molecular analyses of 102 clinically sporadic PanNETs. Whole-genome sequencing of 98 PanNETs defined five distinct mutational signatures: MUTYH, APOBEC, BRCA-deficiency, age, and COSMIC signature 5. The MUTYH signature was previously undescribed and was associated with G:C>T:A transversions in tumors with an inactivating germline mutation in the base excision–repair gene MUTYH, suggesting that MUTYH deficiency may contribute to PanNET. Germline mutations were detected in MEN1, CDKN1B, CHEK2, and VHL1, in addition to BRCA1 and MUTYH. Further, 15,751 somatic coding mutations were identified in 2,787 genes, and MEN1 was the most frequently mutated gene. Tumors with ATRX, DAXX, or MEN1 mutations exhibited increased telomere length. There were an average of 29 structural rearrangements per tumor, with rearrangements leading to inactivation of tumor suppressors such as MTAP, ARID2, SMARCA4, MLL3, CDKN2A, and SETD2, or creating oncogenic gene fusions. In total, 66 somatic in-frame gene fusions were identified, including three EWSR1 fusion events leading to EWSR1–BEND2 or EWSR1–FLI1. Although EWSR1–FLI1 is a characteristic Ewing sarcoma fusion gene, the morphologic and pathologic features were consistent with PanNETs. RNA sequencing of 30 PanNET tumors found that common genetic alterations affected DNA damage and repair, chromatin remodeling, telomere maintenance, and mTOR signaling, suggesting possible therapeutic targets. This comprehensive genomic analysis identified mutations, structural rearrangements, and signaling pathways not previously associated with PanNETs, which may aid in risk stratification and the development of targeted therapies.
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