Alternative Lengthening of Telomeres Phenotype Predicts Progression Risk in Noninsulinomas in a Chinese Cohort

Introduction: Recent studies have suggested that alternative lengthening of telomeres (ALT) is associated with metastasis and poor survival in pancreatic neuroendocrine tumors (PanNETs). This study evaluated whether this association is applicable to Chinese patients as well as the potential somatic mutations associated with ALT. Methods: We assessed the prevalence of ALT by performing telomere-specific fluorescence in situ hybridization and analyzed DAXX/ATRX expression using immunohistochemistry in 112 Chinese patients with PanNETs to evaluate the association between ALT and clinical outcomes. A subset of the noninsulinoma samples (28/60) was subjected to Sanger sequencing and targeted sequencing. Results: The ALT-positive phenotype was identified in 23.2% (26/112) of the samples. The clinicopathologic factors significantly associated with progression in the noninsulinoma (n = 60) cohort were the female sex (p = 0.006), Ki-67 index (p < 0.001), World Health Organization grade (p = 0.031), and ALT positivity (p = 0.013). Patients with ALT-positive PanNETs had significantly shorter progression-free survival than those with ALT-negative PanNETs in the entire cohort (p < 0.001), noninsulinoma subgroup (p = 0.01), and G2 subgroup (p = 0.001). ALT-positive samples frequently harbored somatic mutations in DAXX, ATRX, MEN1, SETBP1, PRKDC, and GNAS. Conclusions: We confirmed that ALT positivity is an effective risk predictor, especially in the noninsulinoma and G2 subgroups. ALT is also related to somatic mutations in MEN1, SETBP1, PRKDC, and GNAS, in addition to DAXX and ATRX.