AIM: To investigate the association between potential risk and protective factors for the occurrence of sporadic PNENs across a European population from several institutions. METHODS: A multinational European case-control study was conducted to examine the association of selected environmental, family and medical exposure factors using a standardized questionnaire in face-to-face interviews. A ratio of 1:3 cases to controls were sex and age matched at each study site. Adjusted univariate and multivariate logistic regression analysis were performed for statistically significant factors. RESULTS: In 201 cases and 603 controls non-recent onset diabetes (OR 2.09, CI 1.27-3.46) was associated with an increased occurrence of PNENs. The prevalence of non-recent onset diabetes was higher both in cases with metastatic disease (TNM stage III-IV) or advanced grade (G3) at the time of diagnosis. The use of metformin in combination with insulin was also associated with a more aggressive phenotype. Drinking coffee was more frequent in cases with localized disease at diagnosis. CONCLUSIONS: Non-recent onset diabetes was associated with an increased occurrence of PNENs and the combination of metformin and insulin was consistent with a more aggressive PNEN phenotype. In contrast to previous studies, smoking, alcohol and first-degree family history of cancer were not associated with PNEN occurrence.
]]>Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors arising from the adrenal medulla and extra-adrenal paraganglia, respectively. Forty percent are explained by germline mutations in known susceptibility genes. Furthermore, somatic mutations were identified in an additional 30% of PPGL, mostly in NF1, RET, VHL, MAX, and HRAS. However, screening is limited to a few studies mainly using Sanger sequencing (Burnichon, et al. 2012; Burnichon, et al. 2011; Crona, et al. 2013; Luchetti, et al. 2015; Stenman, et al. 2016; Weber, et al. 2012; Welander, et al. 2012). Our aim was to look for the prevalence and nature of somatic mutations using a targeted deep-sequencing approach in patients from a Belgian multicentric PPGL cohort. Targeted Next Generation Sequencing was performed in 74 tumors using a panel including 17 susceptibility genes. Variants considered as damaging by at least 5 prediction programs, or present in COSMIC and considered as damaging by at least 3 prediction programs, were considered to be disease-associated mutations. Somatic mutations were identified in 54% of patients. The most frequently mutated genes were NF1 (20.8%) and KIF1B (20.4%). While the high prevalence of somatic mutations in NF1 is in agreement with previous studies, the similarly elevated prevalence of mutations in KIF1B is novel.
]]>