GEP NETs are mostly sporadic neoplasms with few cases related to familial syndromes, like Multiple Endocrine Neoplasia and Von Hippel-Lindau Disease. However, epidemiological studies have demonstrated a hazard ratio of 3.6 for developing GEP NETs in healthy people with an affected first-degree relative. Germline mutation in TSC2 gene causes Tuberous Sclerosis (TS), an autosomal dominant disease with high penetrance and characterized by benign tumours throughout the body. TS is known to predispose to GEP NETs, but until now, this association has been considered weak and only based in some few case reports.
Targeted Next-Generation Sequencing of the coding exons of 8 genes possibly associated with NETs (TSC2, TSC1, MEN1, VHL, NF1, RET, TP53 and FLCN) was carried out in DNA from peripheral blood of patients (pts) with GEP NETs. The functional impact of missense variants was analysed using SIFT and Polyphen2. Only variants with confirmed validation by Sanger sequencing, with damaging functional impact and with minor allele frequency
Ninety-three pts, all phenotypically normal and with no relevant family history, were recruited. The median age at diagnosis was 52 (27-79) and 54.8% were males. The majority had grades 1 and 2 (38.7% and 41.9%, respectively) but there were 18 pts with grade 3 NETs (19.4%). Pancreas was the primary site in 41 cases (44.1%) and small bowel in 33 (35.5%). Nineteen NETs (20.4%) arose in other sites. Damaging germline variants were confirmed in 10 pts (10.8%) with 7 occurring in TSC2 gene (7.5%). Other variants were in TP53 (2) and RET (1). There were no duplicate variants and 6 of them correspond to rare variants already described in the literature. Among TSC2 damaging variants, 3 occurred in conserved protein domains. There were no clear differences on age of diagnosis, primary site or tumor grade comparing pts with or without damaging variants.
Germline TSC2 damaging variants are significantly associated to GEP NETs in phenotypically normal pts, increasing the genetic predisposition to the neoplasia and probably reflecting a new feature of TS.
Clinical trial identification
Legal entity responsible for the study
Hospital Sirio Libanes, Sao Paulo, SP, Br
Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Sao Paulo, SP, BR
All authors have declared no conflicts of interest.