Overlapping Presentations and Diverse Genetic Defects Characterize Neuroendocrine Neoplasms in a Mexican Cohort

Abstract

Context: Genetic tests are part of the routine clinical approach to syndromic and nonsyndromic phenotypes of neuroendocrine neoplasms (NENs). Current data on phenotype-genotype associations in NENs, however, do not accurately represent all populations.

Objective: To describe the frequency, inventory, and clinical associations of germline defects associated with multiple types of NENs in a Mexican cohort.

Methods: Blood DNA from Mexican adults with NENs was analyzed with a 53-gene next-generation sequencing panel developed ad hoc (n = 90) or Sanger sequencing (n = 2). Single nucleotide variants, indels, and structural variants were identified, classified, and subjected to orthogonal confirmation. When possible, tumor samples and blood DNA from additional family members were tested using Sanger sequencing.

Results: Ninety-two probands (70.7% women, 51.5% sporadic) were included; 16 carried pathogenic or likely pathogenic (P/LP) variants and were significantly younger at disease onset than the rest (29.6 ± 10.7 vs 40 [21.5-51.5] years, P = .0384). Likely driving variants were identified in three-quarters of Von Hippel Lindau syndrome cases, one-third of multiple endocrine neoplasia (MEN) type 1, one-quarter of early-onset acromegaly/gigantism, and individual cases of Cushing's disease, MEN2A, and medullary thyroid carcinoma. One patient with clinical MEN1 associated with an SDHA variant and 1 with a pituitary tumor and neurofibromatosis type 1 were also identified. Probands with familial disease were more likely to carry P/LP variants than sporadic cases (26.7 vs 8.5%, P = .0282).

Conclusion: P/LP variants were identified in 17.4% of individuals with NENs. Our research provides a view of the landscape of NEN drivers in a population not previously characterized.

Keywords: familial isolated pituitary adenoma; multiple endocrine neoplasia; neuroendocrine neoplasm; next-generation sequencing; paraganglioma/pheochromocytoma; pituitary neuroendocrine tumor.

Figure 1.

Clinical characteristics of the study population and general description of genetic findings. (A) Sex distribution of the probands (n = 92). (B) Categories of clinical presentation of the study probands (n = 92). The categories were determined according to the clinical features observed at diagnosis and during follow-up. (C) Family history in probands (n = 92). Patients with no relevant family history were classified as sporadic and the rest were grouped into 10 categories, according to the phenotypes described in the family members. (D) All variants (n = 303) identified in the study, according to their predicted effect. (E) ACMG/AMP categories for all variants identified in the study (n = 303). (F) Comparison of the age at disease onset and diagnosis between individuals with a detected pathogenic or likely pathogenic variant (P/LP) and the rest of probands (Rest). The horizontal bar represents median, and the error bars depict interquartile range. CS, Cushing's syndrome; del, deletion; dup, duplication; FIPA, familial isolated pituitary adenoma; FMTC, familial medullary thyroid carcinoma; FPPGLs, familial pheochromocytomas/paragangliomas; gig/EO acro, gigantism and early onset acromegaly; ins, insertion; ins/del, insertion/deletion; LB, likely benign; LFL, Li–Fraumeni-like; LP, likely pathogenic; MEN-like, syndrome similar to multiple endocrine neoplasia; MEN1, multiple endocrine neoplasia type 1; MEN2A, multiple endocrine neoplasia type 2A; MTC, medullary thyroid carcinoma; M GI-NENs, multiple gastrointestinal neuroendocrine neoplasms; M panNENs, multiple pancreatic neuroendocrine neoplasms; NF1, neurofibromatosis type 1; non-GH EO PitNETs, early onset PitNETs not causing GH excess; panNEN, pancreatic neuroendocrine neoplasm; PitNET, pituitary neuroendocrine tumor; PPGL, pheochromocytoma/paraganglioma; VHL, Von Hippel Lindau syndrome; VUS, variants of uncertain significance.