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

Area of Science:

• Genetics
• Oncology
• Endocrinology

Background:

• Genetic testing is integral to diagnosing neuroendocrine neoplasms (NENs).
• Existing data on genotype-phenotype correlations in NENs lack diversity and do not represent all populations.
• Understanding genetic drivers in diverse populations is crucial for comprehensive NEN management.

Purpose of the Study:

• To determine the frequency and types of germline genetic defects in a Mexican cohort with NENs.
• To explore clinical associations of these germline variants.
• To expand the understanding of NEN genetic underpinnings in underrepresented populations.

Main Methods:

• Analyzed germline DNA from 92 Mexican adults with NENs using a 53-gene next-generation sequencing (NGS) panel or Sanger sequencing.
• Identified, classified, and orthogonally confirmed variants, including single nucleotide variants, indels, and structural variants.
• Investigated tumor samples and family member DNA when available.

Main Results:

• Pathogenic or likely pathogenic (P/LP) variants were found in 17.4% of individuals, who were significantly younger at disease onset.
• Identified variants in syndromes like Von Hippel Lindau, multiple endocrine neoplasia type 1 (MEN1), and early-onset acromegaly.
• Found a higher prevalence of P/LP variants in familial NEN cases compared to sporadic ones.

Conclusions:

• Germline P/LP variants are present in a significant proportion of individuals with NENs, particularly in younger patients.
• This study provides novel insights into the genetic landscape of NENs within a previously uncharacterized Mexican population.
• Findings highlight the importance of genetic screening in diverse NEN patient cohorts.