Genetic Bases of Neuroendocrine Neoplasms in Mexican Patients

Introduction.

NENs are a heterogeneous group of human neoplasms with a variable clinical behavior, spanning from indolence to frank aggressiveness and malignancy. They arise from various tissues with common embryological origins that share the capacity for producing hormones. Their growth might compromise surrounding structures and they often cause significant morbidity due to their associated syndromes of hormone oversecretion. Although traditionally considered rare, the frequency of NENs has greatly increased in the last decades, due to improved clinical awareness and diagnostic strategies. This group includes lesions such as bronchopulmonary, gastrointestinal, pancreatic, and thymic NENs, medullary thyroid carcinoma (MTC), paragangliomas and pheochromocytomas (PPGLs), parathyroid adenomas and carcinomas, and pituitary neuroendocrine tumors (PitNETs), among others.

Interestingly, NENs are among the human neoplasms with a strongest heritable component. Some NENs are part of autosomal dominant syndromes of multiple endocrine neoplasia, where they present in combination with other characteristic endocrine and non-endocrine tumors in the same individual and/or family. Clinical descriptions of such entities exist in the literature since the mid-twentieth Century, although their genetic causes were not determined until three or four decades ago. In other instances, a single type of tumor, such as MTC, PitNETs, or PPGLs, arises in multiple members of the same family, without other associated features. Occasionally, individuals with apparently sporadic presentation are indeed simplex cases of familial conditions. It is currently known that around 50% of cases of MTC, 40% of PPGLs, 20% of gastrointestinal, pancreatic, bronchopulmonary, and thymic NENs, 15% of parathyroid NENs, and 5-10% of PitNETs are due to germline defects. Aside from heritable genetic defects, alterations at the somatic level determine specific clinical courses in both sporadic and familial NENs.

In the last decade, the widespread use of powerful tools for genetic analyses has resulted in a dramatic increase in the known genetic causes of NENs. These approaches have also yielded previously unsuspected genotype-phenotype associations and have uncovered a great overlap in the clinical presentation of different syndromes of multiple endocrine neoplasia. Genetic tests are key for early diagnosis, tailored clinical management, and genetic counseling. Moreover, genetic analyses on the tumors have uncovered potential biomarkers and therapeutic targets. Yet, platforms for genetic diagnosis are not widely available and data on genetic disease drivers do not accurately represent all human populations. Genetic tests are not widely available in Mexico and are almost non-existent in its public hospitals, which serve the majority of the country's ∼128 million population. Interestingly, Mestizos, which account for most of the Mexican population, are one of the most genetically diverse human groups. Precision medicine strategies require population-specific information, yet, Mexican Mestizos are poorly represented in international genetic databases.

Aims.