Epidemiology, the study of the spread and distribution of diseases, is an important arm of medical research. Epidemiological studies provide us with a real-world snapshot of the diseases that are prevalent in any given part of the world.
For example, during my time working as a doctor in Borneo, dengue and rabies were prevalent. Governmental campaigns were created to drive awareness of these diseases and to educate the public on how to prevent them from spreading.
In the United States, dengue and rabies are considered low-priority diseases because they are exceedingly rare. However, diseases that are more common in the West, such as autoimmune diseases and certain types of cancers, are hardly seen in the East.
Epidemiological studies help us understand that all diseases are somewhere on the scale in terms of how rare/common they are. This information can then be utilized to target key diseases, fund the right research, and develop therapies that are most needed.
In this article, we will explore the geographical variation in the profile of RET variants in patients with medullary thyroid carcinoma (MTC).
Read more about MTC etiology
The study of geographical variations in genetic mutations falls under a subcategory of epidemiological studies known as molecular epidemiology. In Nature Reviews Genetics, Gardy and Loman wrote, “Coupling genomic diagnostics and epidemiology to innovative digital disease detection platforms raises the possibility of an open, global, real-time digital pathogen surveillance system.”
The Role of the RET Variant in MTC
“Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of MTC, pheochromocytoma, and hyperparathyroidism in nearly 98, 50, and 25% of gene carriers, respectively.” Maciel and Maia wrote in the European Journal of Endocrinology.
There are 2 different types of MTCs: sporadic and familial. Sporadic MTCs make up approximately 75% of cases, and its most frequent molecular alterations are activating RET mutations (approximately 50%).
Barletta and colleagues explained in Endocrine Pathology: “RET activates multiple pathways including the mitogen-activated protein kinase (MAPK) and the phosphoinositide 3-kinase (PI3K) pathways (among others), which, in turn, promote cell growth, proliferation, survival, and differentiation.”
Read more about MTC epidemiology
In sporadic MTC, RET status is an important prognostic predictor. Studies indicate that RET mutations are associated with larger tumors, as well as lymph node involvement and metastases. The presence of RET mutations is also correlated with more advanced stages of the disease upon diagnosis.
Familial MTC, accounting for the remaining 25% of MTC cases, is inherited following an autosomal dominant pattern and is often multifocal. Barletta et al wrote, “Unlike many cancers that have loss of function mutations, these tumors harbor gain of function mutations in the RET proto-oncogene.”
RET Profile Varies Across Geographical Regions
Interestingly, multiple studies have demonstrated that the RET variant profile varies according to geographical location. There are many hypotheses on what drives genetic variability: natural selection, migration, and genetic drift. Genetic variability is what makes humanity (and diseases) so diverse.
First, let’s look at data from France, Italy, and Germany, nations that are geographically close. Maciel and Maia have found that 4 variants—p.Met918Thr, p.Cys620X, p.Glu768Asp, and p.Ser891Ala—are present in roughly similar proportions in these nations. However, the p.Leu790Phe variant is more common in Germany and France, while the p.Ser891Ala variant is more prevalent in Italy.
Next up, Norway and Denmark. Both of these countries have a complete cancer registry database, which includes MEN2 patients and their RET genotypes. Although Norway and Denmark are geographically (and linguistically) close, they have notable differences in the incidence, prevalence, and distribution of MTC-related RET variants. The percentage of hereditary MTC cases also differs significantly (Denmark has roughly twice as many MTC cases as Norway, despite the countries having similar population sizes).
Fascinatingly, RET pathogenic variants in various regions of the world—Africa, the Americas, Asia, Europe, and Oceania—vary greatly. Almost every nation studied has different RET pathogenic variants that are most prevalent; no 2 countries share the same percentages of their top RET variants.
Let’s turn our attention to Brazil, the home country of the researchers Maciel and Maia. There, the main pathogenic RET variants are p.Gly533Cys and p.Met918Val. The relative frequency of codon 634 mutations in Brazil is 47.0%, higher than in Japan, the UK, Germany, Italy, France, or the US.
What could explain such a discrepancy? Maciel and Maia wrote, “One potential explanation could be the fact that RET screening in Brazil is not yet comprehensive, and patients with variants at codon 634 develop the disease earlier, a scenario comparable with that of the early European data on RET variants causing MEN2, when codon 634 variants were found in between 63 and 67.6% of MEN2 patients.”
This brings us to an important point when assessing epidemiological studies: the quality of the collection, storage, and interpretation of data. For us to piece together an accurate epidemiological picture of any disease, technology everywhere needs to be comparably advanced and reporting protocols relatively uniform.
Maciel RMB, Maia AL. Global endocrinology: geographical variation in the profile of RET variants in patients with medullary thyroid cancer: a comprehensive review. Eur J Endocrinol. 2021;186(1):R15-R30. doi:10.1530/EJE-21-0753
Barletta JA, Nosé V, Sadow PM. Genomics and epigenomics of medullary thyroid carcinoma: from sporadic disease to familial manifestations. Endocr Pathol. 2021;32(1):35-43. doi:10.1007/s12022-021-09664-3
Gardy JL, Loman NJ. Towards a genomics-informed, real-time, global pathogen surveillance system. Nat Rev Genet. 2018;19(1):9-20. doi:10.1038/nrg.2017.88