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The RET proto-oncogene: a challenge to our understanding of disease pathogenesis
1Children's Research Centre, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Ireland.
Abstract:
RET gene alterations as disease-causative mutations have been demonstrated in five different disease entities: Hirschsprung's disease (HD); papillary thyroid carcinoma; and three types of inherited cancer syndromes: multiple endocrine neoplasia (MEN) 2A, MEN 2B, and familial medullary thyroid carcinoma. RET is expressed during embryogenesis in a temporally and spatially regulated manner, and plays an important role in the normal development of a variety of cell lineages, particularly in the establishment of the enteric nervous system. RET mutations observed in patients with HD are scattered along the gene without any hot spots, and possess a loss-of-function effect. RET mutations are detected with a higher incidence among familial cases (50%) than sporadic cases (15%-20%), and are more closely associated with long-segment HD than short-segment disease. In contrast to HD mutations, missense mutations observed in MEN 2 syndromes occur at specific codons, and gene rearrangements are characteristic in papillary thyroid carcinoma. Both missense mutations and gene rearrangements act in a dominant fashion, and cause constitutive phosphorylation on the tyrosine of RET and highly enhance RET kinase activity, leading to transforming or oncogenic activity.
Insights
RET gene mutations cause Hirschsprung's disease (HD) and multiple endocrine neoplasia (MEN) syndromes. While HD mutations cause loss-of-function, MEN mutations enhance RET kinase activity, driving cancer development.
Area of Science:
- Genetics
- Developmental Biology
- Oncology
Background:
- The RET proto-oncogene plays a critical role in embryonic development, particularly in the enteric nervous system.
- Alterations in the RET gene are implicated in several human diseases, including Hirschsprung's disease and various endocrine neoplasias.
Purpose of the Study:
- To delineate the distinct mechanisms and clinical associations of RET gene mutations in different disease entities.
- To differentiate the functional consequences of RET alterations in congenital disorders versus hereditary cancers.
Main Methods:
- Analysis of RET gene mutations across patient cohorts with Hirschsprung's disease and MEN syndromes.
- Comparison of mutation locations, frequencies, and functional effects (loss-of-function vs. gain-of-function).
Main Results:
- RET mutations in Hirschsprung's disease (HD) are diverse, scattered, and lead to loss-of-function, more prevalent in familial and long-segment cases.
- In contrast, MEN 2 syndromes feature specific RET missense mutations or rearrangements causing constitutive activation and enhanced kinase activity.
- RET alterations are found in 50% of familial HD cases versus 15%-20% of sporadic cases.
Conclusions:
- RET gene mutations exhibit distinct pathogenetic mechanisms, leading to either loss-of-function in HD or oncogenic gain-of-function in MEN syndromes.
- Understanding these differential mechanisms is crucial for diagnosing and potentially treating RET-associated disorders.