Distribution of RET proto-oncogene variants in children with appendicitis
Jurek Schultz1, Ines Freibothe1, Michael Haase1
1Department of Pediatric Surgery, University of Technology Dresden, Dresden, Germany.
Insights
RET proto-oncogene variants may contribute to appendicitis (AP) development, particularly in severe cases. Mutations found in gangrenous or perforated AP patients suggest a potential genetic link, similar to Hirschsprung disease (HSCR).
Area of Science:
- Genetics and Molecular Biology
- Gastroenterology
- Pediatric Surgery
Background:
- Appendicitis (AP) pathogenesis may involve impaired peristalsis and drainage, alongside genetic factors (30-50%).
- Hirschsprung disease (HSCR), characterized by disturbed peristalsis, is linked to RET proto-oncogene variants.
- This study investigates the hypothesis that RET variants contribute to AP etiology.
Purpose of the Study:
- To explore the association between RET proto-oncogene variants and the development of appendicitis.
- To investigate germline mutations in the RET gene in children with appendicitis, especially severe forms.
Main Methods:
- Analyzed DNA from 264 children's appendices and clinical data for the RET c.135A>G variant (rs1800858).
- Performed RET sequencing on peripheral blood DNA from 46 patients with gangrenous or perforated appendicitis (GAP).
- Compared variant frequencies between AP patients and controls.
Main Results:
- Germline RET mutations were identified in 13% of GAP patients; no mutations were found in controls, except for a benign variant.
- The G-allele in rs2435352 (intron 4) was underrepresented in GAP patients (p=0.0317).
- Observed RET mutations were similar to those in HSCR patients, but without HSCR clinical features.
Conclusions:
- The RET proto-oncogene appears to play a role in the etiology of appendicitis.
- Phenotypic heterogeneity and incomplete penetrance of RET germline mutations may contribute to AP.
- Appendicitis may have a multigenic etiology, potentially involving RET variants similar to HSCR.
Background:
In addition to patient-related systemic factors directing the immune response, the pathomechanisms of appendicitis (AP) might also include insufficient drainage leading to inflammation caused by decreased peristalsis. Genetic predisposition accounts for 30%-50% of AP. M. Hirschsprung (HSCR), also characterized by disturbed peristalsis, is associated with variants in the RET proto-oncogene. We thus hypothesized that RET variants contribute to the etiology of AP.
Methods:
DNA from paraffin-embedded appendices and clinical data of 264 children were analyzed for the RET c.135A>G variant (rs1800858, NC_000010.11:g.43100520A>G). In 46 patients with gangrenous or perforated AP (GAP), peripheral blood DNA was used for RET sequencing.
Results:
Germline mutations were found in 13% of GAP, whereas no RET mutations were found in controls besides the benign variant p.Tyr791Phe (NC_000010.11:g.43118460A>T). In GAP, the polymorphic G-allele in rs2435352 (NC_000010.11:g.43105241A>G) in intron 4 was underrepresented (p = 0.0317).
Conclusion:
Our results suggest an impact of the RET proto-oncogene in the etiology of AP. Mutations were similar to patients with HSCR but no clinical features of HSCR were observed. The pathological phenotypes in both populations might thus represent a multigenic etiology including RET germline mutations with phenotypic heterogeneity and incomplete penetrance.
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