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Tissue specific somatic mutations and aganglionosis in Hirschsprung's disease.
J Pediatr Surg. 2014 Feb; 49(2):258-61; discussion 261.JP

Abstract

BACKGROUND

RET proto-oncogene intron 1 variations [e.g. SNP1 (rs2506004) and SNP2 (rs 2435357)] have been shown to be etiologically important in the pathogenesis of Hirschsprung's disease (HSCR). Although activating somatic RET rearrangements have been identified in certain tumours, this is the first study to confirm somatic gene variation in HSCR.

METHODS

DNA was extracted from 53 paraffin embedded tissue samples (HSCR patients n=33, multiple levels n=17), and controls (n=3). Patients were grouped into aganglionic (Group 1), ganglionated (group 2), and transitional (group 3). PCR products of RET intron 1 were screened for genetic variation by semi-automated bi-directional sequencing analysis and matched to unaffected controls from the general population. Comparison was by Fishers exact test. P <0.05 was regarded as significant.

RESULTS

HSCR patients included short segment (n=26), long segment colonic [(n=4 (24%)], and total colonic aganglionosis (n=3). RET intronic variations [SNP1 (rs2506004) or SNP2 (rs 2435357)] showed somatic homozygous in affected tissue in 9/12 (75%) Group 1 (aganglionic tissue) compared with 2/5 (40%) and 1/10 (10%) of groups 2 and 3 (P<0.001). Homozygous SNP2 variation was observed in all long segment versus 4/10 short segment. 50% of the short segment cases showing homozygous SNP 1 variation.

CONCLUSION

We report somatic mutations in the RET intron 1 region of affected HSCR tissue, confirming for the first time that somatic mutations are present in aganglionic tissue and may promote local aganglionosis through deregulated receptor activity. Detailed understanding of the somatic genetic events that drive congenital aganglionosis may have bearing on diagnosis and therapy.

Authors+Show Affiliations

Division of Pediatric Surgery, Department of Surgical Sciences, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa. Electronic address: swm@sun.ac.za.Division of Pediatric Surgery, Department of Surgical Sciences, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24528961

Citation

Moore, Sam W., and Monique G. Zaahl. "Tissue Specific Somatic Mutations and Aganglionosis in Hirschsprung's Disease." Journal of Pediatric Surgery, vol. 49, no. 2, 2014, pp. 258-61; discussion 261.
Moore SW, Zaahl MG. Tissue specific somatic mutations and aganglionosis in Hirschsprung's disease. J Pediatr Surg. 2014;49(2):258-61; discussion 261.
Moore, S. W., & Zaahl, M. G. (2014). Tissue specific somatic mutations and aganglionosis in Hirschsprung's disease. Journal of Pediatric Surgery, 49(2), 258-61; discussion 261. https://doi.org/10.1016/j.jpedsurg.2013.11.035
Moore SW, Zaahl MG. Tissue Specific Somatic Mutations and Aganglionosis in Hirschsprung's Disease. J Pediatr Surg. 2014;49(2):258-61; discussion 261. PubMed PMID: 24528961.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tissue specific somatic mutations and aganglionosis in Hirschsprung's disease. AU - Moore,Sam W, AU - Zaahl,Monique G, Y1 - 2013/11/15/ PY - 2013/10/31/received PY - 2013/11/09/accepted PY - 2014/2/18/entrez PY - 2014/2/18/pubmed PY - 2014/11/7/medline KW - Genetics KW - Hirschsprung's disease KW - RET proto-oncogene KW - Somatic mutation SP - 258-61; discussion 261 JF - Journal of pediatric surgery JO - J Pediatr Surg VL - 49 IS - 2 N2 - BACKGROUND: RET proto-oncogene intron 1 variations [e.g. SNP1 (rs2506004) and SNP2 (rs 2435357)] have been shown to be etiologically important in the pathogenesis of Hirschsprung's disease (HSCR). Although activating somatic RET rearrangements have been identified in certain tumours, this is the first study to confirm somatic gene variation in HSCR. METHODS: DNA was extracted from 53 paraffin embedded tissue samples (HSCR patients n=33, multiple levels n=17), and controls (n=3). Patients were grouped into aganglionic (Group 1), ganglionated (group 2), and transitional (group 3). PCR products of RET intron 1 were screened for genetic variation by semi-automated bi-directional sequencing analysis and matched to unaffected controls from the general population. Comparison was by Fishers exact test. P <0.05 was regarded as significant. RESULTS: HSCR patients included short segment (n=26), long segment colonic [(n=4 (24%)], and total colonic aganglionosis (n=3). RET intronic variations [SNP1 (rs2506004) or SNP2 (rs 2435357)] showed somatic homozygous in affected tissue in 9/12 (75%) Group 1 (aganglionic tissue) compared with 2/5 (40%) and 1/10 (10%) of groups 2 and 3 (P<0.001). Homozygous SNP2 variation was observed in all long segment versus 4/10 short segment. 50% of the short segment cases showing homozygous SNP 1 variation. CONCLUSION: We report somatic mutations in the RET intron 1 region of affected HSCR tissue, confirming for the first time that somatic mutations are present in aganglionic tissue and may promote local aganglionosis through deregulated receptor activity. Detailed understanding of the somatic genetic events that drive congenital aganglionosis may have bearing on diagnosis and therapy. SN - 1531-5037 UR - https://www.unboundmedicine.com/medline/citation/24528961/Tissue_specific_somatic_mutations_and_aganglionosis_in_Hirschsprung's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3468(13)00895-6 DB - PRIME DP - Unbound Medicine ER -