Tissue specific somatic mutations and aganglionosis in Hirschsprung's disease.

[hirschsprung disease]

RET proto-oncogene intron 1 variations [e .g . SNP 1 (rs 2506004 ) and SNP 2 (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 .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 .HSCR patients included short segment (n =26 ), long segment colonic [(n =4 (24 %)], and total colonic aganglionosis (n =3 ). RET intronic variations [SNP 1 (rs 2506004 ) or SNP 2 (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 SNP 2 variation was observed in all long segment versus 4 /10 short segment . 50 % of the short segment cases showing homozygous SNP 1 variation .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 .

Diseases
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Diseases presenting "long segment" symptom

hirschsprung disease

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