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Inactivation of promoter 1B of APC causes partial gene silencing: evidence for a significant role of the promoter in regulation and causative of familial adenomatous polyposis

Rohlin, A.; Engwall, Y.; Fritzell, K.; Goransson, K.; Bergsten, A.; Einbeigi, Z.; Nilbert, Mef LU ; Karlsson, P.; Bjork, J. and Nordling, M. (2011) In Oncogene 30(50). p.4977-4989
Abstract
Familial adenomatous polyposis (FAP) is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Two promoters, 1A and 1B, have been recognized in APC, and 1B is thought to have a minor role in the regulation of the gene. We have identified a novel deletion encompassing half of this promoter in the largest family (Family 1) of the Swedish Polyposis Registry. The mutation leads to an imbalance in allele-specific expression of APC, and transcription from promoter 1B was highly impaired in both normal colorectal mucosa and blood from mutation carriers. To establish the significance of promoter 1B in normal colorectal mucosa (from controls), expression levels of specific transcripts from each of the promoters, 1A and 1B, were... (More)
Familial adenomatous polyposis (FAP) is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Two promoters, 1A and 1B, have been recognized in APC, and 1B is thought to have a minor role in the regulation of the gene. We have identified a novel deletion encompassing half of this promoter in the largest family (Family 1) of the Swedish Polyposis Registry. The mutation leads to an imbalance in allele-specific expression of APC, and transcription from promoter 1B was highly impaired in both normal colorectal mucosa and blood from mutation carriers. To establish the significance of promoter 1B in normal colorectal mucosa (from controls), expression levels of specific transcripts from each of the promoters, 1A and 1B, were examined, and the expression from 1B was significantly higher compared with 1A. Significant amounts of transcripts generated from promoter 1B were also determined in a panel of 20 various normal tissues examined. In FAP-related tumors, the APC germline mutation is proposed to dictate the second hit. Mutations leaving two or three out of seven 20-amino-acid repeats in the central domain of APC intact seem to be required for tumorigenesis. We examined adenomas from mutation carriers in Family 1 for second hits in the entire gene without any findings, however, loss of the residual expression of the deleterious allele was observed. Three major conclusions of significant importance in relation to the function of APC can be drawn from this study; (i) germline inactivation of promoter 1B is disease causing in FAP; (ii) expression of transcripts from promoter 1B is generated at considerable higher levels compared with 1A, demonstrating a hitherto unknown importance of 1B; (iii) adenoma formation in FAP, caused by impaired function of promoter 1B, does not require homozygous inactivation of APC allowing for alternative genetic models as basis for adenoma formation. Oncogene (2011) 30, 4977-4989; doi:10.1038/onc.2011.201; published online 6 June 2011 (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
familial adenomatous ployposis, APC, mutation, promoter, Q-PCR
in
Oncogene
volume
30
issue
50
pages
4977 - 4989
publisher
Nature Publishing Group
external identifiers
  • wos:000298346500006
  • scopus:83555174494
ISSN
1476-5594
DOI
10.1038/onc.2011.201
language
English
LU publication?
yes
id
af77457a-fccf-4ce5-b234-1994b28f5f7b (old id 2333182)
date added to LUP
2012-02-01 07:37:30
date last changed
2017-10-29 03:07:10
@article{af77457a-fccf-4ce5-b234-1994b28f5f7b,
  abstract     = {Familial adenomatous polyposis (FAP) is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Two promoters, 1A and 1B, have been recognized in APC, and 1B is thought to have a minor role in the regulation of the gene. We have identified a novel deletion encompassing half of this promoter in the largest family (Family 1) of the Swedish Polyposis Registry. The mutation leads to an imbalance in allele-specific expression of APC, and transcription from promoter 1B was highly impaired in both normal colorectal mucosa and blood from mutation carriers. To establish the significance of promoter 1B in normal colorectal mucosa (from controls), expression levels of specific transcripts from each of the promoters, 1A and 1B, were examined, and the expression from 1B was significantly higher compared with 1A. Significant amounts of transcripts generated from promoter 1B were also determined in a panel of 20 various normal tissues examined. In FAP-related tumors, the APC germline mutation is proposed to dictate the second hit. Mutations leaving two or three out of seven 20-amino-acid repeats in the central domain of APC intact seem to be required for tumorigenesis. We examined adenomas from mutation carriers in Family 1 for second hits in the entire gene without any findings, however, loss of the residual expression of the deleterious allele was observed. Three major conclusions of significant importance in relation to the function of APC can be drawn from this study; (i) germline inactivation of promoter 1B is disease causing in FAP; (ii) expression of transcripts from promoter 1B is generated at considerable higher levels compared with 1A, demonstrating a hitherto unknown importance of 1B; (iii) adenoma formation in FAP, caused by impaired function of promoter 1B, does not require homozygous inactivation of APC allowing for alternative genetic models as basis for adenoma formation. Oncogene (2011) 30, 4977-4989; doi:10.1038/onc.2011.201; published online 6 June 2011},
  author       = {Rohlin, A. and Engwall, Y. and Fritzell, K. and Goransson, K. and Bergsten, A. and Einbeigi, Z. and Nilbert, Mef and Karlsson, P. and Bjork, J. and Nordling, M.},
  issn         = {1476-5594},
  keyword      = {familial adenomatous ployposis,APC,mutation,promoter,Q-PCR},
  language     = {eng},
  number       = {50},
  pages        = {4977--4989},
  publisher    = {Nature Publishing Group},
  series       = {Oncogene},
  title        = {Inactivation of promoter 1B of APC causes partial gene silencing: evidence for a significant role of the promoter in regulation and causative of familial adenomatous polyposis},
  url          = {http://dx.doi.org/10.1038/onc.2011.201},
  volume       = {30},
  year         = {2011},
}