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Expanding the genotype–phenotype spectrum in hereditary colorectal cancer by gene panel testing

Rohlin, Anna LU ; Rambech, Eva LU ; Kvist, Anders LU ; Törngren, Therese LU ; Eiengård, Frida; Lundstam, Ulf; Zagoras, Theofanis; Gebre-Medhin, Samuel LU ; Borg, Åke LU and Björk, Jan, et al. (2017) In Familial Cancer 16(2). p.195-203
Abstract

Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Targeted NGS-based sequencing of the whole gene regions including introns of the 19 genes was used. The individuals had a family history of CRC or had a phenotype consistent with a known CRC syndrome. The purpose of the study was to demonstrate the diagnostic difficulties... (More)

Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Targeted NGS-based sequencing of the whole gene regions including introns of the 19 genes was used. The individuals had a family history of CRC or had a phenotype consistent with a known CRC syndrome. The purpose of the study was to demonstrate the diagnostic difficulties linked to genotype-phenotype diversity and the benefits of using a gene panel. Pathogenicity classification was carried out on 46 detected variants. In total we detected sixteen pathogenic or likely pathogenic variants and 30 variants of unknown clinical significance. Four of the pathogenic or likely pathogenic variants were found in BMPR1A in patients with unexplained familial adenomatous polyposis or atypical adenomatous polyposis, which extends the genotype-phenotype spectrum for this gene. Nine patients had more than one variant remaining after the filtration, including three with truncating mutations in BMPR1A, PMS2 and AXIN2. CNVs were found in three patients, in upstream regions of SMAD4, MSH3 and CTNNB1, and one additional individual harbored a 24.2 kb duplication in CDH1 intron1.

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publication status
published
subject
keywords
Colorectal cancer, Familial adenomatous polyposis, FAP, Gene panel, Hereditary, Lynch syndrome
in
Familial Cancer
volume
16
issue
2
pages
195 - 203
publisher
Kluwer
external identifiers
  • scopus:84989211594
  • wos:000398494700005
ISSN
1389-9600
DOI
10.1007/s10689-016-9934-0
language
English
LU publication?
yes
id
c5daada8-9860-4b25-816a-1bce4a5fbf83
date added to LUP
2016-10-19 09:34:12
date last changed
2018-01-07 11:31:23
@article{c5daada8-9860-4b25-816a-1bce4a5fbf83,
  abstract     = {<p>Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Targeted NGS-based sequencing of the whole gene regions including introns of the 19 genes was used. The individuals had a family history of CRC or had a phenotype consistent with a known CRC syndrome. The purpose of the study was to demonstrate the diagnostic difficulties linked to genotype-phenotype diversity and the benefits of using a gene panel. Pathogenicity classification was carried out on 46 detected variants. In total we detected sixteen pathogenic or likely pathogenic variants and 30 variants of unknown clinical significance. Four of the pathogenic or likely pathogenic variants were found in BMPR1A in patients with unexplained familial adenomatous polyposis or atypical adenomatous polyposis, which extends the genotype-phenotype spectrum for this gene. Nine patients had more than one variant remaining after the filtration, including three with truncating mutations in BMPR1A, PMS2 and AXIN2. CNVs were found in three patients, in upstream regions of SMAD4, MSH3 and CTNNB1, and one additional individual harbored a 24.2 kb duplication in CDH1 intron1.</p>},
  author       = {Rohlin, Anna and Rambech, Eva and Kvist, Anders and Törngren, Therese and Eiengård, Frida and Lundstam, Ulf and Zagoras, Theofanis and Gebre-Medhin, Samuel and Borg, Åke and Björk, Jan and Nilbert, Mef and Nordling, Margareta},
  issn         = {1389-9600},
  keyword      = {Colorectal cancer,Familial adenomatous polyposis,FAP,Gene panel,Hereditary,Lynch syndrome},
  language     = {eng},
  number       = {2},
  pages        = {195--203},
  publisher    = {Kluwer},
  series       = {Familial Cancer},
  title        = {Expanding the genotype–phenotype spectrum in hereditary colorectal cancer by gene panel testing},
  url          = {http://dx.doi.org/10.1007/s10689-016-9934-0},
  volume       = {16},
  year         = {2017},
}