TY - JOUR
T1 - Comprehensive Mutation Analysis in Colorectal Flat Adenomas
AU - Voorham, Quirinus J. M.
AU - Carvalho, Beatriz
AU - Spiertz, Angela J.
AU - Claes, Bart
AU - Mongera, Sandra
AU - van Grieken, Nicole C T
AU - Grabsch, Heike
AU - Kliment, Martin
AU - Rembacken, Bjorn
AU - van de Wiel, Mark A.
AU - Quirke, Philip
AU - Mulder, Chris J. J.
AU - Lambrechts, Diether
AU - van Engeland, Manon
AU - Meijer, Gerrit A.
PY - 2012/7/27
Y1 - 2012/7/27
N2 - Background: Flat adenomas are a subgroup of colorectal adenomas that have been associated with a distinct biology and a more aggressive clinical behavior compared to their polypoid counterparts. In the present study, we aimed to compare the mutation spectrum of 14 cancer genes, between these two phenotypes. Methods: A consecutive series of 106 flat and 93 polypoid adenomas was analyzed retrospectively for frequently occurring mutations in "hot spot'' regions of KRAS, BRAF, PIK3CA and NRAS, as well as selected mutations in CTNNB1 (beta-catenin), EGFR, FBXW7 (CDC4), PTEN, STK11, MAP2K4, SMAD4, PIK3R1 and PDGFRA using a high-throughput genotyping technique. Additionally, APC was analyzed using direct sequencing. Results: APC mutations were more frequent in polypoid adenomas compared to flat adenomas (48.5% versus 30.3%, respectively, p = 0.02). Mutations in KRAS, BRAF, NRAS, FBXW7 and CTNNB1 showed similar frequencies in both phenotypes. Between the different subtypes of flat adenomas (0-IIa, LST-F and LST-G) no differences were observed for any of the investigated genes. Conclusion: The lower APC mutation rate in flat adenomas compared to polypoid adenomas suggests that disruption of the Wnt-pathway may occur via different mechanisms in these two phenotypes. Furthermore, in contrast to previous observations our results in this large well-defined sample set indicate that there is no significant association between the different morphological phenotypes and mutations in key genes of the RAS-RAF-MAPK pathway.
AB - Background: Flat adenomas are a subgroup of colorectal adenomas that have been associated with a distinct biology and a more aggressive clinical behavior compared to their polypoid counterparts. In the present study, we aimed to compare the mutation spectrum of 14 cancer genes, between these two phenotypes. Methods: A consecutive series of 106 flat and 93 polypoid adenomas was analyzed retrospectively for frequently occurring mutations in "hot spot'' regions of KRAS, BRAF, PIK3CA and NRAS, as well as selected mutations in CTNNB1 (beta-catenin), EGFR, FBXW7 (CDC4), PTEN, STK11, MAP2K4, SMAD4, PIK3R1 and PDGFRA using a high-throughput genotyping technique. Additionally, APC was analyzed using direct sequencing. Results: APC mutations were more frequent in polypoid adenomas compared to flat adenomas (48.5% versus 30.3%, respectively, p = 0.02). Mutations in KRAS, BRAF, NRAS, FBXW7 and CTNNB1 showed similar frequencies in both phenotypes. Between the different subtypes of flat adenomas (0-IIa, LST-F and LST-G) no differences were observed for any of the investigated genes. Conclusion: The lower APC mutation rate in flat adenomas compared to polypoid adenomas suggests that disruption of the Wnt-pathway may occur via different mechanisms in these two phenotypes. Furthermore, in contrast to previous observations our results in this large well-defined sample set indicate that there is no significant association between the different morphological phenotypes and mutations in key genes of the RAS-RAF-MAPK pathway.
U2 - 10.1371/journal.pone.0041963
DO - 10.1371/journal.pone.0041963
M3 - Article
C2 - 22848674
VL - 7
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 7
M1 - e41963
ER -