TY - JOUR
T1 - Molecular characterization of colorectal adenomas reveals POFUT1 as a candidate driver of tumor progression
AU - In collaboration with the NGS-ProToCol Consortium
AU - Komor, Malgorzata A.
AU - de Wit, Meike
AU - van den Berg, Jose
AU - Martens de Kemp, Sanne R.
AU - Delis-van Diemen, Pien M.
AU - Bolijn, Anne S.
AU - Tijssen, Marianne
AU - Schelfhorst, Tim
AU - Piersma, Sander R.
AU - Chiasserini, Davide
AU - Sanders, Joyce
AU - Rausch, Christian
AU - Hoogstrate, Youri
AU - Stubbs, Andrew P.
AU - de Jong, Mark
AU - Jenster, Guido
AU - Carvalho, Beatriz
AU - Meijer, Gerrit A.
AU - Jimenez, Connie R.
AU - Fijneman, Remond J. A.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - Removal of colorectal adenomas is an effective strategy to reduce colorectal cancer (CRC) mortality rates. However, as only a minority of adenomas progress to cancer, such strategies may lead to overtreatment. The present study aimed to characterize adenomas by in-depth molecular profiling, to obtain insights into altered biology associated with the colorectal adenoma-to-carcinoma progression. We obtained low-coverage whole genome sequencing, RNA sequencing and tandem mass spectrometry data for 30 CRCs, 30 adenomas and 18 normal adjacent colon samples. These data were used for DNA copy number aberrations profiling, differential expression, gene set enrichment and gene-dosage effect analysis. Protein expression was independently validated by immunohistochemistry on tissue microarrays and in patient-derived colorectal adenoma organoids. Stroma percentage was determined by digital image analysis of tissue sections. Twenty-four out of 30 adenomas could be unambiguously classified as high risk (n = 9) or low risk (n = 15) of progressing to cancer, based on DNA copy number profiles. Biological processes more prevalent in high-risk than low-risk adenomas were related to proliferation, tumor microenvironment and Notch, Wnt, PI3K/AKT/mTOR and Hedgehog signaling, while metabolic processes and protein secretion were enriched in low-risk adenomas. DNA copy number driven gene-dosage effect in high-risk adenomas and cancers was observed for POFUT1, RPRD1B and EIF6. Increased POFUT1 expression in high-risk adenomas was validated in tissue samples and organoids. High POFUT1 expression was also associated with Notch signaling enrichment and with decreased goblet cells differentiation. In-depth molecular characterization of colorectal adenomas revealed POFUT1 and Notch signaling as potential drivers of tumor progression.
AB - Removal of colorectal adenomas is an effective strategy to reduce colorectal cancer (CRC) mortality rates. However, as only a minority of adenomas progress to cancer, such strategies may lead to overtreatment. The present study aimed to characterize adenomas by in-depth molecular profiling, to obtain insights into altered biology associated with the colorectal adenoma-to-carcinoma progression. We obtained low-coverage whole genome sequencing, RNA sequencing and tandem mass spectrometry data for 30 CRCs, 30 adenomas and 18 normal adjacent colon samples. These data were used for DNA copy number aberrations profiling, differential expression, gene set enrichment and gene-dosage effect analysis. Protein expression was independently validated by immunohistochemistry on tissue microarrays and in patient-derived colorectal adenoma organoids. Stroma percentage was determined by digital image analysis of tissue sections. Twenty-four out of 30 adenomas could be unambiguously classified as high risk (n = 9) or low risk (n = 15) of progressing to cancer, based on DNA copy number profiles. Biological processes more prevalent in high-risk than low-risk adenomas were related to proliferation, tumor microenvironment and Notch, Wnt, PI3K/AKT/mTOR and Hedgehog signaling, while metabolic processes and protein secretion were enriched in low-risk adenomas. DNA copy number driven gene-dosage effect in high-risk adenomas and cancers was observed for POFUT1, RPRD1B and EIF6. Increased POFUT1 expression in high-risk adenomas was validated in tissue samples and organoids. High POFUT1 expression was also associated with Notch signaling enrichment and with decreased goblet cells differentiation. In-depth molecular characterization of colorectal adenomas revealed POFUT1 and Notch signaling as potential drivers of tumor progression.
UR - http://www.scopus.com/inward/record.url?scp=85071611867&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ijc.32627
DO - https://doi.org/10.1002/ijc.32627
M3 - Article
C2 - 31411736
SN - 0020-7136
VL - 146
SP - 1979
EP - 1992
JO - International journal of cancer
JF - International journal of cancer
IS - 7
ER -