Genomic landscape of metastatic colorectal cancer.
Response to drug therapy in individual colorectal cancer (CRC) patients is associated with tumour biology. Here we describe the genomic landscape of tumour samples of a homogeneous well-annotated series of patients with metastatic CRC (mCRC) of two phase III clinical trials, CAIRO and CAIRO2. DNA copy number aberrations of 349 patients are determined. Within three treatment arms, 194 chromosomal subregions are associated with progression-free survival (PFS; uncorrected single-test P-values <0.005). These subregions are filtered for effect on messenger RNA expression, using an independent data set from The Cancer Genome Atlas which returned 171 genes. Three chromosomal regions are associated with a significant difference in PFS between treatment arms with or without irinotecan. One of these regions, 6q16.1-q21, correlates in vitro with sensitivity to SN-38, the active metabolite of irinotecan. This genomic landscape of mCRC reveals a number of DNA copy number aberrations associated with response to drug therapy.
Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Josien C
JC
Haan
Department of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Mariette
M
Labots
Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Christian
C
Rausch
Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Miriam
M
Koopman
Department of Medical Oncology, Radboud University Medical Centre, Route 452, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Jolien
J
Tol
Department of Pathology, Radboud University Medical Centre, Huispost 824, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Leonie J M
LJ
Mekenkamp
Department of Epidemiology and Biostatistics, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Mark A
MA
van de Wiel
Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Danielle
D
Israeli
Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Hendrik F
HF
van Essen
Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Nicole C T
NC
van Grieken
Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Quirinus J M
QJ
Voorham
Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Linda J W
LJ
Bosch
Oncology Biomarker Development, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 USA.
Xueping
X
Qu
Oncology Biomarker Development, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 USA.
Omar
O
Kabbarah
Department of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Henk M W
HM
Verheul
Department of Pathology, Radboud University Medical Centre, Huispost 824, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Iris D
ID
Nagtegaal
Department of Medical Oncology, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands.
Cornelis J A
CJ
Punt
Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Bauke
B
Ylstra
Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Gerrit A
GA
Meijer
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D001271:Atlases as Topic; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D056915:DNA Copy Number Variations / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D016896:Treatment Outcome
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin