TY - JOUR
T1 - A systematic analysis of oncogenic gene fusions in primary colon cancer
AU - Kloosterman, Wigard P.
AU - Coebergh Van Den Braak, Robert R.J.
AU - Pieterse, Mark
AU - Van Roosmalen, Markus J.
AU - Sieuwerts, Anieta M.
AU - Stangl, Christina
AU - Brunekreef, Ronne
AU - Lalmahomed, Zarina S.
AU - Ooft, Salo
AU - Van Galen, Anne
AU - Smid, Marcel
AU - Lefebvre, Armel
AU - Zwartkruis, Fried
AU - Martens, John W.M.
AU - Foekens, John A.
AU - Biermann, Katharina
AU - Koudijs, Marco J.
AU - Ijzermans, Jan N.M.
AU - Voest, Emile E.
N1 - Publisher Copyright:
©2017 AACR.
PY - 2017/7/15
Y1 - 2017/7/15
N2 - Genomic rearrangements that give rise to oncogenic gene fusions can offer actionable targets for cancer therapy. Here we present a systematic analysis of oncogenic gene fusions among a clinically well-characterized, prospectively collected set of 278 primary colon cancers spanning diverse tumor stages and clinical outcomes. Gene fusions and somatic genetic variations were identified in fresh frozen clinical specimens by Illumina RNA-sequencing, the STAR fusion gene detection pipeline, and GATK RNA-seq variant calling. We considered gene fusions to be pathogenically relevant when recurrent, producing divergent gene expression (outlier analysis), or as functionally important (e.g., kinase fusions). Overall, 2.5% of all specimens were defined as harboring a relevant gene fusion (kinase fusions 1.8%). Novel configurations of BRAF, NTRK3, and RET gene fusions resulting from chromosomal translocations were identified. An R-spondin fusion was found in only one tumor (0.35%), much less than an earlier reported frequency of 10% in colorectal cancers. We also found a novel fusion involving USP9X-ERAS formed by chromothripsis and leading to high expression of ERAS, a constitutively active RAS protein normally expressed only in embryonic stem cells. This USP9X–ERAS fusion appeared highly oncogenic on the basis of its ability to activate AKT signaling. Oncogenic fusions were identified only in lymph node–negative tumors that lacked BRAF or KRAS mutations. In summary, we identified several novel oncogenic gene fusions in colorectal cancer that may drive malignant development and offer new targets for personalized therapy.
AB - Genomic rearrangements that give rise to oncogenic gene fusions can offer actionable targets for cancer therapy. Here we present a systematic analysis of oncogenic gene fusions among a clinically well-characterized, prospectively collected set of 278 primary colon cancers spanning diverse tumor stages and clinical outcomes. Gene fusions and somatic genetic variations were identified in fresh frozen clinical specimens by Illumina RNA-sequencing, the STAR fusion gene detection pipeline, and GATK RNA-seq variant calling. We considered gene fusions to be pathogenically relevant when recurrent, producing divergent gene expression (outlier analysis), or as functionally important (e.g., kinase fusions). Overall, 2.5% of all specimens were defined as harboring a relevant gene fusion (kinase fusions 1.8%). Novel configurations of BRAF, NTRK3, and RET gene fusions resulting from chromosomal translocations were identified. An R-spondin fusion was found in only one tumor (0.35%), much less than an earlier reported frequency of 10% in colorectal cancers. We also found a novel fusion involving USP9X-ERAS formed by chromothripsis and leading to high expression of ERAS, a constitutively active RAS protein normally expressed only in embryonic stem cells. This USP9X–ERAS fusion appeared highly oncogenic on the basis of its ability to activate AKT signaling. Oncogenic fusions were identified only in lymph node–negative tumors that lacked BRAF or KRAS mutations. In summary, we identified several novel oncogenic gene fusions in colorectal cancer that may drive malignant development and offer new targets for personalized therapy.
UR - http://www.scopus.com/inward/record.url?scp=85023745990&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-16-3563
DO - 10.1158/0008-5472.CAN-16-3563
M3 - Article
C2 - 28512242
AN - SCOPUS:85023745990
SN - 0008-5472
VL - 77
SP - 3814
EP - 3822
JO - Cancer research
JF - Cancer research
IS - 14
ER -