Integrative approach for prioritizing cancer genes in sporadic colon cancer.
The current multistep carcinogenesis models of colon cancer do not fully capture the genetic heterogeneity of the disease, which is additionally complicated by the presence of passenger and driver genetic alterations. The aim of this study was to select in the context of this significant heterogeneity additional genes functionally related to colon cancer development. High-throughput copy number and gene expression data of 36 microsatellite stable sporadic colon cancers resected from patients of a single institution characterized for mutations in APC, KRAS, TP53 and loss of 18q were analyzed. Genes whose expression correlated with the underlying copy number pattern were selected, and their association with the above listed mutations and overall survival was evaluated. Gain of 20q was strongly associated with TP53 mutation, and overall survival with alterations on 7p, 8p, 13q, 18q, and 20q. An association with 18q loss and gain of 8q24 was also observed. New candidate genes with a potential role in colon cancer are PLCG1 on 20q, DBC1 on 8q21, and NDGR1 on 8p24. In addition, an unexpected pattern of loss and mutability was found in the region upstream of the KRAS gene. By integrating copy number alterations with gene expression and mutations in colon cancer associated genes, we have developed a strategy that identifies previously known molecular features and additional players in the molecular landscape of colon cancer.
Reid
James F
JF
Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori Milano, Italy.
Gariboldi
Manuela
M
Sokolova
Viktorija
V
Capobianco
Patrizia
P
Lampis
Andrea
A
Perrone
Federica
F
Signoroni
Stefano
S
Costa
Aurora
A
Leo
Ermanno
E
Pilotti
Silvana
S
Pierotti
Marco A
MA
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001185:Artificial Intelligence; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D043171:Chromosomal Instability; D002887:Chromosomes, Human, Pair 18; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins