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2018 ; 7
(7
): 55
Nephropedia Template TP
gab.com Text
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Deep sequencing and pathway-focused analysis revealed multigene oncodriver
signatures predicting survival outcomes in advanced colorectal cancer
#MMPMID30032163
De Nicola F
; Goeman F
; Pallocca M
; Sperati F
; Pizzuti L
; Melucci E
; Casini B
; Amoreo CA
; Gallo E
; Diodoro MG
; Buglioni S
; Mazzotta M
; Vici P
; Sergi D
; Di Lauro L
; Barba M
; Pescarmona E
; Ciliberto G
; De Maria R
; Fanciulli M
; Maugeri-Saccà M
Oncogenesis
2018[Jul]; 7
(7
): 55
PMID30032163
show ga
Genomic technologies are reshaping the molecular landscape of colorectal cancer
(CRC), revealing that oncogenic driver mutations (APC and TP53) coexist with
still underappreciated genetic events. We hypothesized that mutational analysis
of CRC-linked genes may provide novel information on the connection between
genetically-deregulated pathways and clinical outcomes. We performed
next-generation sequencing (NGS) analysis of 16 recurrently mutated genes in CRC
exploiting tissue specimens from 98 advanced CRC patients. Multiple
correspondence analysis (MCA) was used to identify gene sets characterizing
negative and positive outliers (patients in the lowest and highest quartile of
progression-free survival, PFS). Variables potentially affecting PFS and overall
survival (OS) were tested in univariate and multivariate Cox proportional hazard
models. Sensitivity analyses and resampling were used to assess the robustness of
genomic predictors. MCA revealed that APC and TP53 mutations were close to the
negative outlier group, whereas mutations in other WNT pathway genes were in
proximity of the positive outliers. Reasoning that genetic alterations interact
epistatically, producing greater or weaker consequences in combination than when
individually considered, we tested whether patients whose tumors carried a
genetic background characterized by APC and TP53 mutations without coexisting
mutations in other WNT genes (AMER1, FBXW7, TCF7L2, CTNNB1, SOX9) had adverse
survival outcomes. With this approach, we identified two oncodriver signatures
(ODS1 and ODS2) associated with shorter PFS (ODS1 multivariate Cox for PFS: HR
2.16, 95%CI: 1.28-3.64, p?=?0.004; ODS2 multivariate Cox for PFS: HR 2.61, 95%CI:
1.49-4.58, p?=?0.001). Clinically-focused and molecularly-focused sensitivity
analyses, resampling, and reclassification of mutations confirmed the stability
of ODS1/2. Moreover, ODS1/2 negatively impacted OS. Collectively, our results
point to co-occurring driver mutations as an adverse molecular factor in advanced
CRC. This relationship depends on a broader genetic context highlighting the
importance of genetic interactions.