Abstract
Despite global progress in research, improved screening and refined treatment strategies, colorectal cancer (CRC) remains as the third most common malignancy. As each type of cancer is different and exhibits unique alteration patterns, identifying and characterizing gene alterations in CRC that may serve as biomarkers might help to improve diagnosis, prognosis and predict potential response to therapy. With the emergence of next generation sequencing technologies (NGS), it is now possible to extensively and rapidly identify the gene profile of individual tumors. In this study, we aimed to identify actionable somatic alterations in Dukes’ B and C in CRC via NGS. Targeted sequencing of 409 cancer-related genes using the Ion AmpliseqTM Comprehensive Cancer Panel was performed on genomic DNA obtained from paired fresh frozen tissues, cancer and normal, of Dukes’ B (n = 10) and Dukes’ C (n = 9) CRC. The sequencing results were analyzed using Torrent Suite, annotated using ANNOVAR and validated using Sanger sequencing. A total of 141 somatic non-synonymous sequence variations were identified in 86 genes. Among these, 64 variants (45%) were predicted to be deleterious, 38 variants (27%) possibly deleterious while the other 39 variants (28%) have low or neutral protein impact. Seventeen genes have alterations with frequencies of ≥10% in the patient cohort and with 14 overlapped genes in both Dukes’ B and C. The adenomatous polyposis coli gene (APC) was the most frequently altered gene in both groups (n = 6 in Dukes’ B and C). In addition, TP53 was more frequently altered in Dukes’ C (n = 7) compared to Dukes’ B (n = 4). Ten variants in APC, namely p.R283∗, p.N778fs, p.R805∗, p.Y935fs, p.E941fs, p.E1057∗, p.I1401fs, p.Q1378∗, p.E1379∗, and p.A1485fs were predicted to be driver variants. APC remains as the most frequently altered gene in the intermediate stages of CRC. Wnt signaling pathway is the major affected pathway followed by P53, RAS, TGF-β, and PI3K signaling. We reported the alteration profiles in each of the patient which has the potential to affect the clinical decision. We believe that this study will add further to the understanding of CRC molecular landscape.
Highlights
MATERIALS AND METHODSColorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide (Siegel et al, 2016)
Researchers are still debating the role of TP53 alterations as prognostic indicators, as some have reported that overexpression of TP53 with elevated serum carcinoembryonic antigen (CEA) or carbohydrate antigen 199 (CA199) levels is significantly associated with poor outcome [median time from progression to death (TTD) for CEA ≥ 5 U/ml and P53 positive was 23.2 months
SYNE1 have been reported in glioblastoma our CRC patients (7/19) and this is concordant with a study (GBM) where these alterations were significantly correlated with the overexpression of several known GBM survival genes (Masica and Karchin, 2011) and the polymorphism of SYNE1 was associated with an increased risk of invasive ovarian cancer, with a per-T-allele odds ratio (OR) of 1.24 [95% confidence interval (CI), 1.06–1.44, P = 0.006] (Doherty et al, 2010)
Summary
MATERIALS AND METHODSColorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide (Siegel et al, 2016). According to Lim (2014), the cumulative lifetime risk of developing CRC for Malaysians was 1:38 in men and 1:50 in women. Survival rate of CRC is highly dependent on the stage of disease at diagnosis (Jemal et al, 2011). The 5-year survival rate for early stage is 60–95% but this dramatically decreases to 35% for those with lymph nodes involvement, indicating that early screening and treatment are crucial to improve management of CRC patients (Sengupta et al, 2008). Dukes’ staging (Dukes, 1932) and TNM classification (Version 7) (Edge et al, 2009) are the two staging systems used in CRC worldwide. Current standard therapies for CRC patients depend on the stages. Due to heterogeneity nature of cancers, clinical outcome of patients with the same histo-clinical staging could differ
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