Subsequently, we examined the predictive role of GALNT14 “TT” genotype in various clinical subgroups using Cox proportional hazard method (Figure 1). These data were further examined using the Kaplan–Meier plot with log-rank analysis. The “TT” and “non-TT” patients had distinguishable survival curves not only in all stage III CRC patients included but also in the following subgroups: age ≤65 years (Figure 2B, P = 0.012), men (Figure 2C, P = 0.011), CEA >5 ng/mL (Figure 2D, P = 0.013), left CRC (Figure 2E, P = 0.009), N2 stage (Figure 2F, P = 0.025), and mucinous histology (Figure 2G, P = 0.007).
Other Clinicopathological Predictors for RFS and OS
To identify other clinicopathological predictors for RFS and OS, univariate followed by multivariate Cox proportional hazard analysis was performed (Table 2). The CEA level (P = 0.030), tumor size (P = 0.012), surface area (P = 0.022), and N stage (P = 0.014) were associated with RFS by univariate analysis. After adjusting for the confounding factors, multivariate analysis showed that CEA level (P = 0.027) and N stage (P = 0.004) were independent predictors for RFS.
For OS, the GALNT14 “TT” genotype (P = 0.019), the T4 stage (P = 0.003), and the mucinous histology (P = 0.028) were associated with poor prognosis by univariate Cox proportional models. Multivariate analysis revealed that only T4 stage (P = 0.021) was the independent predictor for OS.
GALNT14 “TT” Genotype as an Independent Outcome Predictor in Clinical Subgroups
Because GALNT14 genotypes were associated with both T4 stage (Table 1) and OS (Figures 1 and 2), we subsequently examined the predictive value of GALNT14 “TT” genotype in the T4 stage patient subgroup (n = 66, Table 3). The result showed that “TT” genotype was the only independent predictor for RFS in this subgroup (Figure 2H, Cox P = 0.024, log-rank P = 0.007). For OS, the mucinous histology was the only unfavorable predictor (Cox P = 0.040, log-rank P = 0.021).
In addition to T4 stage subgroup, we also analyzed the prognosis predictive value of GALNT14 genotype in other clinical subgroups associated with poor OS (Figure 1). It was found that in patients with CEA >5 ng/mL (n = 94, supplementary Table 1, http://links.lww.com/MD/A919), “TT” genotype was the only unfavorable factor for OS (Cox P = 0.049). In patients with mucinous histology (n = 27, supplementary Table 2, http://links.lww.com/MD/A919), the “TT” genotype was the only unfavorable predictor for OS (Cox P = 0.037). Other analysis for the predictive value of GALNT14 genotype in clinical subgroups was given in supplementary Tables 3–6, http://links.lww.com/MD/A919.
At this time, routine adjuvant chemotherapeutic treatment is recommended for patients with high-risk stage II and stage III CRC. It has been documented that oxaliplatin-based adjuvant chemotherapy confers survival advantage in stage III CRC patients. However, no pretreatment prognostic molecular biomarkers for stage III CRC receiving oxaliplatin-based adjuvant chemotherapy regimen has been established until now. The present study demonstrated that the GALNT14 “TT” genotype was positively associated with T4 stage, a well-known poor prognostic predictor. Further analysis showed that the “TT” genotype was associated with poor OS in all included patients and several clinical subgroups, including age ≤65 years, men, CEA >5 ng/mL, left-side CRC, N2 stage, and mucinous histology.
In addition to GALNT14 “TT” genotype, several poor prognostic subgroups were identified including CEA >5 ng/mL, N2 stage, T4 stage, and mucinous histology. This is consistent with previous studies from other groups.1,16,17 To identify useful prognostic predictors within these subgroups, we further analyzed the RFS and OS with respect to the clinicopathological parameters and GALNT14 genotype. Intriguingly, GALNT14 was again identified as a valuable prognostic predictor in these subgroups. For patients in T4 stage, the “TT” genotype was significantly associated with poor RFS. For patients with CEA >5 ng/mL or mucinous histology, the “TT” genotype was the only predictor associated with poor OS.
Like many other cancers, development and progression of CRC are affected by multiple factors. Most research efforts have been focused on the underlying molecular mechanisms of CRC carcinogenesis, and a variety of candidate genetic markers with predictive value of outcome have been discovered by studying the cancerous tissues (e.g., KRAS expression, levels of DNA mismatch repair, 18q deletion, and p53 expression).7–9,18,19 However, personal genetic background might contribute greatly to this disease. Our study showed that patients with GALNT14 “TT” genotype had a higher rate to develop tumor invasion (T4 stage) and thus have an unfavorable OS. Furthermore, the “TT” genotype was associated with poor RFS in T4 stage patients. Thus, GALNT14 “TT” genotype has 2 major clinicopathological implications. First, tumors with GALNT14 “TT” genotype have more aggressive cancer invasion property during oncogenesis. Second, tumors with “TT” genotype may have decreased drug sensitivity to oxaliplatin, which is reflected from its association with poor RFS in T4 stage patients. Therefore, other more potent cytotoxic agents should be considered in patients with GALNT14 “TT” genotype.
Oxaliplatin is a platin analogue that has been widely used in treating a variety of solid tumors, especially in CRCs. It induces apoptosis and cell death through the inhibition of DNA replication by forming intrastrand cross-link DNA adducts.20 Several factors may affect the therapeutic outcome of oxaliplatin-based chemotherapy including genetic polymorphism. It has been demonstrated that metastatic CRC with the SNP located within excision repair cross-complementing rodent repair deficiency complementation group1 (ERCC1) codon 118C/T or T/T genotype was associated with worse survival,21–23 whereas other groups showed that metastatic CRC patients with the same genotype had better response or survival compared with C/C patients.24,25 Although the results on the predictive value of ERCC1 codon 118 polymorphism have been inconsistent, these studies raise the possibility that genetic SNP might play a role in therapeutic response. Our current study of GALNT14 genotype supported this view. Moreover, the gene product of GALNT14 is an enzyme that catalyzes O-glycosylation of many proteins including the DR-4 and -5. It has been reported that the cytotoxic effects of oxaliplatin in CRC can be enhanced by tenovin-6 through upregulating DR-5,14 suggesting that modulation of DR-mediated signaling may affect the effects of oxaliplatin-based chemotherapy. In this study, 1 convenient explanation for the GALNT14 genotypes–associated therapeutic outcomes is the differential intensities of DR-mediated apoptosis signaling between the “TT” and “non-TT” genotypes. However, because O-glycosylation is a body-wise process, it is unclear whether there are other unrecognized important glycoproteins involved. Moreover, several genetic alternations in colorectal cancerous tissues, such as 18q loss of heterozygosity, microsatellite instability, and large deletions in heat shock protein 110, have been proposed as candidate prognostic markers, but the association between GALNT14 genotypes and these genetic makers is unclear. Further studies to clarify these issues are needed.
This study had several limitations, including its retrospective nature, limited case number, and restriction of the sample to a Chinese population from a single medical center. Our eligibility criteria confined the treatment to oxaliplatin-based chemotherapies (mFOLFOX6 and XELOX) for interpretative clarity. Therefore, it may not pertain to other regimens not containing oxaliplatin. The decision of which oxaliplatin-based regimens to be used was not only dependent on clinical criteria but also on nonclinical considerations such as doctors’ decision and patients’ willingness. The age of patients in this cohort study was relatively young compared with other CRC cohort studies. This was because elderly CRC patients were more often willing to have chemotherapy via oral route than intravenous route. Despite all these drawbacks, our study results are considered useful in routine clinical practice.
In conclusion, GALNT14 “TT” genotype was correlated with T4 stage and associated with poor OS in stage III CRC patients receiving curative resection and adjuvant oxaliplatin-based chemotherapy. It was further associated with poor treatment outcome in subgroups of T4 stage, CEA >5 ng/mL, or mucinous histology. Taken together, GALNT14 genotype is a valuable prognostic predictor in advanced CRC.
The authors thank the staff members (Yen-Ling Chuang, Tzu-Chi Yu, Chien Chih Wang, and Hsiu Min Tseng) of the Liver Research Center and Tissue Bank in Linkou Chang Gung Memorial Hospital for their technical assistance. The authors also thank the volunteer technical work from Miss Cassandra Yeh.
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