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Polymorphisms in the mitochondrial oxidative phosphorylation chain genes as prognostic markers for colorectal cancer.

Lascorz J, Bevier M, Schönfels WV, Kalthoff H, Aselmann H, Beckmann J, Egberts J, Buch S, Becker T, Schreiber S, Hampe J, Hemminki K, Försti A, Schafmayer C - BMC Med. Genet. (2012)

Bottom Line: Two SNPs in the 3' untranslated region of UQCRB (complex III), rs7836698 and rs10504961, were associated with overall survival (HR = 0.52, 95% CI 0.32-0.85 and HR = 0.64, 95% CI 0.42-0.99, for TT carriers).Two SNPs in COX6B1 (complex IV) were associated with lymph node metastasis in a dominant model (rs6510502, OR = 1.75, 95% CI 1.20-2.57; rs10420252, OR = 1.68, 95% CI 1.11-2.53); rs6510502 was associated also with distant metastasis (OR = 1.67, 95% CI 1.09-2.56 in a dominant model).Additional studies replicating the presented findings are needed.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, Heidelberg, 69120, Germany.

ABSTRACT

Background: Currently, the TNM classification of malignant tumours based on clinicopathological staging remains the standard for colorectal cancer (CRC) prognostication. Recently, we identified the mitochondrial oxidative phosphorylation chain as a consistently overrepresented category in the published gene expression profiling (GEP) studies on CRC prognosis.

Methods: We evaluated associations of putative regulatory single nucleotide polymorphisms (SNPs) in genes from the oxidative phosphorylation chain with survival and disease prognosis in 613 CRC patients from Northern Germany (PopGen cohort).

Results: Two SNPs in the 3' untranslated region of UQCRB (complex III), rs7836698 and rs10504961, were associated with overall survival (HR = 0.52, 95% CI 0.32-0.85 and HR = 0.64, 95% CI 0.42-0.99, for TT carriers). These associations were restricted to the group of patients with cancer located in the colon (HR = 0.42, 95% CI 0.22-0.82 and HR = 0.46, 95% CI 0.25-0.83). Multivariate analysis indicated that both markers might act as independent prognostic markers. Additionally, the TT carriers were ~2 times more likely to develop tumours in the colon than in the rectum. Two SNPs in COX6B1 (complex IV) were associated with lymph node metastasis in a dominant model (rs6510502, OR = 1.75, 95% CI 1.20-2.57; rs10420252, OR = 1.68, 95% CI 1.11-2.53); rs6510502 was associated also with distant metastasis (OR = 1.67, 95% CI 1.09-2.56 in a dominant model).

Conclusions: This is the first report suggesting that markers in genes from the mitochondrial oxidative chain might be prognostic factors for CRC. Additional studies replicating the presented findings are needed.

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Kaplan-Meier estimates of CRC specific survival (months) according to UQCRB genotypes, (a) rs7836698, all CRC patients (n = 606), log rank p value = 0.07, (b) rs7836698, all patients diagnosed with colon cancer (n = 324), log rank p value = 0.05, (c) rs10504961, all CRC patients (n = 606), log rank p value = 0.55, and (d) rs10504961, all patients diagnosed with colon cancer (n = 324), log rank p value = 0.06.
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Figure 1: Kaplan-Meier estimates of CRC specific survival (months) according to UQCRB genotypes, (a) rs7836698, all CRC patients (n = 606), log rank p value = 0.07, (b) rs7836698, all patients diagnosed with colon cancer (n = 324), log rank p value = 0.05, (c) rs10504961, all CRC patients (n = 606), log rank p value = 0.55, and (d) rs10504961, all patients diagnosed with colon cancer (n = 324), log rank p value = 0.06.

Mentions: The two polymorphisms in the 3′-UTR region of UQCRB (complex III) showed association with CRC survival (Table 3 and Additional file 1: Table S2). The marker rs7836698 was statistically significantly associated with a decreased risk of death due to CRC (HR = 0.53, 95% CI 0.31–0.91 for TT), or due to any cause (HR = 0.52, 95% CI 0.32–0.85). For rs10504961, only the association with overall survival was statistically significant (HR = 0.64, 95% CI 0.42–0.99 for TT). Interestingly, for both UQCRB polymorphisms, the TT carriers were more likely to develop tumours in the colon than in the rectum, with ORs of 2.02 (95% CI 1.24–3.28) for rs7836698 (TT vs. CC) and 1.74 (95% CI 1.08–2.78) for rs10504961 (TT vs. CC). When survival was analysed according to the cancer site, both SNPs showed association exclusively in the group of patients with cancer located in the colon (HR for overall survival 0.42, 95% CI 0.22–0.82 for rs7836698 TT carriers and 0.46, 95% CI 0.25–0.83 for rs10504961 TT carriers), but not in the rectum (Table 3). The Kaplan-Meier survival curves representing the survival rates of the patients according to their genotypes, as well as the P values for the log-rank test are presented in Figure 1.


Polymorphisms in the mitochondrial oxidative phosphorylation chain genes as prognostic markers for colorectal cancer.

Lascorz J, Bevier M, Schönfels WV, Kalthoff H, Aselmann H, Beckmann J, Egberts J, Buch S, Becker T, Schreiber S, Hampe J, Hemminki K, Försti A, Schafmayer C - BMC Med. Genet. (2012)

Kaplan-Meier estimates of CRC specific survival (months) according to UQCRB genotypes, (a) rs7836698, all CRC patients (n = 606), log rank p value = 0.07, (b) rs7836698, all patients diagnosed with colon cancer (n = 324), log rank p value = 0.05, (c) rs10504961, all CRC patients (n = 606), log rank p value = 0.55, and (d) rs10504961, all patients diagnosed with colon cancer (n = 324), log rank p value = 0.06.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3420261&req=5

Figure 1: Kaplan-Meier estimates of CRC specific survival (months) according to UQCRB genotypes, (a) rs7836698, all CRC patients (n = 606), log rank p value = 0.07, (b) rs7836698, all patients diagnosed with colon cancer (n = 324), log rank p value = 0.05, (c) rs10504961, all CRC patients (n = 606), log rank p value = 0.55, and (d) rs10504961, all patients diagnosed with colon cancer (n = 324), log rank p value = 0.06.
Mentions: The two polymorphisms in the 3′-UTR region of UQCRB (complex III) showed association with CRC survival (Table 3 and Additional file 1: Table S2). The marker rs7836698 was statistically significantly associated with a decreased risk of death due to CRC (HR = 0.53, 95% CI 0.31–0.91 for TT), or due to any cause (HR = 0.52, 95% CI 0.32–0.85). For rs10504961, only the association with overall survival was statistically significant (HR = 0.64, 95% CI 0.42–0.99 for TT). Interestingly, for both UQCRB polymorphisms, the TT carriers were more likely to develop tumours in the colon than in the rectum, with ORs of 2.02 (95% CI 1.24–3.28) for rs7836698 (TT vs. CC) and 1.74 (95% CI 1.08–2.78) for rs10504961 (TT vs. CC). When survival was analysed according to the cancer site, both SNPs showed association exclusively in the group of patients with cancer located in the colon (HR for overall survival 0.42, 95% CI 0.22–0.82 for rs7836698 TT carriers and 0.46, 95% CI 0.25–0.83 for rs10504961 TT carriers), but not in the rectum (Table 3). The Kaplan-Meier survival curves representing the survival rates of the patients according to their genotypes, as well as the P values for the log-rank test are presented in Figure 1.

Bottom Line: Two SNPs in the 3' untranslated region of UQCRB (complex III), rs7836698 and rs10504961, were associated with overall survival (HR = 0.52, 95% CI 0.32-0.85 and HR = 0.64, 95% CI 0.42-0.99, for TT carriers).Two SNPs in COX6B1 (complex IV) were associated with lymph node metastasis in a dominant model (rs6510502, OR = 1.75, 95% CI 1.20-2.57; rs10420252, OR = 1.68, 95% CI 1.11-2.53); rs6510502 was associated also with distant metastasis (OR = 1.67, 95% CI 1.09-2.56 in a dominant model).Additional studies replicating the presented findings are needed.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, Heidelberg, 69120, Germany.

ABSTRACT

Background: Currently, the TNM classification of malignant tumours based on clinicopathological staging remains the standard for colorectal cancer (CRC) prognostication. Recently, we identified the mitochondrial oxidative phosphorylation chain as a consistently overrepresented category in the published gene expression profiling (GEP) studies on CRC prognosis.

Methods: We evaluated associations of putative regulatory single nucleotide polymorphisms (SNPs) in genes from the oxidative phosphorylation chain with survival and disease prognosis in 613 CRC patients from Northern Germany (PopGen cohort).

Results: Two SNPs in the 3' untranslated region of UQCRB (complex III), rs7836698 and rs10504961, were associated with overall survival (HR = 0.52, 95% CI 0.32-0.85 and HR = 0.64, 95% CI 0.42-0.99, for TT carriers). These associations were restricted to the group of patients with cancer located in the colon (HR = 0.42, 95% CI 0.22-0.82 and HR = 0.46, 95% CI 0.25-0.83). Multivariate analysis indicated that both markers might act as independent prognostic markers. Additionally, the TT carriers were ~2 times more likely to develop tumours in the colon than in the rectum. Two SNPs in COX6B1 (complex IV) were associated with lymph node metastasis in a dominant model (rs6510502, OR = 1.75, 95% CI 1.20-2.57; rs10420252, OR = 1.68, 95% CI 1.11-2.53); rs6510502 was associated also with distant metastasis (OR = 1.67, 95% CI 1.09-2.56 in a dominant model).

Conclusions: This is the first report suggesting that markers in genes from the mitochondrial oxidative chain might be prognostic factors for CRC. Additional studies replicating the presented findings are needed.

Show MeSH
Related in: MedlinePlus