Pre-diagnostic leukocyte mitochondrial DNA copy number and colorectal cancer risk

Keming Yang, Xin Li, Michele R. Forman, Patrick O. Monahan, Bret H. Graham, Amit Joshi, Mingyang Song, Dong Hang, Shuji Ogino, Edward L. Giovannucci, Immaculata De Vivo, Andrew T. Chan, Hongmei Nan

Research output: Contribution to journalArticle

Abstract

Mitochondrial DNA (mtDNA) is susceptible to oxidative stress and mutation. Few epidemiological studies have assessed the relationship between mtDNA copy number (mtDNAcn) and risk of colorectal cancer (CRC), with inconsistent findings. In this study, we examined the association between pre-diagnostic leukocyte mtDNAcn and CRC risk in a case-control study of 324 female cases and 658 matched controls nested within the Nurses' Health Study (NHS). Relative mtDNAcn in peripheral blood leukocytes was measured by quantitative polymerase chain reaction-based assay. Conditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association of interest. Results showed lower log-mtDNAcn was significantly associated with increased risk of CRC, in a dose-dependent relationship (P for trend < 0.0001). Compared to the fourth quartile, multivariable-adjusted OR [95% confidence interval (CI)] was 1.10 (0.69, 1.76) for the third quartile, 1.40 (0.89, 2.19) for the second quartile and 2.19 (1.43, 3.35) for the first quartile. In analysis by anatomic subsite of CRC, we found a significant inverse association for proximal colon cancer [lowest versus highest quartile, multivariable-adjusted OR (95% CI) = 3.31 (1.70, 6.45), P for trend = 0.0003]. Additionally, stratified analysis according to the follow-up time since blood collection showed that the inverse association between mtDNAcn and CRC remained significant among individuals with ≥ 5 years' follow-up, and marginally significant among those with ≥ 10 years' follow-up since mtDNAcn testing, suggesting that mtDNAcn may serve as a long-term predictor for risk of CRC. In conclusion, pre-diagnostic leukocyte mtDNAcn was inversely associated with CRC risk. Further basic experimental studies are needed to explore the underlying biological mechanisms linking mtDNAcn to CRC carcinogenesis.

Original languageEnglish (US)
Pages (from-to)1462-1468
Number of pages7
JournalCarcinogenesis
Volume40
Issue number12
DOIs
StatePublished - Dec 31 2019

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Mitochondrial DNA
Colorectal Neoplasms
Leukocytes
Odds Ratio
Confidence Intervals
Logistic Models
Colonic Neoplasms
Case-Control Studies
Epidemiologic Studies
Carcinogenesis
Oxidative Stress
Nurses
Polymerase Chain Reaction
Mutation
Health

ASJC Scopus subject areas

  • Cancer Research

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Pre-diagnostic leukocyte mitochondrial DNA copy number and colorectal cancer risk. / Yang, Keming; Li, Xin; Forman, Michele R.; Monahan, Patrick O.; Graham, Bret H.; Joshi, Amit; Song, Mingyang; Hang, Dong; Ogino, Shuji; Giovannucci, Edward L.; De Vivo, Immaculata; Chan, Andrew T.; Nan, Hongmei.

In: Carcinogenesis, Vol. 40, No. 12, 31.12.2019, p. 1462-1468.

Research output: Contribution to journalArticle

Yang, K, Li, X, Forman, MR, Monahan, PO, Graham, BH, Joshi, A, Song, M, Hang, D, Ogino, S, Giovannucci, EL, De Vivo, I, Chan, AT & Nan, H 2019, 'Pre-diagnostic leukocyte mitochondrial DNA copy number and colorectal cancer risk', Carcinogenesis, vol. 40, no. 12, pp. 1462-1468. https://doi.org/10.1093/carcin/bgz159
Yang, Keming ; Li, Xin ; Forman, Michele R. ; Monahan, Patrick O. ; Graham, Bret H. ; Joshi, Amit ; Song, Mingyang ; Hang, Dong ; Ogino, Shuji ; Giovannucci, Edward L. ; De Vivo, Immaculata ; Chan, Andrew T. ; Nan, Hongmei. / Pre-diagnostic leukocyte mitochondrial DNA copy number and colorectal cancer risk. In: Carcinogenesis. 2019 ; Vol. 40, No. 12. pp. 1462-1468.
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abstract = "Mitochondrial DNA (mtDNA) is susceptible to oxidative stress and mutation. Few epidemiological studies have assessed the relationship between mtDNA copy number (mtDNAcn) and risk of colorectal cancer (CRC), with inconsistent findings. In this study, we examined the association between pre-diagnostic leukocyte mtDNAcn and CRC risk in a case-control study of 324 female cases and 658 matched controls nested within the Nurses' Health Study (NHS). Relative mtDNAcn in peripheral blood leukocytes was measured by quantitative polymerase chain reaction-based assay. Conditional logistic regression models were applied to estimate odds ratios (ORs) and 95{\%} confidence intervals (95{\%} CIs) for the association of interest. Results showed lower log-mtDNAcn was significantly associated with increased risk of CRC, in a dose-dependent relationship (P for trend < 0.0001). Compared to the fourth quartile, multivariable-adjusted OR [95{\%} confidence interval (CI)] was 1.10 (0.69, 1.76) for the third quartile, 1.40 (0.89, 2.19) for the second quartile and 2.19 (1.43, 3.35) for the first quartile. In analysis by anatomic subsite of CRC, we found a significant inverse association for proximal colon cancer [lowest versus highest quartile, multivariable-adjusted OR (95{\%} CI) = 3.31 (1.70, 6.45), P for trend = 0.0003]. Additionally, stratified analysis according to the follow-up time since blood collection showed that the inverse association between mtDNAcn and CRC remained significant among individuals with ≥ 5 years' follow-up, and marginally significant among those with ≥ 10 years' follow-up since mtDNAcn testing, suggesting that mtDNAcn may serve as a long-term predictor for risk of CRC. In conclusion, pre-diagnostic leukocyte mtDNAcn was inversely associated with CRC risk. Further basic experimental studies are needed to explore the underlying biological mechanisms linking mtDNAcn to CRC carcinogenesis.",
author = "Keming Yang and Xin Li and Forman, {Michele R.} and Monahan, {Patrick O.} and Graham, {Bret H.} and Amit Joshi and Mingyang Song and Dong Hang and Shuji Ogino and Giovannucci, {Edward L.} and {De Vivo}, Immaculata and Chan, {Andrew T.} and Hongmei Nan",
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T1 - Pre-diagnostic leukocyte mitochondrial DNA copy number and colorectal cancer risk

AU - Yang, Keming

AU - Li, Xin

AU - Forman, Michele R.

AU - Monahan, Patrick O.

AU - Graham, Bret H.

AU - Joshi, Amit

AU - Song, Mingyang

AU - Hang, Dong

AU - Ogino, Shuji

AU - Giovannucci, Edward L.

AU - De Vivo, Immaculata

AU - Chan, Andrew T.

AU - Nan, Hongmei

PY - 2019/12/31

Y1 - 2019/12/31

N2 - Mitochondrial DNA (mtDNA) is susceptible to oxidative stress and mutation. Few epidemiological studies have assessed the relationship between mtDNA copy number (mtDNAcn) and risk of colorectal cancer (CRC), with inconsistent findings. In this study, we examined the association between pre-diagnostic leukocyte mtDNAcn and CRC risk in a case-control study of 324 female cases and 658 matched controls nested within the Nurses' Health Study (NHS). Relative mtDNAcn in peripheral blood leukocytes was measured by quantitative polymerase chain reaction-based assay. Conditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association of interest. Results showed lower log-mtDNAcn was significantly associated with increased risk of CRC, in a dose-dependent relationship (P for trend < 0.0001). Compared to the fourth quartile, multivariable-adjusted OR [95% confidence interval (CI)] was 1.10 (0.69, 1.76) for the third quartile, 1.40 (0.89, 2.19) for the second quartile and 2.19 (1.43, 3.35) for the first quartile. In analysis by anatomic subsite of CRC, we found a significant inverse association for proximal colon cancer [lowest versus highest quartile, multivariable-adjusted OR (95% CI) = 3.31 (1.70, 6.45), P for trend = 0.0003]. Additionally, stratified analysis according to the follow-up time since blood collection showed that the inverse association between mtDNAcn and CRC remained significant among individuals with ≥ 5 years' follow-up, and marginally significant among those with ≥ 10 years' follow-up since mtDNAcn testing, suggesting that mtDNAcn may serve as a long-term predictor for risk of CRC. In conclusion, pre-diagnostic leukocyte mtDNAcn was inversely associated with CRC risk. Further basic experimental studies are needed to explore the underlying biological mechanisms linking mtDNAcn to CRC carcinogenesis.

AB - Mitochondrial DNA (mtDNA) is susceptible to oxidative stress and mutation. Few epidemiological studies have assessed the relationship between mtDNA copy number (mtDNAcn) and risk of colorectal cancer (CRC), with inconsistent findings. In this study, we examined the association between pre-diagnostic leukocyte mtDNAcn and CRC risk in a case-control study of 324 female cases and 658 matched controls nested within the Nurses' Health Study (NHS). Relative mtDNAcn in peripheral blood leukocytes was measured by quantitative polymerase chain reaction-based assay. Conditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association of interest. Results showed lower log-mtDNAcn was significantly associated with increased risk of CRC, in a dose-dependent relationship (P for trend < 0.0001). Compared to the fourth quartile, multivariable-adjusted OR [95% confidence interval (CI)] was 1.10 (0.69, 1.76) for the third quartile, 1.40 (0.89, 2.19) for the second quartile and 2.19 (1.43, 3.35) for the first quartile. In analysis by anatomic subsite of CRC, we found a significant inverse association for proximal colon cancer [lowest versus highest quartile, multivariable-adjusted OR (95% CI) = 3.31 (1.70, 6.45), P for trend = 0.0003]. Additionally, stratified analysis according to the follow-up time since blood collection showed that the inverse association between mtDNAcn and CRC remained significant among individuals with ≥ 5 years' follow-up, and marginally significant among those with ≥ 10 years' follow-up since mtDNAcn testing, suggesting that mtDNAcn may serve as a long-term predictor for risk of CRC. In conclusion, pre-diagnostic leukocyte mtDNAcn was inversely associated with CRC risk. Further basic experimental studies are needed to explore the underlying biological mechanisms linking mtDNAcn to CRC carcinogenesis.

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