Association of cancer susceptibility variants with risk of multiple primary cancers

The population architecture using genomics and epidemiology study

S. Lani Park, Christian P. Caberto, Yi Lin, Robert J. Goodloe, Logan Dumitrescu, Shelly Ann Love, Tara C. Matise, Lucia A. Hindorff, Jay Fowke, Fredrick R. Schumacher, Jennifer Beebe-Dimmer, Chu Chen, Lifang Hou, Fridtjof Thomas, Ewa Deelman, Ying Han, Ulrike Peters, Kari E. North, Gerardo Heiss, Dana C. Crawford & 6 others Christopher A. Haiman, Lynne R. Wilkens, William S. Bush, Charles Kooperberg, Iona Cheng, Loïc Le Marchand

Research output: Contribution to journalArticle

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Abstract

Background: Multiple primary cancers account for approximately 16% of all incident cancers in the United States. Although genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC). Methods: As part of the National Human Genome Research Institute (NHGRI) Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort (MEC) and Women's Health Initiative (WHI). Incident MPC (IMPC) cases (n = 1,385) were defined as participants diagnosed with more than one incident cancer after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n = 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the associations between 188 cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false-positive report probability (FPRP) to determine statistical significance. Results: A nicotine dependence-associated and lung cancer variant, CHRNA3 rs578776 [OR, 1.16; 95% confidence interval (CI), 1.05-1.26; P = 0.004], and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR, 1.16; 95% CI, 1.04-1.28; P = 0.005 and OR, 1.13; 95% CI, 1.03-1.23; P = 0.006), were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (P < 0.05) after removing subjects who had lung or breast cancers, respectively (P ≤ 0.046). These associations did not show significant heterogeneity by smoking status (Pheterogeneity ≥ 0.53). Conclusions: Our study has identified rs578776 and rs11249433 as risk variants for IMPC. Impact: These findings may help to identify genetic regions associated with IMPC risk.

Original languageEnglish (US)
Pages (from-to)2568-2578
Number of pages11
JournalCancer Epidemiology Biomarkers and Prevention
Volume23
Issue number11
DOIs
StatePublished - Nov 1 2014

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Genomics
Epidemiology
Population
Neoplasms
Confidence Intervals
National Human Genome Research Institute (U.S.)
Lung Neoplasms
Breast Neoplasms
Tobacco Use Disorder
Genome-Wide Association Study
Women's Health
Meta-Analysis
Logistic Models
Smoking
Regression Analysis

All Science Journal Classification (ASJC) codes

  • Epidemiology
  • Oncology

Cite this

Association of cancer susceptibility variants with risk of multiple primary cancers : The population architecture using genomics and epidemiology study. / Park, S. Lani; Caberto, Christian P.; Lin, Yi; Goodloe, Robert J.; Dumitrescu, Logan; Love, Shelly Ann; Matise, Tara C.; Hindorff, Lucia A.; Fowke, Jay; Schumacher, Fredrick R.; Beebe-Dimmer, Jennifer; Chen, Chu; Hou, Lifang; Thomas, Fridtjof; Deelman, Ewa; Han, Ying; Peters, Ulrike; North, Kari E.; Heiss, Gerardo; Crawford, Dana C.; Haiman, Christopher A.; Wilkens, Lynne R.; Bush, William S.; Kooperberg, Charles; Cheng, Iona; Le Marchand, Loïc.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 23, No. 11, 01.11.2014, p. 2568-2578.

Research output: Contribution to journalArticle

Park, SL, Caberto, CP, Lin, Y, Goodloe, RJ, Dumitrescu, L, Love, SA, Matise, TC, Hindorff, LA, Fowke, J, Schumacher, FR, Beebe-Dimmer, J, Chen, C, Hou, L, Thomas, F, Deelman, E, Han, Y, Peters, U, North, KE, Heiss, G, Crawford, DC, Haiman, CA, Wilkens, LR, Bush, WS, Kooperberg, C, Cheng, I & Le Marchand, L 2014, 'Association of cancer susceptibility variants with risk of multiple primary cancers: The population architecture using genomics and epidemiology study', Cancer Epidemiology Biomarkers and Prevention, vol. 23, no. 11, pp. 2568-2578. https://doi.org/10.1158/1055-9965.EPI-14-0129
Park, S. Lani ; Caberto, Christian P. ; Lin, Yi ; Goodloe, Robert J. ; Dumitrescu, Logan ; Love, Shelly Ann ; Matise, Tara C. ; Hindorff, Lucia A. ; Fowke, Jay ; Schumacher, Fredrick R. ; Beebe-Dimmer, Jennifer ; Chen, Chu ; Hou, Lifang ; Thomas, Fridtjof ; Deelman, Ewa ; Han, Ying ; Peters, Ulrike ; North, Kari E. ; Heiss, Gerardo ; Crawford, Dana C. ; Haiman, Christopher A. ; Wilkens, Lynne R. ; Bush, William S. ; Kooperberg, Charles ; Cheng, Iona ; Le Marchand, Loïc. / Association of cancer susceptibility variants with risk of multiple primary cancers : The population architecture using genomics and epidemiology study. In: Cancer Epidemiology Biomarkers and Prevention. 2014 ; Vol. 23, No. 11. pp. 2568-2578.
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abstract = "Background: Multiple primary cancers account for approximately 16{\%} of all incident cancers in the United States. Although genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC). Methods: As part of the National Human Genome Research Institute (NHGRI) Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort (MEC) and Women's Health Initiative (WHI). Incident MPC (IMPC) cases (n = 1,385) were defined as participants diagnosed with more than one incident cancer after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n = 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the associations between 188 cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false-positive report probability (FPRP) to determine statistical significance. Results: A nicotine dependence-associated and lung cancer variant, CHRNA3 rs578776 [OR, 1.16; 95{\%} confidence interval (CI), 1.05-1.26; P = 0.004], and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR, 1.16; 95{\%} CI, 1.04-1.28; P = 0.005 and OR, 1.13; 95{\%} CI, 1.03-1.23; P = 0.006), were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (P < 0.05) after removing subjects who had lung or breast cancers, respectively (P ≤ 0.046). These associations did not show significant heterogeneity by smoking status (Pheterogeneity ≥ 0.53). Conclusions: Our study has identified rs578776 and rs11249433 as risk variants for IMPC. Impact: These findings may help to identify genetic regions associated with IMPC risk.",
author = "Park, {S. Lani} and Caberto, {Christian P.} and Yi Lin and Goodloe, {Robert J.} and Logan Dumitrescu and Love, {Shelly Ann} and Matise, {Tara C.} and Hindorff, {Lucia A.} and Jay Fowke and Schumacher, {Fredrick R.} and Jennifer Beebe-Dimmer and Chu Chen and Lifang Hou and Fridtjof Thomas and Ewa Deelman and Ying Han and Ulrike Peters and North, {Kari E.} and Gerardo Heiss and Crawford, {Dana C.} and Haiman, {Christopher A.} and Wilkens, {Lynne R.} and Bush, {William S.} and Charles Kooperberg and Iona Cheng and {Le Marchand}, Lo{\"i}c",
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T1 - Association of cancer susceptibility variants with risk of multiple primary cancers

T2 - The population architecture using genomics and epidemiology study

AU - Park, S. Lani

AU - Caberto, Christian P.

AU - Lin, Yi

AU - Goodloe, Robert J.

AU - Dumitrescu, Logan

AU - Love, Shelly Ann

AU - Matise, Tara C.

AU - Hindorff, Lucia A.

AU - Fowke, Jay

AU - Schumacher, Fredrick R.

AU - Beebe-Dimmer, Jennifer

AU - Chen, Chu

AU - Hou, Lifang

AU - Thomas, Fridtjof

AU - Deelman, Ewa

AU - Han, Ying

AU - Peters, Ulrike

AU - North, Kari E.

AU - Heiss, Gerardo

AU - Crawford, Dana C.

AU - Haiman, Christopher A.

AU - Wilkens, Lynne R.

AU - Bush, William S.

AU - Kooperberg, Charles

AU - Cheng, Iona

AU - Le Marchand, Loïc

PY - 2014/11/1

Y1 - 2014/11/1

N2 - Background: Multiple primary cancers account for approximately 16% of all incident cancers in the United States. Although genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC). Methods: As part of the National Human Genome Research Institute (NHGRI) Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort (MEC) and Women's Health Initiative (WHI). Incident MPC (IMPC) cases (n = 1,385) were defined as participants diagnosed with more than one incident cancer after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n = 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the associations between 188 cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false-positive report probability (FPRP) to determine statistical significance. Results: A nicotine dependence-associated and lung cancer variant, CHRNA3 rs578776 [OR, 1.16; 95% confidence interval (CI), 1.05-1.26; P = 0.004], and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR, 1.16; 95% CI, 1.04-1.28; P = 0.005 and OR, 1.13; 95% CI, 1.03-1.23; P = 0.006), were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (P < 0.05) after removing subjects who had lung or breast cancers, respectively (P ≤ 0.046). These associations did not show significant heterogeneity by smoking status (Pheterogeneity ≥ 0.53). Conclusions: Our study has identified rs578776 and rs11249433 as risk variants for IMPC. Impact: These findings may help to identify genetic regions associated with IMPC risk.

AB - Background: Multiple primary cancers account for approximately 16% of all incident cancers in the United States. Although genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC). Methods: As part of the National Human Genome Research Institute (NHGRI) Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort (MEC) and Women's Health Initiative (WHI). Incident MPC (IMPC) cases (n = 1,385) were defined as participants diagnosed with more than one incident cancer after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n = 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the associations between 188 cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false-positive report probability (FPRP) to determine statistical significance. Results: A nicotine dependence-associated and lung cancer variant, CHRNA3 rs578776 [OR, 1.16; 95% confidence interval (CI), 1.05-1.26; P = 0.004], and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR, 1.16; 95% CI, 1.04-1.28; P = 0.005 and OR, 1.13; 95% CI, 1.03-1.23; P = 0.006), were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (P < 0.05) after removing subjects who had lung or breast cancers, respectively (P ≤ 0.046). These associations did not show significant heterogeneity by smoking status (Pheterogeneity ≥ 0.53). Conclusions: Our study has identified rs578776 and rs11249433 as risk variants for IMPC. Impact: These findings may help to identify genetic regions associated with IMPC risk.

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