Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer

Ryan Langdon; Rebecca Richmond; Hannah R Elliott; Tom Dudding; Nabila Kazmi; Chris Penfold; Kate Ingarfield; Karen Ho; Andrew Bretherick; Chris Haley; Yanni Zeng; Rosie M Walker; Michael Pawlita; Tim Waterboer; Tom Gaunt; George Davey Smith; Matthew Suderman; Steve Thomas; Andy Ness; Caroline Relton

doi:10.1186/s13148-020-00870-0

Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer

Ryan Langdon, Rebecca Richmond, Hannah R Elliott, Tom Dudding, Nabila Kazmi, Chris Penfold, Kate Ingarfield, Karen Ho, Andrew Bretherick, Chris Haley, Yanni Zeng, Rosie M Walker, Michael Pawlita, Tim Waterboer, Tom Gaunt, George Davey Smith, Matthew Suderman, Steve Thomas, Andy Ness, Caroline Relton

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Abstract / Description of output

BACKGROUND: Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conducted single-site and differentially methylated region (DMR) epigenome-wide association studies (EWAS) of these factors, in addition to ∼ 3-year survival, using Illumina Methylation EPIC DNA methylation profiles from whole blood in 409 individuals as part of the Head and Neck 5000 (HN5000) study. Overlapping sites between each factor and survival were then assessed using two-step Mendelian randomization to assess whether methylation at these positions causally affected survival.

RESULTS: Using the MethylationEPIC array in an OPC dataset, we found novel CpG associations with smoking, alcohol consumption and ~ 3-year survival. We found no CpG associations below our multiple testing threshold associated with HPV16 E6 serological response (used as a proxy for HPV infection). CpG site associations below our multiple-testing threshold (PBonferroni < 0.05) for both a prognostic factor and survival were observed at four gene regions: SPEG (smoking), GFI1 (smoking), PPT2 (smoking) and KHDC3L (alcohol consumption). Evidence for a causal effect of DNA methylation on survival was only observed in the SPEG gene region (HR per SD increase in methylation score 1.28, 95% CI 1.14 to 1.43, P 2.12 × 10-05).

CONCLUSIONS: Part of the effect of smoking on survival in those with oropharyngeal cancer may be mediated by methylation at the SPEG gene locus. Replication in data from independent datasets and data from HN5000 with longer follow-up times is needed to confirm these findings.

Original language	English
Pages (from-to)	95
Journal	Clinical Epigenetics
Volume	12
Issue number	1
DOIs	https://doi.org/10.1186/s13148-020-00870-0
Publication status	Published - 29 Jun 2020

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Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancerFinal published version, 2.74 MBLicence: Creative Commons: Attribution (CC-BY)

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Langdon, R., Richmond, R., Elliott, H. R., Dudding, T., Kazmi, N., Penfold, C., Ingarfield, K., Ho, K., Bretherick, A., Haley, C., Zeng, Y., Walker, R. M., Pawlita, M., Waterboer, T., Gaunt, T., Smith, G. D., Suderman, M., Thomas, S., Ness, A., & Relton, C. (2020). Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer. Clinical Epigenetics, 12(1), 95. https://doi.org/10.1186/s13148-020-00870-0

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title = "Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer",

abstract = "BACKGROUND: Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conducted single-site and differentially methylated region (DMR) epigenome-wide association studies (EWAS) of these factors, in addition to ∼ 3-year survival, using Illumina Methylation EPIC DNA methylation profiles from whole blood in 409 individuals as part of the Head and Neck 5000 (HN5000) study. Overlapping sites between each factor and survival were then assessed using two-step Mendelian randomization to assess whether methylation at these positions causally affected survival.RESULTS: Using the MethylationEPIC array in an OPC dataset, we found novel CpG associations with smoking, alcohol consumption and ~ 3-year survival. We found no CpG associations below our multiple testing threshold associated with HPV16 E6 serological response (used as a proxy for HPV infection). CpG site associations below our multiple-testing threshold (PBonferroni < 0.05) for both a prognostic factor and survival were observed at four gene regions: SPEG (smoking), GFI1 (smoking), PPT2 (smoking) and KHDC3L (alcohol consumption). Evidence for a causal effect of DNA methylation on survival was only observed in the SPEG gene region (HR per SD increase in methylation score 1.28, 95% CI 1.14 to 1.43, P 2.12 × 10-05).CONCLUSIONS: Part of the effect of smoking on survival in those with oropharyngeal cancer may be mediated by methylation at the SPEG gene locus. Replication in data from independent datasets and data from HN5000 with longer follow-up times is needed to confirm these findings.",

author = "Ryan Langdon and Rebecca Richmond and Elliott, {Hannah R} and Tom Dudding and Nabila Kazmi and Chris Penfold and Kate Ingarfield and Karen Ho and Andrew Bretherick and Chris Haley and Yanni Zeng and Walker, {Rosie M} and Michael Pawlita and Tim Waterboer and Tom Gaunt and Smith, {George Davey} and Matthew Suderman and Steve Thomas and Andy Ness and Caroline Relton",

year = "2020",

month = jun,

day = "29",

doi = "10.1186/s13148-020-00870-0",

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journal = "Clinical Epigenetics",

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publisher = "Springer",

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Langdon, R, Richmond, R, Elliott, HR, Dudding, T, Kazmi, N, Penfold, C, Ingarfield, K, Ho, K, Bretherick, A , Haley, C, Zeng, Y, Walker, RM, Pawlita, M, Waterboer, T, Gaunt, T, Smith, GD, Suderman, M, Thomas, S, Ness, A & Relton, C 2020, 'Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer', Clinical Epigenetics, vol. 12, no. 1, pp. 95. https://doi.org/10.1186/s13148-020-00870-0

TY - JOUR

T1 - Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer

AU - Langdon, Ryan

AU - Richmond, Rebecca

AU - Elliott, Hannah R

AU - Dudding, Tom

AU - Kazmi, Nabila

AU - Penfold, Chris

AU - Ingarfield, Kate

AU - Ho, Karen

AU - Bretherick, Andrew

AU - Haley, Chris

AU - Zeng, Yanni

AU - Walker, Rosie M

AU - Pawlita, Michael

AU - Waterboer, Tim

AU - Gaunt, Tom

AU - Smith, George Davey

AU - Suderman, Matthew

AU - Thomas, Steve

AU - Ness, Andy

AU - Relton, Caroline

PY - 2020/6/29

Y1 - 2020/6/29

N2 - BACKGROUND: Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conducted single-site and differentially methylated region (DMR) epigenome-wide association studies (EWAS) of these factors, in addition to ∼ 3-year survival, using Illumina Methylation EPIC DNA methylation profiles from whole blood in 409 individuals as part of the Head and Neck 5000 (HN5000) study. Overlapping sites between each factor and survival were then assessed using two-step Mendelian randomization to assess whether methylation at these positions causally affected survival.RESULTS: Using the MethylationEPIC array in an OPC dataset, we found novel CpG associations with smoking, alcohol consumption and ~ 3-year survival. We found no CpG associations below our multiple testing threshold associated with HPV16 E6 serological response (used as a proxy for HPV infection). CpG site associations below our multiple-testing threshold (PBonferroni < 0.05) for both a prognostic factor and survival were observed at four gene regions: SPEG (smoking), GFI1 (smoking), PPT2 (smoking) and KHDC3L (alcohol consumption). Evidence for a causal effect of DNA methylation on survival was only observed in the SPEG gene region (HR per SD increase in methylation score 1.28, 95% CI 1.14 to 1.43, P 2.12 × 10-05).CONCLUSIONS: Part of the effect of smoking on survival in those with oropharyngeal cancer may be mediated by methylation at the SPEG gene locus. Replication in data from independent datasets and data from HN5000 with longer follow-up times is needed to confirm these findings.

AB - BACKGROUND: Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conducted single-site and differentially methylated region (DMR) epigenome-wide association studies (EWAS) of these factors, in addition to ∼ 3-year survival, using Illumina Methylation EPIC DNA methylation profiles from whole blood in 409 individuals as part of the Head and Neck 5000 (HN5000) study. Overlapping sites between each factor and survival were then assessed using two-step Mendelian randomization to assess whether methylation at these positions causally affected survival.RESULTS: Using the MethylationEPIC array in an OPC dataset, we found novel CpG associations with smoking, alcohol consumption and ~ 3-year survival. We found no CpG associations below our multiple testing threshold associated with HPV16 E6 serological response (used as a proxy for HPV infection). CpG site associations below our multiple-testing threshold (PBonferroni < 0.05) for both a prognostic factor and survival were observed at four gene regions: SPEG (smoking), GFI1 (smoking), PPT2 (smoking) and KHDC3L (alcohol consumption). Evidence for a causal effect of DNA methylation on survival was only observed in the SPEG gene region (HR per SD increase in methylation score 1.28, 95% CI 1.14 to 1.43, P 2.12 × 10-05).CONCLUSIONS: Part of the effect of smoking on survival in those with oropharyngeal cancer may be mediated by methylation at the SPEG gene locus. Replication in data from independent datasets and data from HN5000 with longer follow-up times is needed to confirm these findings.

U2 - 10.1186/s13148-020-00870-0

DO - 10.1186/s13148-020-00870-0

M3 - Article

C2 - 32600451

SN - 1868-7075

VL - 12

SP - 95

JO - Clinical Epigenetics

JF - Clinical Epigenetics

IS - 1

ER -

Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer

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