Integrative genomic analysis identifies ancestry-related expression quantitative trait loci on DNA polymerase β and supports the association of genetic ancestry with survival disparities in head and neck squamous cell carcinoma

Meganathan P. Ramakodi; Karthik Devarajan; Elizabeth Blackman; Denise Gibbs; Danièle Luce; Jacqueline Deloumeaux; Suzy Duflo; Jeffrey C. Liu; Ranee Mehra; Rob J. Kulathinal; Camille C. Ragin

doi:10.1002/cncr.30457

Integrative genomic analysis identifies ancestry-related expression quantitative trait loci on DNA polymerase β and supports the association of genetic ancestry with survival disparities in head and neck squamous cell carcinoma

Meganathan P. Ramakodi, Karthik Devarajan, Elizabeth Blackman, Denise Gibbs, Danièle Luce, Jacqueline Deloumeaux, Suzy Duflo, Jeffrey C. Liu, Ranee Mehra, Rob J. Kulathinal, Camille C. Ragin

School of Medicine

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

BACKGROUND: African Americans with head and neck squamous cell carcinoma (HNSCC) have a lower survival rate than whites. This study investigated the functional importance of ancestry-informative single-nucleotide polymorphisms (SNPs) in HNSCC and also examined the effect of functionally important genetic elements on racial disparities in HNSCC survival. METHODS: Ancestry-informative SNPs, RNA sequencing, methylation, and copy number variation data for 316 oral cavity and laryngeal cancer patients were analyzed across 178 DNA repair genes. The results of expression quantitative trait locus (eQTL) analyses were also replicated with a Gene Expression Omnibus (GEO) data set. The effects of eQTLs on overall survival (OS) and disease-free survival (DFS) were evaluated. RESULTS: Five ancestry-related SNPs were identified as cis-eQTLs in the DNA polymerase β (POLB) gene (false discovery rate [FDR] < 0.01). The homozygous/heterozygous genotypes containing the African allele showed higher POLB expression than the homozygous white allele genotype (P <.001). A replication study using a GEO data set validated all 5 eQTLs and also showed a statistically significant difference in POLB expression based on genetic ancestry (P =.002). An association was observed between these eQTLs and OS (P <.037; FDR < 0.0363) as well as DFS (P =.018 to.0629; FDR < 0.079) for oral cavity and laryngeal cancer patients treated with platinum-based chemotherapy and/or radiotherapy. Genotypes containing the African allele were associated with poor OS/DFS in comparison with homozygous genotypes harboring the white allele. CONCLUSIONS: Analyses show that ancestry-related alleles could act as eQTLs in HNSCC and support the association of ancestry-related genetic factors with survival disparities in patients diagnosed with oral cavity and laryngeal cancer. Cancer 2017;123:849–60.

Original language	English (US)
Pages (from-to)	849-860
Number of pages	12
Journal	Cancer
Volume	123
Issue number	5
DOIs	https://doi.org/10.1002/cncr.30457
State	Published - Mar 1 2017

Keywords

DNA polymerase β
expression quantitative trait locus (eQTL)
genetic ancestry
head and neck squamous cell carcinoma
survival disparity

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1002/cncr.30457

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Ramakodi, M. P., Devarajan, K., Blackman, E., Gibbs, D., Luce, D., Deloumeaux, J., Duflo, S., Liu, J. C., Mehra, R., Kulathinal, R. J., & Ragin, C. C. (2017). Integrative genomic analysis identifies ancestry-related expression quantitative trait loci on DNA polymerase β and supports the association of genetic ancestry with survival disparities in head and neck squamous cell carcinoma. Cancer, 123(5), 849-860. https://doi.org/10.1002/cncr.30457

Integrative genomic analysis identifies ancestry-related expression quantitative trait loci on DNA polymerase β and supports the association of genetic ancestry with survival disparities in head and neck squamous cell carcinoma. / Ramakodi, Meganathan P.; Devarajan, Karthik; Blackman, Elizabeth et al.
In: Cancer, Vol. 123, No. 5, 01.03.2017, p. 849-860.

Research output: Contribution to journal › Article › peer-review

Ramakodi, MP, Devarajan, K, Blackman, E, Gibbs, D, Luce, D, Deloumeaux, J, Duflo, S, Liu, JC, Mehra, R, Kulathinal, RJ & Ragin, CC 2017, 'Integrative genomic analysis identifies ancestry-related expression quantitative trait loci on DNA polymerase β and supports the association of genetic ancestry with survival disparities in head and neck squamous cell carcinoma', Cancer, vol. 123, no. 5, pp. 849-860. https://doi.org/10.1002/cncr.30457

@article{8abbd1ea83b8409d975a98f7010134fe,

title = "Integrative genomic analysis identifies ancestry-related expression quantitative trait loci on DNA polymerase β and supports the association of genetic ancestry with survival disparities in head and neck squamous cell carcinoma",

abstract = "BACKGROUND: African Americans with head and neck squamous cell carcinoma (HNSCC) have a lower survival rate than whites. This study investigated the functional importance of ancestry-informative single-nucleotide polymorphisms (SNPs) in HNSCC and also examined the effect of functionally important genetic elements on racial disparities in HNSCC survival. METHODS: Ancestry-informative SNPs, RNA sequencing, methylation, and copy number variation data for 316 oral cavity and laryngeal cancer patients were analyzed across 178 DNA repair genes. The results of expression quantitative trait locus (eQTL) analyses were also replicated with a Gene Expression Omnibus (GEO) data set. The effects of eQTLs on overall survival (OS) and disease-free survival (DFS) were evaluated. RESULTS: Five ancestry-related SNPs were identified as cis-eQTLs in the DNA polymerase β (POLB) gene (false discovery rate [FDR] < 0.01). The homozygous/heterozygous genotypes containing the African allele showed higher POLB expression than the homozygous white allele genotype (P <.001). A replication study using a GEO data set validated all 5 eQTLs and also showed a statistically significant difference in POLB expression based on genetic ancestry (P =.002). An association was observed between these eQTLs and OS (P <.037; FDR < 0.0363) as well as DFS (P =.018 to.0629; FDR < 0.079) for oral cavity and laryngeal cancer patients treated with platinum-based chemotherapy and/or radiotherapy. Genotypes containing the African allele were associated with poor OS/DFS in comparison with homozygous genotypes harboring the white allele. CONCLUSIONS: Analyses show that ancestry-related alleles could act as eQTLs in HNSCC and support the association of ancestry-related genetic factors with survival disparities in patients diagnosed with oral cavity and laryngeal cancer. Cancer 2017;123:849–60.",

keywords = "DNA polymerase β, expression quantitative trait locus (eQTL), genetic ancestry, head and neck squamous cell carcinoma, survival disparity",

author = "Ramakodi, {Meganathan P.} and Karthik Devarajan and Elizabeth Blackman and Denise Gibbs and Dani{\`e}le Luce and Jacqueline Deloumeaux and Suzy Duflo and Liu, {Jeffrey C.} and Ranee Mehra and Kulathinal, {Rob J.} and Ragin, {Camille C.}",

note = "Publisher Copyright: {\textcopyright} 2016 American Cancer Society",

year = "2017",

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doi = "10.1002/cncr.30457",

language = "English (US)",

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T1 - Integrative genomic analysis identifies ancestry-related expression quantitative trait loci on DNA polymerase β and supports the association of genetic ancestry with survival disparities in head and neck squamous cell carcinoma

AU - Ramakodi, Meganathan P.

AU - Devarajan, Karthik

AU - Blackman, Elizabeth

AU - Gibbs, Denise

AU - Luce, Danièle

AU - Deloumeaux, Jacqueline

AU - Duflo, Suzy

AU - Liu, Jeffrey C.

AU - Mehra, Ranee

AU - Kulathinal, Rob J.

AU - Ragin, Camille C.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - BACKGROUND: African Americans with head and neck squamous cell carcinoma (HNSCC) have a lower survival rate than whites. This study investigated the functional importance of ancestry-informative single-nucleotide polymorphisms (SNPs) in HNSCC and also examined the effect of functionally important genetic elements on racial disparities in HNSCC survival. METHODS: Ancestry-informative SNPs, RNA sequencing, methylation, and copy number variation data for 316 oral cavity and laryngeal cancer patients were analyzed across 178 DNA repair genes. The results of expression quantitative trait locus (eQTL) analyses were also replicated with a Gene Expression Omnibus (GEO) data set. The effects of eQTLs on overall survival (OS) and disease-free survival (DFS) were evaluated. RESULTS: Five ancestry-related SNPs were identified as cis-eQTLs in the DNA polymerase β (POLB) gene (false discovery rate [FDR] < 0.01). The homozygous/heterozygous genotypes containing the African allele showed higher POLB expression than the homozygous white allele genotype (P <.001). A replication study using a GEO data set validated all 5 eQTLs and also showed a statistically significant difference in POLB expression based on genetic ancestry (P =.002). An association was observed between these eQTLs and OS (P <.037; FDR < 0.0363) as well as DFS (P =.018 to.0629; FDR < 0.079) for oral cavity and laryngeal cancer patients treated with platinum-based chemotherapy and/or radiotherapy. Genotypes containing the African allele were associated with poor OS/DFS in comparison with homozygous genotypes harboring the white allele. CONCLUSIONS: Analyses show that ancestry-related alleles could act as eQTLs in HNSCC and support the association of ancestry-related genetic factors with survival disparities in patients diagnosed with oral cavity and laryngeal cancer. Cancer 2017;123:849–60.

AB - BACKGROUND: African Americans with head and neck squamous cell carcinoma (HNSCC) have a lower survival rate than whites. This study investigated the functional importance of ancestry-informative single-nucleotide polymorphisms (SNPs) in HNSCC and also examined the effect of functionally important genetic elements on racial disparities in HNSCC survival. METHODS: Ancestry-informative SNPs, RNA sequencing, methylation, and copy number variation data for 316 oral cavity and laryngeal cancer patients were analyzed across 178 DNA repair genes. The results of expression quantitative trait locus (eQTL) analyses were also replicated with a Gene Expression Omnibus (GEO) data set. The effects of eQTLs on overall survival (OS) and disease-free survival (DFS) were evaluated. RESULTS: Five ancestry-related SNPs were identified as cis-eQTLs in the DNA polymerase β (POLB) gene (false discovery rate [FDR] < 0.01). The homozygous/heterozygous genotypes containing the African allele showed higher POLB expression than the homozygous white allele genotype (P <.001). A replication study using a GEO data set validated all 5 eQTLs and also showed a statistically significant difference in POLB expression based on genetic ancestry (P =.002). An association was observed between these eQTLs and OS (P <.037; FDR < 0.0363) as well as DFS (P =.018 to.0629; FDR < 0.079) for oral cavity and laryngeal cancer patients treated with platinum-based chemotherapy and/or radiotherapy. Genotypes containing the African allele were associated with poor OS/DFS in comparison with homozygous genotypes harboring the white allele. CONCLUSIONS: Analyses show that ancestry-related alleles could act as eQTLs in HNSCC and support the association of ancestry-related genetic factors with survival disparities in patients diagnosed with oral cavity and laryngeal cancer. Cancer 2017;123:849–60.

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Integrative genomic analysis identifies ancestry-related expression quantitative trait loci on DNA polymerase β and supports the association of genetic ancestry with survival disparities in head and neck squamous cell carcinoma

Abstract

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