Pleiotropic and sex-specific effects of cancer GWAS SNPs on melanoma risk in the Population Architecture Using Genomics and Epidemiology (PAGE) study

Jonathan M. Kocarnik, S. Lani Park, Jiali Han, Logan Dumitrescu, Iona Cheng, Lynne R. Wilkens, Fredrick R. Schumacher, Laurence Kolonel, Chris S. Carlson, Dana C. Crawford, Robert J. Goodloe, Holli H. Dilks, Paxton Baker, Danielle Richardson, Tara C. Matise, José Luis Ambite, Fengju Song, Abrar A. Qureshi, Mingfeng Zhang, David Duggan & 6 others Carolyn Hutter, Lucia Hindorff, William S. Bush, Charles Kooperberg, Loic Le Marchand, Ulrike Peters

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Abstract

Background: Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk. Methods: We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies. Results: We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8×10-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0×10-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e-4). Conclusions: We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.

Original languageEnglish (US)
Article numbere0120491
JournalPLoS One
Volume10
Issue number3
DOIs
StatePublished - Mar 19 2015

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Epidemiology
Genome-Wide Association Study
melanoma
Genomics
Single Nucleotide Polymorphism
epidemiology
Melanoma
Genes
genomics
neoplasms
gender
Ions
Population
Neoplasms
Polymorphism
Ion Transport
Pigmentation
ion transport
lung neoplasms
pigmentation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Pleiotropic and sex-specific effects of cancer GWAS SNPs on melanoma risk in the Population Architecture Using Genomics and Epidemiology (PAGE) study. / Kocarnik, Jonathan M.; Park, S. Lani; Han, Jiali; Dumitrescu, Logan; Cheng, Iona; Wilkens, Lynne R.; Schumacher, Fredrick R.; Kolonel, Laurence; Carlson, Chris S.; Crawford, Dana C.; Goodloe, Robert J.; Dilks, Holli H.; Baker, Paxton; Richardson, Danielle; Matise, Tara C.; Ambite, José Luis; Song, Fengju; Qureshi, Abrar A.; Zhang, Mingfeng; Duggan, David; Hutter, Carolyn; Hindorff, Lucia; Bush, William S.; Kooperberg, Charles; Le Marchand, Loic; Peters, Ulrike.

In: PLoS One, Vol. 10, No. 3, e0120491, 19.03.2015.

Research output: Contribution to journalArticle

Kocarnik, JM, Park, SL, Han, J, Dumitrescu, L, Cheng, I, Wilkens, LR, Schumacher, FR, Kolonel, L, Carlson, CS, Crawford, DC, Goodloe, RJ, Dilks, HH, Baker, P, Richardson, D, Matise, TC, Ambite, JL, Song, F, Qureshi, AA, Zhang, M, Duggan, D, Hutter, C, Hindorff, L, Bush, WS, Kooperberg, C, Le Marchand, L & Peters, U 2015, 'Pleiotropic and sex-specific effects of cancer GWAS SNPs on melanoma risk in the Population Architecture Using Genomics and Epidemiology (PAGE) study', PLoS One, vol. 10, no. 3, e0120491. https://doi.org/10.1371/journal.pone.0120491
Kocarnik, Jonathan M. ; Park, S. Lani ; Han, Jiali ; Dumitrescu, Logan ; Cheng, Iona ; Wilkens, Lynne R. ; Schumacher, Fredrick R. ; Kolonel, Laurence ; Carlson, Chris S. ; Crawford, Dana C. ; Goodloe, Robert J. ; Dilks, Holli H. ; Baker, Paxton ; Richardson, Danielle ; Matise, Tara C. ; Ambite, José Luis ; Song, Fengju ; Qureshi, Abrar A. ; Zhang, Mingfeng ; Duggan, David ; Hutter, Carolyn ; Hindorff, Lucia ; Bush, William S. ; Kooperberg, Charles ; Le Marchand, Loic ; Peters, Ulrike. / Pleiotropic and sex-specific effects of cancer GWAS SNPs on melanoma risk in the Population Architecture Using Genomics and Epidemiology (PAGE) study. In: PLoS One. 2015 ; Vol. 10, No. 3.
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abstract = "Background: Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk. Methods: We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies. Results: We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8×10-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0×10-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e-4). Conclusions: We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.",
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T1 - Pleiotropic and sex-specific effects of cancer GWAS SNPs on melanoma risk in the Population Architecture Using Genomics and Epidemiology (PAGE) study

AU - Kocarnik, Jonathan M.

AU - Park, S. Lani

AU - Han, Jiali

AU - Dumitrescu, Logan

AU - Cheng, Iona

AU - Wilkens, Lynne R.

AU - Schumacher, Fredrick R.

AU - Kolonel, Laurence

AU - Carlson, Chris S.

AU - Crawford, Dana C.

AU - Goodloe, Robert J.

AU - Dilks, Holli H.

AU - Baker, Paxton

AU - Richardson, Danielle

AU - Matise, Tara C.

AU - Ambite, José Luis

AU - Song, Fengju

AU - Qureshi, Abrar A.

AU - Zhang, Mingfeng

AU - Duggan, David

AU - Hutter, Carolyn

AU - Hindorff, Lucia

AU - Bush, William S.

AU - Kooperberg, Charles

AU - Le Marchand, Loic

AU - Peters, Ulrike

PY - 2015/3/19

Y1 - 2015/3/19

N2 - Background: Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk. Methods: We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies. Results: We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8×10-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0×10-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e-4). Conclusions: We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.

AB - Background: Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk. Methods: We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies. Results: We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8×10-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0×10-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e-4). Conclusions: We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.

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