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Parkinson's Disease Genes Do Not Segregate with Breast Cancer Genes' Loci

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Parkinson's Disease Genes Do Not Segregate with Breast Cancer Genes' Loci Author Manuscript Published OnlineFirst on June 13, 2013; DOI: 10.1158/1055-9965.EPI-13-0472 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Parkinson’s Disease Genes do not Segregate with Breast Cancer Genes’ Loci Efrat Kravitz1,2, Yael Laitman3, Sharon Hassin-Baer1,4, Rivka Inzelberg1,2,4, Eitan Friedman3,4 1 The Parkinson Disease and Movement Disorders Clinic, and Department of Neurology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel 52621 2 The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel 52621 3 The Susanne-Levy Gertner Oncogenetics Unit, The Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Ramat Gan, 52621 Israel 4 The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Running title: Loci of Parkinson’s disease and breast cancer genes do not segregate Key words: Allele sharing; Breast cancer; Genetic loci; Parkinson's disease; SNP's Financial support: No specific funding was available for this study. Corresponding author: Prof Eitan Friedman, Director, The Susanne-Levy Gertner Oncogenetics Unit, The Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Ramat Gan, 52621, Israel. Email: [email protected] or [email protected] Telephone: +972-3-5303173 or +972-52-2891561; Fax: +972-3-535-7308 Disclosure of potential conflict of interest: All authors declare that they have no conflicts of interest. Word count: 797 Total number of figures and tables: 2 Page | 1 Downloaded from cebp.aacrjournals.org on October 2, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 13, 2013; DOI: 10.1158/1055-9965.EPI-13-0472 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Background: Breast cancer (BC) and skin cancer rates among Parkinson’s disease (PD) patients are higher than in non PD cases, and Jewish-Ashkenazi LRRK2*G2019S mutation carriers have higher BC rates than non-carriers. Since additional PD-predisposition genes are implicated in the malignant transformation process, we hypothesized that the association between BC and PD may be related to segregation of BC loci with known PD predisposition loci. Methods: Data mining for single nucleotide polymorphisms (SNPs) reportedly associated with BC in GWAS that localize to chromosomes bearing known PD predisposition loci: PARK7, PINK1 (chromosome 1); SNCA (chromosome 4); PARK2 (chromosome 6); and LRRK2 (chromosome 12) was carried out. Results: A total of 188 BC-associated SNPs were identified in 29 eligible manuscripts: 43 SNPs on chromosome 1 (PINK1); 46 SNPs on chromosome 4 (SNCA), 72 SNPs on chromosome 6 (PARK2) and 27 SNPs on chromosome 12 (LRRK2). No BC-associated SNP was located at distance<500,000bp from any of the analyzed PD predisposition genes. Conclusion: The association between BC and the most common genetic-inherited forms of PD cannot be accounted for by allele co-segregation at the genomic level. Impact: To elucidate the association between PD and BC a comprehensive approach that spans beyond a simple genetic association is required. Page | 2 Downloaded from cebp.aacrjournals.org on October 2, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 13, 2013; DOI: 10.1158/1055-9965.EPI-13-0472 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Breast cancer (BC) is more frequently diagnosed in patients with sporadic (1) and inherited forms (2) of PD than in the general population, yet the molecular basis for this association remains elusive. Given the involvement of PD predisposition genes in cell cycle, their reported functions as oncogenes and tumor suppressor genes (3), and somatic involvement in BC tumorigenesis (e.g., 4), we hypothesized that the PD-BC association may be attributed to co-segregation and in linkage disequilibrium of BC and PD predisposition genes. To test this notion, we performed a focused literature search for single nucleotide polymorphisms (SNPs) that have been associated with BC predisposition through genome-wide association studies (GWAS) and assessed if they are overrepresented in chromosomal regions associated with inherited forms of PD. Methods Search Procedure Database searches were carried out in PubMed (5), GWAS catalog of the National Human Genome Research Institute (NHGRI) (6), and the publication database of the Breast Cancer Association Consortium (BCAC) (7), to identify GWAS studies published until July 2012. Inherited PD Genes and Chromosomal loci The following PD predisposition loci were targeted: 1) PARK7 (OMIM# 602533), chromosome 1p36.23; 2) PINK1 (OMIM# 608309), chromosome 1p36.12; 3) SNCA (OMIM# 163890), chromosome 4q22.1; 4) PARK2 (OMIM# 602544), chromosome 6q25.2–q27; 5) LRRK2 (OMIM# 609007); chromosome 12q12. Page | 3 Downloaded from cebp.aacrjournals.org on October 2, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 13, 2013; DOI: 10.1158/1055-9965.EPI-13-0472 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Selection Criteria and SNP's We searched peer-reviewed, English-language publications reporting GWAS analyses on all pathological types of BC cases and controls of all ethnicities. Publications assessing interactions between SNPs and other risk factors or BC mortality risk, and candidate gene based studies were excluded. Only results from GWAS replication stage with SNPs showing p ≤ 0.05 that localize to one of the four chromosomes of interest were considered. After removal of duplicates, SNPs located to the chromosomes of interest, were plotted using the NCBI Sequence Viewer 2.23 tool (8). The distances between each of the genes of interest and the identified SNPs on the same chromosome were calculated. Results Of 194 articles identified, 153 articles did not meet the selection criteria, and 14 did not report any chromosomally relevant SNP. The 29 articles that met all review criteria are listed in Table 1. Overall, 188 BC associated SNPs located to one of the four "target chromosomes" were identified (Table 2): 43 SNPs localize to chromosome 1 (minimal distance from PINK1 = 916,731 bps; minimal distance from PARK7 = 6,096,002 bps); 46 SNPs localize to chromosome 4 (minimal distance from SNCA = 3,606,769 bps); 72 SNPs localize to chromosome 6 (minimal distance from PARK2 = 1,654,718 bps); 27 SNPs localize to chromosome 12 (minimal distance from LRRK2 = 7,186,058 bps). None of the identified BC associated SNPs were located at genomic distance <500,000 bps from any of the analyzed PD genes. Page | 4 Downloaded from cebp.aacrjournals.org on October 2, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 13, 2013; DOI: 10.1158/1055-9965.EPI-13-0472 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Discussion No BC-associated SNPs localized in the genomic proximity of PD predisposition genes found on chromosomes 1, 4, 6, or 12. Thus, the observed increased BC rates in inherited forms of PD cannot be accounted for by a simple co-segregation and shared genomic loci. Despite the lack of association at the genomic level between BC SNPs and PD predisposition genes, other genetic or epigenetic mechanisms may still be operative. If BC results from the actions of multiple rare alleles, each one with a medium effect on BC risk, then the methodology used in GWAS would have missed these relatively rare sequence variants. This explanation seems less likely as there was no association reported between family history of BC and PD risk in a large US cohort (9). To assess this possibility, a whole exome—or even a whole genome—dataset of BC and PD cases should be queried, when it becomes available. Another possible explanation for the BC-PD association may be epigenetic: miRNA’s may be involved in promoting the expression of BC related genes and concomitantly, repress genes that are needed for normal dopaminergic function. Indeed, miR-7, which represses α- synuclein protein levels and protects cells against oxidative stress, also inhibits epithelial-to- mesenchymal transition and metastasis of BC cells via focal adhesion kinase (FAK) expression (10). Lastly, the reported association between BC and PD may relate to abnormal estrogen metabolism. Women have a reduced PD risk compared with age-matched men, a phenomenon attributed by some researchers to the neuro-protective properties of estrogen in PD relevant neurons (11). Tamoxifen, a selective estrogen receptor (ER) modulator, given to patients with ER positive BC, has been reported to increase PD rates (12). Thus, in post- menopausal women, markedly reduced estrogen synthesis may both increase the risk of PD, Page | 5 Downloaded from cebp.aacrjournals.org on October 2, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 13, 2013; DOI: 10.1158/1055-9965.EPI-13-0472 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. and promote the expression of estrogen receptor genes in breast tissue to enhance BC risk of BC. Noteworthy this is a viable speculation that should be viewed as such. In conclusion, the association between BC and the most common genetic forms of inherited PD cannot be accounted for by allele co-segregation at the genomic level. Authors’ contributions Conception and design: R. Inzelberg, E. Friedman Development of methodology: E. Kravitz, Y. Laitman, E. Friedman Acquisition of data: E. Kravitz Analysis and interpretation of data: E. Kravitz, Y. Laitman, S. Hassin-Baer, R. Inzelberg, E. Friedman Writing, review and/or revision of the manuscript: E. Kravitz, Y. Laitman, S. Hassin-Baer, R. Inzelberg, E. Friedman Administrative, technical, or material support: E. Kravitz Study supervision: R. Inzelberg, E. Friedman Grant support Not applicable Page | 6 Downloaded from cebp.aacrjournals.org on October 2, 2021.
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