Published OnlineFirst June 13, 2013; DOI: 10.1158/1055-9965.EPI-13-0472 Cancer Epidemiology, Null Results in Brief Biomarkers & Prevention 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, and Eitan Friedman3,4 Abstract Background: Breast cancer and skin cancer rates among patients with Parkinson’s disease are higher than in non-Parkinson’s disease cases, and Jewish-Ashkenazi LRRK2ÃG2019S mutation carriers have higher breast cancer rates than noncarriers. Because additional Parkinson’s disease predisposition genes are implicated in the malignant transformation process, we hypothesized that the association between breast cancer and Parkinson’s disease may be related to segregation of breast cancer loci with known Parkinson’s disease predisposition loci. Methods: Data mining for single-nucleotide polymorphisms (SNP), reportedly associated with breast cancer in genome-wide association study (GWAS) that localize to chromosomes bearing known Parkinson’s disease predisposition loci: PARK7, PINK1 (chromosome 1); SNCA (chromosome 4); PARK2 (chromosome 6); and LRRK2 (chromosome 12), was carried out. Results: A total of 188 breast cancer–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 breast cancer–associated SNP was located at distance less than 500,000 bp from any of the analyzed Parkinson’s disease predisposition genes. Conclusions: The association between breast cancer and the most common genetic-inherited forms of Parkinson’s disease cannot be accounted for by allele cosegregation at the genomic level. Impact: To elucidate the association between Parkinson’s disease and breast cancer, a comprehensive approach that spans beyond a simple genetic association is required. Cancer Epidemiol Biomarkers Prev; 22(8); 1464–72. Ó2013 AACR. Introduction cancer predisposition through genome-wide association Breast cancer is more frequently diagnosed in patients studies (GWAS) and assessed if they are overrepresented with sporadic (1) and inherited forms (2) of Parkinson’s in chromosomal regions associated with inherited forms disease than in the general population, yet the molecular of Parkinson’s disease. basis for this association remains elusive. Given the Materials and Methods involvement of Parkinson’s disease predisposition genes in cell cycle, their reported functions as oncogenes and Search procedure tumor suppressor genes (3), and somatic involvement in Database searches were carried out in PubMed (5), breast cancer tumorigenesis (e.g., ref. 4), we hypothesized GWAS catalog of the National Human Genome Research that the Parkinson’s disease–breast cancer association Institute (6), and the publication database of the Breast may be attributed to cosegregation and in linkage dis- Cancer Association Consortium (7) to identify GWAS equilibrium of breast cancer and Parkinson’s disease studies published until July 2012. predisposition genes. To test this notion, we conducted a focused literature search for single-nucleotide poly- Inherited Parkinson’s disease genes and morphisms (SNP) that have been associated with breast chromosomal loci The following Parkinson’s disease predisposition loci were targeted: (i) PARK7 (OMIM# 602533), chromosome Authors' Affiliations: 1The Parkinson Disease and Movement Disorders Clinic, and Department of Neurology; 2The Joseph Sagol Neuroscience 1p36.23; (ii) PINK1 (OMIM# 608309), chromosome 1p36.12; Center; 3The Susanne-Levy Gertner Oncogenetics Unit, The Institute of (iii) SNCA (OMIM# 163890), chromosome 4q22.1; (iv) Human Genetics, Sheba Medical Center, Tel Hashomer, Ramat Gan; and PARK2 4The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (OMIM# 602544), chromosome 6q25.2–q27; and (v) LRRK2 (OMIM# 609007); chromosome 12q12. Corresponding Author: Eitan Friedman, The Susanne-Levy Gertner Oncogenetics Unit, The Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel. Phone: 972-3- Selection criteria and SNPs 5303173; Fax: 972-3-535-7308; E-mail: [email protected] We searched peer-reviewed, English language publica- doi: 10.1158/1055-9965.EPI-13-0472 tions reporting GWAS analyses on all pathologic types Ó2013 American Association for Cancer Research. of breast cancer cases and controls of all ethnicities. 1464 Cancer Epidemiol Biomarkers Prev; 22(8) August 2013 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst June 13, 2013; DOI: 10.1158/1055-9965.EPI-13-0472 Loci of Parkinson's Disease and Breast Cancer Genes Do Not Segregate Table 1. Articles included in this review Populationa GWAS Article ref. Title Ethnicity Casesb Controlsb 13 Common variants at 12p11, 12q24, 9p21, Varied 10,200 9,531 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers 14 Genome-wide association analysis European, Asian 70,000 68,000 identifies three new breast cancer susceptibility loci 15 Genome-wide association study in East East-Asian 19,091 20,606 Asians identifies novel susceptibility (Chinese, Korean, Loci for breast cancer and Japanese) 16 Novel breast cancer susceptibility locus Varied (European, 11,880 12,487 at 9q31.2: results of a genome-wide West African, and association study East Asian) 17 Replication of breast cancer GWAS African American 316 7,484 susceptibility loci in the Women's Health Initiative African American SHARe Study 18 A combined analysis of genome-wide European 2,702 5,726 association studies in breast cancer 19 Replication of genome-wide discovered Cypriot 1,109 1,177 breast cancer risk loci in the Cypriot population 20 Potential novel candidate polymorphisms Canadian 1,501 1,563 identified in genome-wide association (predominantly study for breast cancer susceptibility Caucasian) 21 Common breast cancer susceptibility loci Caucasian 2,980 4,978 are associated with triple-negative breast cancer 22 A locus on 19p13 modifies risk of breast North American, 1,193 1,190 cancer in BRCA1 mutation carriers and European and is associated with hormone receptor- Australian negative breast cancer in the general population 23 Common genetic variants and European 2,680 2,546 modification of penetrance of BRCA2- associated breast cancer 24 Identification of a functional genetic Chinese, Japanese 12,671 10,339 variant at 16q12.1 for breast cancer risk: results from the Asia Breast Cancer Consortium 25 Ancestry-shift refinement mapping of Asian, European, 10,176 13,286 the C6orf97-ESR1 breast cancer and African susceptibility locus 26 Genome-wide association study European 16,235 17,120 identifies five new breast cancer susceptibility loci 27 Evidence for SMAD3 as a modifier of North American, 4,035 3,382 breast cancer risk in BRCA2 mutation European and carriers Australian (Continued on the following page) www.aacrjournals.org Cancer Epidemiol Biomarkers Prev; 22(8) August 2013 1465 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst June 13, 2013; DOI: 10.1158/1055-9965.EPI-13-0472 Kravitz et al. Table 1. Articles included in this review (Cont'd ) Populationa GWAS Article ref. Title Ethnicity Casesb Controlsb 28 Common variants associated with breast Caucasian 3,030 2,427 cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers 29 Newly discovered breast cancer Predominantly 4,380 4,280 susceptibility loci on 3p24 and 17q23.2 European 30 Association of ESR1 gene tagging SNPs European >25,000 >25,000 with breast cancer risk 31 Common genetic variation in candidate Predominantly 4,470 4,560 genes and susceptibility to subtypes of Caucasian breast cancer 32 A risk variant in an miR-125b binding site Predominantly 455 1,142 in BMPR1B is associated with breast Caucasian cancer pathogenesis 33 A multistage genome-wide association European 9,770 10,799 study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1) 34 Genome-wide association study Chinese 6,531 3,998 identifies a new breast cancer susceptibility locus at 6q25.1 35 Genome-wide association study provides Ashkenazi Jews 1,442 1,465 evidence for a breast cancer risk locus at 6q22.33 36 A common coding variant in CASP8 is Predominantly 11,391–18,290 14,753–22,670 associated with breast cancer risk European, Asian 37 Genome-wide association study European, Asian 26,258 26,894 identifies novel breast cancer susceptibility loci 38 Genetic variation in TNF and Caucasian 5,546 5,219 lymphotoxin-alpha (TNF-LTA) and breast cancer risk 39 A genome-wide association study Predominantly 2,921 3,214 identifies alleles in FGFR2 associated Caucasian with risk of sporadic postmenopausal breast cancer 40 Common variants on chromosomes 2q35 European, 4,554 17,577 and 16q12 confer susceptibility to multiethnic estrogen receptor-positive breast cancer 41 Commonly studied single-nucleotide Predominantly >20,000 >20,000 polymorphisms and breast cancer: European, Asian results from the Breast Cancer Association Consortium aPopulation of the entire study, including all stages/population sets. bNumber of cases/controls for all population sets. Publications assessing interactions between SNPs and from GWAS replication stage with SNPs showing P 0.05 other risk factors or breast cancer mortality risk, and that localize