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 LRRK2*G2019S 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. ©2013 AACR.

Breast cancer is more frequently diagnosed in patients with sporadic (1) and inherited forms (2) of Parkinson's disease than in the general population, yet the molecular basis for this association remains elusive. Given the involvement of Parkinson's disease predisposition genes in cell cycle, their reported functions as oncogenes and tumor suppressor genes (3), and somatic involvement in breast cancer tumorigenesis (e.g., ref. 4), we hypothesized that the Parkinson's disease–breast cancer association may be attributed to cosegregation and in linkage disequilibrium of breast cancer and Parkinson's disease predisposition genes. To test this notion, we conducted a focused literature search for single-nucleotide polymorphisms (SNP) that have been associated with breast cancer predisposition through genome-wide association studies (GWAS) and assessed if they are overrepresented in chromosomal regions associated with inherited forms of Parkinson's disease.

Search procedure

Database searches were carried out in PubMed (5), GWAS catalog of the National Human Genome Research Institute (6), and the publication database of the Breast Cancer Association Consortium (7) to identify GWAS studies published until July 2012.

Inherited Parkinson's disease genes and chromosomal loci

The following Parkinson's disease predisposition loci were targeted: (i) PARK7 (OMIM# 602533), chromosome 1p36.23; (ii) PINK1 (OMIM# 608309), chromosome 1p36.12; (iii) SNCA (OMIM# 163890), chromosome 4q22.1; (iv) PARK2 (OMIM# 602544), chromosome 6q25.2–q27; and (v) LRRK2 (OMIM# 609007); chromosome 12q12.

Selection criteria and SNPs

We searched peer-reviewed, English language publications reporting GWAS analyses on all pathologic types of breast cancer cases and controls of all ethnicities. Publications assessing interactions between SNPs and other risk factors or breast cancer 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 4 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.

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 breast cancer-associated SNPs located to one of the 4 “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 breast cancer-associated SNPs were located at genomic distance less than 500,000 bps from any of the analyzed Parkinson's disease genes.

Table 1.

Articles included in this review

Populationa
GWAS Article ref.TitleEthnicityCasesbControlsb
13 Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers Varied 10,200 9,531 
14 Genome-wide association analysis identifies three new breast cancer susceptibility loci European, Asian ∼70,000 ∼68,000 
15 Genome-wide association study in East Asians identifies novel susceptibility Loci for breast cancer East-Asian (Chinese, Korean, and Japanese) 19,091 20,606 
16 Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study Varied (European, West African, and East Asian) 11,880 12,487 
17 Replication of breast cancer GWAS susceptibility loci in the Women's Health Initiative African American SHARe Study African American 316 7,484 
18 A combined analysis of genome-wide association studies in breast cancer European 2,702 5,726 
19 Replication of genome-wide discovered breast cancer risk loci in the Cypriot population Cypriot 1,109 1,177 
20 Potential novel candidate polymorphisms identified in genome-wide association study for breast cancer susceptibility Canadian (predominantly Caucasian) 1,501 1,563 
21 Common breast cancer susceptibility loci are associated with triple-negative breast cancer Caucasian 2,980 4,978 
22 A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population North American, European and Australian 1,193 1,190 
23 Common genetic variants and modification of penetrance of BRCA2-associated breast cancer European 2,680 2,546 
24 Identification of a functional genetic variant at 16q12.1 for breast cancer risk: results from the Asia Breast Cancer Consortium Chinese, Japanese 12,671 10,339 
25 Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus Asian, European, and African 10,176 13,286 
26 Genome-wide association study identifies five new breast cancer susceptibility loci European 16,235 17,120 
27 Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers North American, European and Australian 4,035 3,382 
28 Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers Caucasian 3,030 2,427 
29 Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2 Predominantly European 4,380 4,280 
30 Association of ESR1 gene tagging SNPs with breast cancer risk European >25,000 >25,000 
31 Common genetic variation in candidate genes and susceptibility to subtypes of breast cancer Predominantly Caucasian 4,470 4,560 
32 A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis Predominantly Caucasian 455 1,142 
33 A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1) European 9,770 10,799 
34 Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1 Chinese 6,531 3,998 
35 Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33 Ashkenazi Jews 1,442 1,465 
36 A common coding variant in CASP8 is associated with breast cancer risk Predominantly European, Asian 11,391–18,290 14,753–22,670 
37 Genome-wide association study identifies novel breast cancer susceptibility loci European, Asian 26,258 26,894 
38 Genetic variation in TNF and lymphotoxin-alpha (TNF-LTA) and breast cancer risk Caucasian 5,546 5,219 
39 A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer Predominantly Caucasian 2,921 3,214 
40 Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer European, multiethnic 4,554 17,577 
41 Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium Predominantly European, Asian >20,000 >20,000 
Populationa
GWAS Article ref.TitleEthnicityCasesbControlsb
13 Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers Varied 10,200 9,531 
14 Genome-wide association analysis identifies three new breast cancer susceptibility loci European, Asian ∼70,000 ∼68,000 
15 Genome-wide association study in East Asians identifies novel susceptibility Loci for breast cancer East-Asian (Chinese, Korean, and Japanese) 19,091 20,606 
16 Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study Varied (European, West African, and East Asian) 11,880 12,487 
17 Replication of breast cancer GWAS susceptibility loci in the Women's Health Initiative African American SHARe Study African American 316 7,484 
18 A combined analysis of genome-wide association studies in breast cancer European 2,702 5,726 
19 Replication of genome-wide discovered breast cancer risk loci in the Cypriot population Cypriot 1,109 1,177 
20 Potential novel candidate polymorphisms identified in genome-wide association study for breast cancer susceptibility Canadian (predominantly Caucasian) 1,501 1,563 
21 Common breast cancer susceptibility loci are associated with triple-negative breast cancer Caucasian 2,980 4,978 
22 A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population North American, European and Australian 1,193 1,190 
23 Common genetic variants and modification of penetrance of BRCA2-associated breast cancer European 2,680 2,546 
24 Identification of a functional genetic variant at 16q12.1 for breast cancer risk: results from the Asia Breast Cancer Consortium Chinese, Japanese 12,671 10,339 
25 Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus Asian, European, and African 10,176 13,286 
26 Genome-wide association study identifies five new breast cancer susceptibility loci European 16,235 17,120 
27 Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers North American, European and Australian 4,035 3,382 
28 Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers Caucasian 3,030 2,427 
29 Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2 Predominantly European 4,380 4,280 
30 Association of ESR1 gene tagging SNPs with breast cancer risk European >25,000 >25,000 
31 Common genetic variation in candidate genes and susceptibility to subtypes of breast cancer Predominantly Caucasian 4,470 4,560 
32 A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis Predominantly Caucasian 455 1,142 
33 A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1) European 9,770 10,799 
34 Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1 Chinese 6,531 3,998 
35 Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33 Ashkenazi Jews 1,442 1,465 
36 A common coding variant in CASP8 is associated with breast cancer risk Predominantly European, Asian 11,391–18,290 14,753–22,670 
37 Genome-wide association study identifies novel breast cancer susceptibility loci European, Asian 26,258 26,894 
38 Genetic variation in TNF and lymphotoxin-alpha (TNF-LTA) and breast cancer risk Caucasian 5,546 5,219 
39 A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer Predominantly Caucasian 2,921 3,214 
40 Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer European, multiethnic 4,554 17,577 
41 Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium Predominantly European, Asian >20,000 >20,000 

aPopulation of the entire study, including all stages/population sets.

bNumber of cases/controls for all population sets.

View Large
Table 2.

Breast cancer–associated SNPs on chromosomes of interest

ChrGene/regionaSNPChromosomal positionbPc
1 RIZ1 rs2235515 14,141,344 0.0204 
1 ALPL rs3200254 21,894,735 0.038 
1 ALPL rs3738097 21,894,816 0.036 
1 WNT4 rs2473253 22,538,787 0.023 
1 TRIT1 rs17570439 40,324,210 <0.0001 
1 MYCL1 rs3134615 40,362,066 <0.0001 
1 MAST2 rs4660891 46,319,447 0.004 
1 PIK3R3 rs785467 46,521,559 0.019 
1 GNG12 rs3766265 68,198,152 <0.0002 
1 GNG12 rs3766270 68,215,424 <0.0005 
1 DPYD rs12133176 97,706,237 0.0284 
1 DPYD rs4950025 97,717,279 0.0121 
1 DPYD rs528455 97,749,198 0.0442 
1 DPYD rs10875071 97,814,678 0.0013 
1 DPYD rs11165845 97,819,405 0.0273 
1 DPYD rs12566907 97,862,237 0.0051 
1 DPYD rs7548189 97,867,713 <0.0005 
1 DPYD rs4434871 97,873,007 0.0066 
1 DPYD rs4497250 97,882,933 0.0174 
1 DPYD rs4379706 98,322,379 0.0418 
1 DPYD rs6677116 98,337,283 0.0409 
1 DPYD rs1801265 98,348,885 0.0493 
1 COL11A1 rs1451036 103,149,593 0.0082 
1 VAV3 rs2494059 108,239,958 0.0448 
1 VAV3 rs1332684 108,414,230 0.0469 
1 TRIM45 rs1048635 117,654,858 0.0013 
1  rs11249433 121,280,613 <0.0001 
1 IL6R rs1386821 154,382,049 0.019 
1 ARHGEF2 rs1889532 155,951,502 0.032 
1 CD1A rs411089 158,224,825 0.0452 
1 CD1C rs10797006 158,257,838 0.0286 
1 TBX19 rs2075976 168,269,338 0.0565 
1 CACNA1E rs3820260 181,638,511 <0.0001 
1 PLA2G4A rs6683363 186,927,369 0.0274 
1 CR1 rs650877 207,748,793 0.0192 
1 CR1 rs11118131 207,761,196 0.0221 
1 CR1 rs677066 207,773,991 0.0036 
1 CR1 rs6691117 207,782,931 0.0039 
1 CR1 rs12034383 207,803,595 0.002 
1  rs4546928 222,079,537 0.0095 
1 ENAH rs3795443 225,675,003 0.0354 
1 ENAH rs4653643 225,675,459 0.0063 
1 ENAH rs2840967 225,824,028 0.008 
1 PARK7 Range: 8,021,714–8,045,342 Strand: plus 
1 PINK1 Range: 20,959,948–20,978,004 Strand: plus 
4 TACC3 Rs1374468 1,724,579 0.04 
4 ACOX3 Rs747580 8,373,088 0.0321 
4 ACOX3 Rs2631731 8,429,817 0.0207 
4  Rs2222309 12,691,840 0.0123 
4 LDB2 Rs6837118 16,729,576 0.049 
4  Rs2697705 17,418,921 <0.0001 
4 KCNIP4 Rs1460475 21,565,822 0.02 
4  Rs10025483 24,454,338 0.0122 
4  Rs9884706 32,632,087 <0.0005 
4  Rs2166278 32,642,222 <0.0006 
4 KIAA1239 Rs12505080 37,349,340 <0.0001 
4  Rs7696175 38,820,986 <0.0001 
4 SHISA3 Rs3109633 42,380,579 0.047 
4 TEC Rs2352593 48,197,767 0.026 
4 FRYL Rs6843340 48,619,937 0.0009 
4 UGT2B4 Rs1389930 70,347,172 0.0488 
4 UGT2A1 Rs6600793 70,477,984 0.006 
4 STE Rs3775775 70,718,282 0.0182 
4 STE Rs3736599 70,725,821 0.0053 
4 HNRPDL Rs1559949 83,340,605 0.0165 
4 HNRPDL Rs4285076 83,369,287 0.038 
4 MAPK10 Rs4403040 87,038,481 <0.0009 
4 BMPR1B Rs1970801 96,070,525 <0.0002 
4 BMPR1B Rs1434536 96,075,965 <0.0002 
4 BMPR1B Rs11097457 96,076,813 <0.0002 
4 ADH1B Rs1042026 100,228,466 0.0253 
4 ADH1C Rs698 100,260,789 0.0196 
4 MANBA Rs2866413 103,557,077 0.05 
4 MANBA Rs228611 103,561,709 0.0259 
4 MANBA Rs228614 103,578,637 0.0085 
4 MANBA Rs228617 103,580,788 0.0047 
4 MANBA Rs227284 103,607,635 0.0227 
4 MANBA Rs227368 103,611,845 0.0101 
4 MANBA Rs223502 103,640,758 0.034 
4 MANBA Rs223500 103,647,047 0.0248 
4  Rs9761051 120,013,590 <0.0006 
4 LOC644624 Rs1433211 124,763,465 0.014 
4  Rs724950 128,342,120 <0.0001 
4  Rs2862752 132,285,856 0.0134 
4 NR3C2 Rs16998733 149,337,408 <0.0001 
4  Rs6837016 155,890,241 0.0004 
4 PDGFC Rs1816164 157,696,636 0.0475 
4  Rs581849 159,981,640 0.0385 
4  Rs2014078 160,019,492 0.0127 
4  Rs11721955 160,046,565 0.011 
4 DDX60L Rs13110927 169,299,528 <0.0001 
4 SNCA Range: 90,645,250–90,759,447 Strand: minus 
6 IRF4 Rs12203592 396,321 0.0017 
6  Rs1265273 4,469,641 <0.0002 
6  Rs9393089 9,095,364 0.0247 
6 PHACTR1 Rs9473086 12,957,035 0.0047 
6 TPMT Rs9367980 18,131,464 0.014 
6 THEM2 Rs3777663 24,700,235 0.013 
6 THEM2 Rs9356943 24,709,830 0.029 
6 LOC134997 Rs9393597 24,973,108 <0.0001 
6 LRRC16A Rs9467504 25,414,325 <0.0001 
6 TNF Rs361525 31,543,101 0.008 
6 LSM2 rs480092 31,764,899 0.0465 
6 BAT8 rs535586 31,860,337 0.0138 
6 HLA-DRA rs3129871 32,406,342 0.0147 
6 HLA-DRA rs2395182 32,413,317 0.0155 
6 TCP11 rs2057537 35,090,279 <0.0005 
6 CDKN1A rs3176336 36,648,816 0.003 
6 C6orf89 rs9380618 36,853,543 <0.0008 
6  rs2799359 46,144,252 <0.0010 
6 GFRAL rs12210212 55,202,199 0.019 
6 HMGCLL1 rs4072373 55,317,936 0.029 
6  rs9454109 67,947,988 0.0178 
6  rs6919990 77,384,675 0.0019 
6  rs3857481 87,124,569 <0.0001 
6 QRSL1 rs12333016 107,099,191 <0.0004 
6 CDC40 rs7761436 110,502,831 0.0163 
6 FYN rs6914091 112,081,735 0.0077 
6 ROS1 rs9401003 117,718,303 <0.0007 
6 RNF146 rs2180341 127,600,630 <0.0001 
6 RNF146 rs6569479 127,606,588 <0.0001 
6 ECHDC1 rs6569480 127,621,748 <0.0001 
6 ECHDC1 rs7776136 127,638,348 <0.0001 
6  rs11759744 127,708,247 0.0608 
6 THEMIS rs9491859 128,064,363 <0.0001 
6 VNN2 rs12211125 133,065,049 0.0103 
6  rs9485372 149,608,874 <0.0001 
6 C6orf97 rs3757318 151,914,113 <0.0001 
6 C6orf97 rs12662670 151,918,856 <0.0001 
6 C6orf97 rs9383932 151,919,720 <0.0003 
6 C6orf97 rs1038304 151,933,175 <0.0001 
6 C6orf97 rs6929137 151,936,677 0.017 
6 C6orf97 rs3734804 151,939,181 0.0014 
6 C6orf97 rs3734805 151,939,350 <0.0001 
6 C6orf97 rs6932260 151,939,560 <0.0008 
6 C6orf97 rs9383589 151,940,260 <0.0001 
6 C6orf97 rs10872676 151,943,977 0.0016 
6 C6orf97-ESR1 rs12665607 151,946,629 <0.0001 
6 C6orf97-ESR1 rs7752591 151,947,068 0.0003 
6 C6orf97-ESR1 rs2046210 151,948,366 <0.0001 
6 C6orf97-ESR1 rs9397435 151,951,220 <0.0001 
6  rs6900157 151,954,127 <0.0001 
6 C6orf97-ESR1 rs6930633 151,958,091 0.0504 
6 C6orf97-ESR1 rs852003 151,962,202 <0.0002 
6 C6orf97-ESR1 rs77275268 151,969,198 0.0074 
6 C6orf97-ESR1 rs9383938 151,987,357 <0.0004 
6 ESR1 rs3020314 152,270,672 <0.0001 
6 ESR1 rs3020377 152,272,398 0.0043 
6 ESR1 rs3020390 152,276,458 0.0046 
6 ESR1 rs3020317 152,278,741 0.003 
6 ESR1 rs3020394 152,279,213 0.0034 
6 ESR1 rs3020396 152,279,878 0.0038 
6 ESR1 rs3020400 152,282,546 0.0047 
6 ESR1 rs3020401 152,283,044 0.0039 
6 ESR1 rs1884051 152,283,279 0.0299 
6 ESR1 rs1884054 152,291,566 0.0328 
6 ESR1 rs9383951 152,295,613 <0.0001 
6 ESR1 rs3020405 152,299,953 0.0077 
6 ESR1 rs726282 152,302,654 0.0167 
6 ESR1 rs3020407 152,307,261 0.0062 
6  rs694975 153,189,269 0.034 
6 TIAM2 rs9478620 155,513,482 0.0351 
6 TIAM2 rs3749870 155,554,351 0.0362 
6 SOD2 rs4880 160,113,872 0.056 
6 PARK2 Range: 161,768,590–163,148,834 Strand: minus 
12 FOXM1 rs2074985 2,978,254 0.034 
12 PRMT8 rs10774156 3,664,704 0.0462 
12 PRMT8 rs1029766 3,703,500 0.0017 
12 FGF23 rs7961824 4,476,217 0.0387 
12 MLF2 rs2302371 6,858,126 0.0494 
12 CDKN1B rs34330 12,870,695 0.012 
12 GRIN2B rs2284424 13,988,870 <0.0009 
12  rs7313833 28,083,196 <0.0001 
12 PTHLH rs10771399 28,155,080 <0.0001 
12 FGD4 rs10771973 32,792,974 <0.0002 
12  rs12304191 47,949,145 0.0334 
12 OR6C74 rs4388990 55,641,295 0.0076 
12 RASSF3 rs15958 65,091,314 0.016 
12 TMTC2 rs17740709 83,423,340 <0.0001 
12 MKRN5 rs1461282 88,186,449 0.0444 
12  rs7310517 89,149,235 <0.0006 
12  rs10507088 97,879,744 <0.0003 
12 GLTP rs7966820 110,302,270 0.0004 
12  rs10850145 113,944,129 <0.0001 
12  rs1292011 115,836,522 <0.0001 
12  rs7955262 116,206,962 <0.0001 
12 KSR2 rs12425296 117,987,574 0.042 
12 KSR2 rs4766886 118,345,121 0.047 
12 CIT rs4766950 120,278,241 0.024 
12 AACS rs7307700 125,588,197 0.002 
12  rs6489171 127,882,841 <0.0001 
12  rs11609565 132,093,024 0.047 
12 LRRK2 Range: 40,618,813–40,763,087 Strand: plus 
ChrGene/regionaSNPChromosomal positionbPc
1 RIZ1 rs2235515 14,141,344 0.0204 
1 ALPL rs3200254 21,894,735 0.038 
1 ALPL rs3738097 21,894,816 0.036 
1 WNT4 rs2473253 22,538,787 0.023 
1 TRIT1 rs17570439 40,324,210 <0.0001 
1 MYCL1 rs3134615 40,362,066 <0.0001 
1 MAST2 rs4660891 46,319,447 0.004 
1 PIK3R3 rs785467 46,521,559 0.019 
1 GNG12 rs3766265 68,198,152 <0.0002 
1 GNG12 rs3766270 68,215,424 <0.0005 
1 DPYD rs12133176 97,706,237 0.0284 
1 DPYD rs4950025 97,717,279 0.0121 
1 DPYD rs528455 97,749,198 0.0442 
1 DPYD rs10875071 97,814,678 0.0013 
1 DPYD rs11165845 97,819,405 0.0273 
1 DPYD rs12566907 97,862,237 0.0051 
1 DPYD rs7548189 97,867,713 <0.0005 
1 DPYD rs4434871 97,873,007 0.0066 
1 DPYD rs4497250 97,882,933 0.0174 
1 DPYD rs4379706 98,322,379 0.0418 
1 DPYD rs6677116 98,337,283 0.0409 
1 DPYD rs1801265 98,348,885 0.0493 
1 COL11A1 rs1451036 103,149,593 0.0082 
1 VAV3 rs2494059 108,239,958 0.0448 
1 VAV3 rs1332684 108,414,230 0.0469 
1 TRIM45 rs1048635 117,654,858 0.0013 
1  rs11249433 121,280,613 <0.0001 
1 IL6R rs1386821 154,382,049 0.019 
1 ARHGEF2 rs1889532 155,951,502 0.032 
1 CD1A rs411089 158,224,825 0.0452 
1 CD1C rs10797006 158,257,838 0.0286 
1 TBX19 rs2075976 168,269,338 0.0565 
1 CACNA1E rs3820260 181,638,511 <0.0001 
1 PLA2G4A rs6683363 186,927,369 0.0274 
1 CR1 rs650877 207,748,793 0.0192 
1 CR1 rs11118131 207,761,196 0.0221 
1 CR1 rs677066 207,773,991 0.0036 
1 CR1 rs6691117 207,782,931 0.0039 
1 CR1 rs12034383 207,803,595 0.002 
1  rs4546928 222,079,537 0.0095 
1 ENAH rs3795443 225,675,003 0.0354 
1 ENAH rs4653643 225,675,459 0.0063 
1 ENAH rs2840967 225,824,028 0.008 
1 PARK7 Range: 8,021,714–8,045,342 Strand: plus 
1 PINK1 Range: 20,959,948–20,978,004 Strand: plus 
4 TACC3 Rs1374468 1,724,579 0.04 
4 ACOX3 Rs747580 8,373,088 0.0321 
4 ACOX3 Rs2631731 8,429,817 0.0207 
4  Rs2222309 12,691,840 0.0123 
4 LDB2 Rs6837118 16,729,576 0.049 
4  Rs2697705 17,418,921 <0.0001 
4 KCNIP4 Rs1460475 21,565,822 0.02 
4  Rs10025483 24,454,338 0.0122 
4  Rs9884706 32,632,087 <0.0005 
4  Rs2166278 32,642,222 <0.0006 
4 KIAA1239 Rs12505080 37,349,340 <0.0001 
4  Rs7696175 38,820,986 <0.0001 
4 SHISA3 Rs3109633 42,380,579 0.047 
4 TEC Rs2352593 48,197,767 0.026 
4 FRYL Rs6843340 48,619,937 0.0009 
4 UGT2B4 Rs1389930 70,347,172 0.0488 
4 UGT2A1 Rs6600793 70,477,984 0.006 
4 STE Rs3775775 70,718,282 0.0182 
4 STE Rs3736599 70,725,821 0.0053 
4 HNRPDL Rs1559949 83,340,605 0.0165 
4 HNRPDL Rs4285076 83,369,287 0.038 
4 MAPK10 Rs4403040 87,038,481 <0.0009 
4 BMPR1B Rs1970801 96,070,525 <0.0002 
4 BMPR1B Rs1434536 96,075,965 <0.0002 
4 BMPR1B Rs11097457 96,076,813 <0.0002 
4 ADH1B Rs1042026 100,228,466 0.0253 
4 ADH1C Rs698 100,260,789 0.0196 
4 MANBA Rs2866413 103,557,077 0.05 
4 MANBA Rs228611 103,561,709 0.0259 
4 MANBA Rs228614 103,578,637 0.0085 
4 MANBA Rs228617 103,580,788 0.0047 
4 MANBA Rs227284 103,607,635 0.0227 
4 MANBA Rs227368 103,611,845 0.0101 
4 MANBA Rs223502 103,640,758 0.034 
4 MANBA Rs223500 103,647,047 0.0248 
4  Rs9761051 120,013,590 <0.0006 
4 LOC644624 Rs1433211 124,763,465 0.014 
4  Rs724950 128,342,120 <0.0001 
4  Rs2862752 132,285,856 0.0134 
4 NR3C2 Rs16998733 149,337,408 <0.0001 
4  Rs6837016 155,890,241 0.0004 
4 PDGFC Rs1816164 157,696,636 0.0475 
4  Rs581849 159,981,640 0.0385 
4  Rs2014078 160,019,492 0.0127 
4  Rs11721955 160,046,565 0.011 
4 DDX60L Rs13110927 169,299,528 <0.0001 
4 SNCA Range: 90,645,250–90,759,447 Strand: minus 
6 IRF4 Rs12203592 396,321 0.0017 
6  Rs1265273 4,469,641 <0.0002 
6  Rs9393089 9,095,364 0.0247 
6 PHACTR1 Rs9473086 12,957,035 0.0047 
6 TPMT Rs9367980 18,131,464 0.014 
6 THEM2 Rs3777663 24,700,235 0.013 
6 THEM2 Rs9356943 24,709,830 0.029 
6 LOC134997 Rs9393597 24,973,108 <0.0001 
6 LRRC16A Rs9467504 25,414,325 <0.0001 
6 TNF Rs361525 31,543,101 0.008 
6 LSM2 rs480092 31,764,899 0.0465 
6 BAT8 rs535586 31,860,337 0.0138 
6 HLA-DRA rs3129871 32,406,342 0.0147 
6 HLA-DRA rs2395182 32,413,317 0.0155 
6 TCP11 rs2057537 35,090,279 <0.0005 
6 CDKN1A rs3176336 36,648,816 0.003 
6 C6orf89 rs9380618 36,853,543 <0.0008 
6  rs2799359 46,144,252 <0.0010 
6 GFRAL rs12210212 55,202,199 0.019 
6 HMGCLL1 rs4072373 55,317,936 0.029 
6  rs9454109 67,947,988 0.0178 
6  rs6919990 77,384,675 0.0019 
6  rs3857481 87,124,569 <0.0001 
6 QRSL1 rs12333016 107,099,191 <0.0004 
6 CDC40 rs7761436 110,502,831 0.0163 
6 FYN rs6914091 112,081,735 0.0077 
6 ROS1 rs9401003 117,718,303 <0.0007 
6 RNF146 rs2180341 127,600,630 <0.0001 
6 RNF146 rs6569479 127,606,588 <0.0001 
6 ECHDC1 rs6569480 127,621,748 <0.0001 
6 ECHDC1 rs7776136 127,638,348 <0.0001 
6  rs11759744 127,708,247 0.0608 
6 THEMIS rs9491859 128,064,363 <0.0001 
6 VNN2 rs12211125 133,065,049 0.0103 
6  rs9485372 149,608,874 <0.0001 
6 C6orf97 rs3757318 151,914,113 <0.0001 
6 C6orf97 rs12662670 151,918,856 <0.0001 
6 C6orf97 rs9383932 151,919,720 <0.0003 
6 C6orf97 rs1038304 151,933,175 <0.0001 
6 C6orf97 rs6929137 151,936,677 0.017 
6 C6orf97 rs3734804 151,939,181 0.0014 
6 C6orf97 rs3734805 151,939,350 <0.0001 
6 C6orf97 rs6932260 151,939,560 <0.0008 
6 C6orf97 rs9383589 151,940,260 <0.0001 
6 C6orf97 rs10872676 151,943,977 0.0016 
6 C6orf97-ESR1 rs12665607 151,946,629 <0.0001 
6 C6orf97-ESR1 rs7752591 151,947,068 0.0003 
6 C6orf97-ESR1 rs2046210 151,948,366 <0.0001 
6 C6orf97-ESR1 rs9397435 151,951,220 <0.0001 
6  rs6900157 151,954,127 <0.0001 
6 C6orf97-ESR1 rs6930633 151,958,091 0.0504 
6 C6orf97-ESR1 rs852003 151,962,202 <0.0002 
6 C6orf97-ESR1 rs77275268 151,969,198 0.0074 
6 C6orf97-ESR1 rs9383938 151,987,357 <0.0004 
6 ESR1 rs3020314 152,270,672 <0.0001 
6 ESR1 rs3020377 152,272,398 0.0043 
6 ESR1 rs3020390 152,276,458 0.0046 
6 ESR1 rs3020317 152,278,741 0.003 
6 ESR1 rs3020394 152,279,213 0.0034 
6 ESR1 rs3020396 152,279,878 0.0038 
6 ESR1 rs3020400 152,282,546 0.0047 
6 ESR1 rs3020401 152,283,044 0.0039 
6 ESR1 rs1884051 152,283,279 0.0299 
6 ESR1 rs1884054 152,291,566 0.0328 
6 ESR1 rs9383951 152,295,613 <0.0001 
6 ESR1 rs3020405 152,299,953 0.0077 
6 ESR1 rs726282 152,302,654 0.0167 
6 ESR1 rs3020407 152,307,261 0.0062 
6  rs694975 153,189,269 0.034 
6 TIAM2 rs9478620 155,513,482 0.0351 
6 TIAM2 rs3749870 155,554,351 0.0362 
6 SOD2 rs4880 160,113,872 0.056 
6 PARK2 Range: 161,768,590–163,148,834 Strand: minus 
12 FOXM1 rs2074985 2,978,254 0.034 
12 PRMT8 rs10774156 3,664,704 0.0462 
12 PRMT8 rs1029766 3,703,500 0.0017 
12 FGF23 rs7961824 4,476,217 0.0387 
12 MLF2 rs2302371 6,858,126 0.0494 
12 CDKN1B rs34330 12,870,695 0.012 
12 GRIN2B rs2284424 13,988,870 <0.0009 
12  rs7313833 28,083,196 <0.0001 
12 PTHLH rs10771399 28,155,080 <0.0001 
12 FGD4 rs10771973 32,792,974 <0.0002 
12  rs12304191 47,949,145 0.0334 
12 OR6C74 rs4388990 55,641,295 0.0076 
12 RASSF3 rs15958 65,091,314 0.016 
12 TMTC2 rs17740709 83,423,340 <0.0001 
12 MKRN5 rs1461282 88,186,449 0.0444 
12  rs7310517 89,149,235 <0.0006 
12  rs10507088 97,879,744 <0.0003 
12 GLTP rs7966820 110,302,270 0.0004 
12  rs10850145 113,944,129 <0.0001 
12  rs1292011 115,836,522 <0.0001 
12  rs7955262 116,206,962 <0.0001 
12 KSR2 rs12425296 117,987,574 0.042 
12 KSR2 rs4766886 118,345,121 0.047 
12 CIT rs4766950 120,278,241 0.024 
12 AACS rs7307700 125,588,197 0.002 
12  rs6489171 127,882,841 <0.0001 
12  rs11609565 132,093,024 0.047 
12 LRRK2 Range: 40,618,813–40,763,087 Strand: plus 

aIf applicable.

bActual position for SNP search on map.

cSmallest P value of all appearances.

View Large

No breast cancer-associated SNPs localized in the genomic proximity of Parkinson's disease predisposition genes found on chromosomes 1, 4, 6, or 12. Thus, the observed increased breast cancer rates in inherited forms of Parkinson's disease cannot be accounted for by a simple cosegregation and shared genomic loci.

Despite the lack of association at the genomic level between breast cancer SNPs and Parkinson's disease predisposition genes, other genetic or epigenetic mechanisms may still be operative. If breast cancer results from the actions of multiple rare alleles, each one with a medium effect on breast cancer 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 breast cancer and Parkinson's disease risk in a large U.S. cohort (9). To assess this possibility, a whole-exome, or even a whole-genome, dataset of breast cancer and Parkinson's disease cases should be queried, when it becomes available.

Another possible explanation for the breast cancer–Parkinson's disease association may be epigenetic: microRNAs (miR) may be involved in promoting the expression of breast cancer-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 breast cancer cells via focal adhesion kinase expression (10). Finally, the reported association between breast cancer and Parkinson's disease may relate to abnormal estrogen metabolism. Women have a reduced Parkinson's disease risk compared with age-matched men, a phenomenon attributed by some researchers to the neuroprotective properties of estrogen in Parkinson's disease relevant neurons (11). Tamoxifen, a selective estrogen receptor (ER) modulator given to patients with ER-positive breast cancer, has been reported to increase Parkinson's disease rates (12). Thus, in postmenopausal women, markedly reduced estrogen synthesis may both increase the risk of Parkinson's disease and promote the expression of ER genes in breast tissue to enhance breast cancer risk. Noteworthy this is a viable speculation that should be viewed as such.

In conclusion, the association between breast cancer and the most common genetic forms of inherited Parkinson's disease cannot be accounted for by allele cosegregation at the genomic level.

No potential conflicts of interest were disclosed.

Conception and design: S.B. Hassin, R. Inzelberg, E. Friedman

Development of methodology: E. Kravitz, Y. Laitman, R. Inzelberg, E. Friedman

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): E. Kravitz, Y. Laitman, S.B. Hassin

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): E. Kravitz, Y. Laitman, E. Friedman

Writing, review, and/or revision of the manuscript: E. Kravitz, S.B. Hassin, R. Inzelberg, E. Friedman

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): E. Kravitz, Y. Laitman

Study supervision: R. Inzelberg

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2013