Genetic Susceptibility to Triple-Negative Breast Cancer

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  • 2013;73:2025-2030. Published OnlineFirst March 27, 2013.Cancer Res

    Kristen N. Stevens, Celine M. Vachon and Fergus J. Couch

    Genetic Susceptibility to Triple-Negative Breast Cancer

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    10.1158/0008-5472.CAN-12-1699doi:Access the most recent version of this article at:

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  • Review

    Genetic Susceptibility to Triple-Negative Breast Cancer

    Kristen N. Stevens1, Celine M. Vachon1, and Fergus J. Couch1,2

    AbstractTriple-negative breast cancers (TNBC), dened by the absence of estrogen receptor, progesterone receptor, and

    HER-2 expression, account for 12% to 24% of all breast cancers. TNBC is associated with early recurrence ofdisease and poor outcome. Germline mutations in the BRCA1 and BRCA2 breast cancer susceptibility genes havebeen associated with up to 15% of TNBC, and TNBC accounts for 70% of breast tumors arising in BRCA1mutationcarriers and 16% to 23% of breast tumors in BRCA2 carriers. Whether germline mutations in other breast cancersusceptibility genes also predispose to TNBC remains to be determined. Common variation in a subset of the 72known breast cancer susceptibility loci identied through genome-wide association studies and other large-scalegenotyping efforts have also been associated with risk of TNBC (TOX3, ESR1, RAD51L1, TERT, 19p13.1, 20q11,MDM4, 2p24.1, and FTO). Furthermore, variation in the 19p13.1 locus and the MDM4 locus has been associatedwith TNBC, but not other forms of breast cancer, suggesting that these are TNBC-specic loci. Thus, TNBC can bedistinguished fromother breast cancer subtypes by a unique pattern of common and rare germline predispositionalleles. Additional efforts to combine genetic and epidemiologic data are needed to better understand the etiologyof this aggressive form of breast cancer, to identify prevention and therapeutic targets, and to impact clinicalpractice through the development of risk prediction models. Cancer Res; 73(7); 202530. 2012 AACR.

    Triple-Negative Breast Cancer: Epidemiologicand Clinical Characteristics

    Triple-negative breast cancers (TNBC) are dened by theabsence of estrogen receptor (ER), progesterone receptor (PR),and HER2 expression (1). Triple-negative breast tumorsaccount for 12% to 24% of themore than 200,000 breast cancersdiagnosed each year in the United States (1, 2). Compared withother breast cancer subtypes, TNBC is associatedwith a distinctset of epidemiologic risk factors, which has been reviewed indetail (1, 3). Briey, women with TNBC are more likely to beyoung or premenopausal, African American or Hispanic, lowsocioeconomic status, andBRCA1mutation carriers. Additionalfactors associatedwith risk ofTNBCare earlier age atmenarche,higher body mass index during premenopausal years, higherparity, and lower lifetime duration of breastfeeding. Recurrenceand disease progression are also relatively common for womenwithTNBC,with a peak risk of recurrencewithin therst 3 yearsafter treatment (4). Poor clinical outcomes for women withtriple-negative tumors may in part be explained by intrinsicallyaggressive tumor pathology, including high mitotic index andnuclear pleomorphism yielding high histologic grade, high

    proliferation, medullary and metaplastic features, and a highfrequency of TP53 mutation (1, 5).

    Molecular Classication of TNBCWhile the 3 immunohistochemical markers, ER, PR, and

    HER2, are routinely used in clinical practice to classify breasttumors and thereby determine potential courses of therapy,more detailed molecular characterization of breast cancers bygene expression proling has identied at least 5 distinct"intrinsic" breast cancer subtypes that seem to representdistinct disease processes (6). These intrinsic subtypes include2 luminal epithelial/ER-positive subgroups (A and B) differ-entiated by the level of expression of HER-2 and/or prolifer-ation genes, a HER-2 overexpressing group, a normal breast-like or unclassied group, and a basal-like group that is largelyTNBC and expresses basal epithelial cell layer proteins includ-ing cytokeratins 5 and 6 (CK5/6) and EGF receptor (EGFR). Inaddition, a claudin-low group has been identied that is alsocomposed largely of triple-negative tumors (71%), character-ized by lack of expression of luminal differentiation markers,enrichment for epithelial-to-mesenchymal transition markers,immune response genes, and cancer stem cell-like features (7).Most recently, a study of 1,992 breast tumors using geneexpression arrays and copy number variation identied 10possible subtypes of breast cancer, which differed by clinicaloutcome (8). The majority of basal-like tumors within thatstudy again formed a single stable high genomic instabilitysubgroup associated with rapid recurrence.

    While basal-like tumors seem to have very similar molecularcharacteristics, it is clear that triple-negative tumors are notsynonymous with basal-like tumors. Specically, 15% to 20% oftriple-negative tumors do not express basal markers and 15%

    Authors' Afliations: Departments of 1Health Sciences Research and2Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota

    Note: Supplementary data for this article are available at Cancer ResearchOnline (http://cancerres.aacrjournals.org/).

    Corresponding Author: Fergus J. Couch, Mayo Clinic, Stabile 2-42, 200First Street SW, Rochester, MN 55905. Phone: 507-284-3623; Fax: 507-538-1937; E-mail: couch.fergus@mayo.edu

    doi: 10.1158/0008-5472.CAN-12-1699

    2012 American Association for Cancer Research.

    CancerResearch

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  • to 20% of nontriple-negative tumors express basal markers.Furthermore, as recent studies have suggested further subdi-vision of TNBC into immunomodulatory, mesenchymal, mes-enchymal stem-like, luminal androgen receptor, and distinctbasal-like subtypes (9), there are likely subtypes of TNBC thatdiffer substantially from basal-like tumors. However, becausethe basal-like denition of tumors is typically available only inan experimental research setting, based on gene expressionproling, the triple-negative phenotype is often used as asurrogate for basal-like status in clinical and observationalstudies. Additional work is necessary to better dene triple-negative subtypes and the epidemiologic, clinical, and prog-nostic characteristics of these tumors.

    High-Risk Susceptibility Genes for TNBCGenetic susceptibility to TNBC has been associated with

    rare, highly penetrant, germline mutations in the BRCA1 andBRCA2 breast cancer predisposition genes. Approximately 70%of breast tumors that develop in women with inherited muta-tions in BRCA1 exhibit low or absent expression of ER, PR andHER-2 histologic markers, and morphologic features, recur-rence patterns, and death rates (10) are similar to unselectedTNBC tumors (1). Consistent with these observations, severalstudies of unselected triple-negative cases have shown that 9%to 14% overall and approximately 20% of cases diagnosedunder the age of 50 years harbor germline BRCA1 mutations(11). Similarly, as many as 34% of triple-negative cases with afamily history of breast cancer and 30% of triple-negative casesfrom women of Ashkenazi Jewish ancestry are associated withgermline BRCA1 mutations (12, 13). To a lesser extent, BRCA2mutations are also associated with TNBC in that 16% to 23% ofbreast tumors arising in BRCA2 mutation carriers displaytriple-negative properties (10). While few breast cancer sus-ceptibility genes have been systematically evaluated for muta-tions in triple-negative cases, it is already clear that up to 15%ofunselected triple-negative cases result from inherited muta-tions in the BRCA1 and BRCA2 high-risk susceptibility genes.

    A recent report from The Cancer Genome Atlas (TCGA)Network provides further insight into the distribution ofmutations in high-risk genes by breast cancer subtypes, where49 deleterious variants in 9 genes (ATM, BRCA1, BRCA2, BRIP1,CHEK2, NBN, PTEN, RAD51C, and TP53) were detected inexome-sequencing data from 507 breast tumors (14). Amongthe 93 basal-like tumors in this group, mutations were iden-tied in BRCA1 (9/13 BRCA1 mutations), BRCA2 (3/14 BRCA2mutations), RAD51C (1/1 RAD51C mutation), and TP53 (1/2TP53 mutations). This conrms the known associations withBRCA1 and BRCA2 and suggests that germline RAD51C andTP53 mutations may be found among basal-like breast cancercases. Interestingly, no mutations in the remaining 5 genes(ATM, BRIP1, CHEK2, NBN, and PTEN) were detected amongbasal tumors. Large-scale examination of the mutational spec-trum of all known breast cancer susceptibility genes (BRCA1,BRCA2, CHEK2, PALB2, BRIP1, TP53, PTEN, STK11, CDH1, ATM,BARD1, RAD51C, RAD51D, NBN, and XRCC2; ref. 15) in womenwith TNBC, and the individual TNBC subtypes, will be neces-sary to fully understand the role of these genes in triple-negative risk.

    Genetic Risk Factors for Breast Cancer by ERStatus

    Excluding BRCA1 and BRCA2, relatively little is known aboutthe inherited genetic factors that increase risk for TNBC. Themajority of information on genetic susceptibility to this aggres-sive form of breast cancer has come from investigation ofcommonly inherited variants with small effects (OR

  • 2013 American Association for Cancer Research

    A ER-positive

    Triple-negative risk: Strong evidence

    Triple-negative risk: Strong evidence

    Triple-negative risk: Marginal evidence

    Triple-negative risk: Marginal evidence

    rs17468277d

    rs13387042rs889312rs3817198rs1982073

    rs10069690rs2046210a

    rs12662670b

    rs10483813c

    rs3803662rs8170rs8100241rs22843378rs4245739rs12710696rs11075995

    rs17468277d

    rs13387042rs889312rs3817198rs1982073

    rs10069690rs2046210a

    rs12662670b

    rs10483813c

    rs3803662rs8170rs8100241rs22843378rs4245739rs12710696rs11075995

    566

    141619192012

    16

    TERTESR1ESR1

    RAD51L1TOX3

    19p1319p13

    RALY/EIF2S2MDM42p24.1FTO

    1.031.261.170.901.260.990.991.010.991.011.02

    1.161.351.300.931.151.090.881.141.141.101.11

    41,5751,3852,7594,9774,973

    52,15824,71522,90241,45141,45341,453

    7,4352,7072,7072,9782,9803,5662,6664,0756,5126,5126,513

    (36)(22)(34)(21)(33)(35)(35)(28)(31)(31)(31)

    1.7104.2102.510

    0.0042.1106.7104.5106.0102.1104.6104.010

    -12

    0.901.091.091.051.06

    0.0382.9106.010

    0.0560.033

    4,9774,9762,7574,756

    14,526

    2,9792,9772,8442,929

    885

    (33)(33)(33)(33)(33)

    1.161.171.280.961.111.260.84

    0.851.14d

    0.991.051.01

    4.8104.5101.310

    0.070.004

    2.0106.010

    5,3026,2014,3723,0314,2034,199

    5,5156,3744,4833,2634,1604,161

    (36)(40)(40)(42)(42)(27)(27)

    0.010.0050.900.900.82

    2,2414,2686,2724,203

    2,6034,7633,4694,781

    (42)(42)(42)(42)(38)

    0.0117.1102.4101.3109.610

    0.380.610.670.560.53

    0.083

    (36)(22)(34)(21)(33)(35)(35)(28)(31)(31)(31)

    41,7493,692

    11,22835,20934,85748,30621,52122,90240,60040,60240,602

    27,0743,6544,310

    16,69319,42025,64912,2679,965

    25,22525,22525,220

    0.961.161.111.071.04

    1.1104.4101.1103.0103.1104.2101.9106.4103.1106.710

    0.007

    19,7281,3852,7594,9774,973

    52,15824,71514,82733,40033,40133,401

    3,7072,7072,7072,9782,9803,5662,6661,0922,4652,4662,466

    (26)(37)(37)(37)(37)(35)(35)(28)(31)(31)(31)

    0.0050.0010.0160.0110.038

    4,9774,9762,7574,756

    14,526

    2,9792,9772,8442,929

    885

    (37)(37)(37)(37)(33)

    1.251.291.330.861.171.250.811.161.171.151.11

    0.870.961.071.031.11

    0.0588.5109.3101.410

    0.011

    36,97638,12034,32531,89127,745

    17,80519,31018,83517,42711,495

    (33)(33)(33)(33)(33)

    CASP82q35

    MAP3K1LSP1

    TGFB1

    TERTESR1ESR1

    RAD51L1TOX3

    19p1319p13

    RALY/EIF2S2MDM42p24.1FTO

    CASP82q35

    MAP3K1LSP1

    TGFB1

    225

    1119

    566

    141619192012

    16

    225

    1119

    B ER-negative

    SNP Chr. Locus OR P Ref. Ref. UnaffectedAffectedCases Controls

    SNP Chr. Locus OR P Ref. Cases Controls OR P Ref. Cases Controls

    C Triple-negative D BRCA1

    OR 95% CI

    HR P

    0.6 0.8 1.0 1.2 1.4 1.6

    OR 95% CI0.6 0.8 1.0 1.2 1.4 1.6

    OR 95% CI0.6 0.8 1.0 1.2 1.4 1.6

    OR 95% CI0.6 0.8 1.0 1.2 1.4 1.6

    -12-10

    -3

    -6

    -6

    -6

    -12

    -8-8

    -5-5

    -13

    -9

    -9

    -9

    -8

    -5

    -3

    -9-60

    -30

    -14

    -5

    -9

    -7

    -4

    -4

    -6

    -13

    -12

    -3

    -5

    -5

    Figure 1. TNBC susceptibility loci across breast cancer subtypes. Forest plots for 13 TNBC susceptibility variants are shown to provide visual comparison ofthe strength and direction of association between each SNP and risk of ER-positive breast cancer (A), ER-negative breast cancer (B), TNBC (C),andBRCA1-related breast cancers (D). The 13SNPs are stratiedby strength of evidence for associationwith TNBC risk (strong vs.marginal). For each breastcancer subtype, estimates (OR) and 95% CIs are shown for each variant from the largest study of each relevant breast cancer subtype. ORs aredenoted by black boxes and 95% CIs are denoted by corresponding black lines. Box heights are inversely proportional to precision of the OR estimate asinuenced by sample size such that a larger OR box indicates larger sample size and better precision. A vertical gray line is shown at the null value of 1, suchthat ORs to the left of the null line are less than 1 and ORs to the right of the null line are more than 1. Estimates with condence intervals that do notoverlap the null line indicate signicance at P < 0.05. aDenotes ER-positive and ER-negative estimates from a GWAS of Asian women; triple-negative andBRCA1 carrier estimates from studies of women of European ancestry. bDenotes the estimate shown for rs12662670 TNBC and for rs9397435 inER-positives, ER-negatives, and BRCA1 carriers. cDenotes the estimate shown for rs10483813/rs999737 in ER-negatives and ER-positives, rs999737 inTNBC, and rs1801320 (HR for GG vs. CC) in BRCA1 carriers. dDenotes the estimate shown for rs17468277/rs1045485 in ER-negatives and ER-positives,rs17468277 in TNBC, and rs1045485 in BRCA1 carriers.

    Predisposition to Triple-Negative Breast Cancer

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  • rs2046210 and rs12662670 in the ESR1 locus (rs2046210 OR 1.29; P 4.4 107; rs12662670 OR 1.33; P 1.1 104) andrs10483813 in the RAD51L1 locus (OR 0.86; P 3.0 104),were strongly associated with TNBC. These RAD51L1 ndingswere consistent with evidence from a recent BCAC study ofTNBC (OR 0.89; P 0.02; ref. 32; Fig. 1C). In contrast, anassociation between CASP8 and TNBC risk was observed byTNBCC (OR 0.87; P 0.005), but not by BCAC (OR 0.92; P0.15; ref. 33). Thus, SNPs in the TOX3, ESR1, and RAD51L1 loci,and possibly in 2q35, MAP3K1, LSP1, TGFB1, and CASP8, thatinuence the risk of both ER-positive and ER-negative breastcancer (Fig. 1A and B) have also been identied as genetic riskfactors for TNBC (Fig. 1C).

    Several of the loci identied in ER-negative breast cancerstudies also seem to inuence the risk of TNBC. The ER-negative TERT variant rs10069690 has been associated withan increased risk of TNBC [rs10069690 OR 1.25; 95% con-dence interval (CI), 1.161.34; P 1.1 109; Fig. 1C; ref. 26].In addition, separation of HER-2positive ER/PR-negativecases (n 376; OR 1.03; P 0.71) from HER-2negativecases (n 3,707; OR 1.25; P 1.1 109) has suggested thatthis variant may be uniquely associated with TNBC (Fig. 1C;ref. 26). However, given the complexity of the associationsbetween variation in this locus and breast cancer risk (36),further work must be done to evaluate the relevance of the 3TERT signals to TNBC. The 20q11 locus from the Siddiq andcolleaguesmeta-analysis of ER-negative breast cancer was alsoshown to be strongly associated with TNBC (rs22843378 OR1.16; 95% CI 1.041.29; P 6.4 103; Fig. 1C; ref. 28).Furthermore, of the 4 loci identied by Garcia-Closas andcolleagues, MDM4 (OR 1.17; 95% CI, 1.091.26; P 3.1 105), 2p24.1 (OR 1.15; 95%CI, 1.071.23; P 6.7 105), andFTO (OR 1.11; 95% CI, 1.031.20; P 0.007) were associatedwith TNBC in subtype analyses (Fig. 1C; ref. 31). Of these, theMDM4 locus may have a specic association with TNBC [OR1.17; P 3.1 105), as no signicant association hasbeen seen with nontriple-negative ER-negative breast cancer(OR 1.02; 95% CI, 0.921.12; P 0.711; pHet 0.005).Common Susceptibility Loci for BRCA1MutationCarriers

    Because TNBC and breast cancer in BRCA1 mutation car-riers are phenotypically similar, studies of genetic modiers ofbreast cancer risk in BRCA1 mutation carriers have providedfurther insight into the genetic risk factors for TNBC. Specif-ically, SNPs in the 19p13.1 locus that displayed genome-widesignicant associations with breast cancer in a GWAS ofBRCA1 mutation carriers (rs8170 HR 1.26; P 2.3 109;rs8100241 HR 0.84; P 3.9 109; Fig. 1D; ref. 27) have alsobeen associated with TNBC risk in the general population(rs8170 OR 1.27; P 2.3 108; rs8100241 OR 0.84; P 8.7 107; Fig. 1C; ref. 37). In BCAC and TNBCC combined, the19p13.1 locuswas associatedwithTNBC risk (rs8170OR 1.25;P 4.2 1013; rs8100241 OR 0.81; P 1.9 1012) but wasnot associated with the risk of ER-positive or ER-negative nontriple-negative breast cancer (Fig. 1C; ref. 35). Furthermore,these variants seemed to be specically associatedwith tumorsthat were positive for the basal markers CK5/6 or EGFR (OR

    1.27; 95%CI, 1.071.50; P 0.0069), indicating specicity for thebasal subtype. In addition, variants in ESR1, PTHLH, TOX3,CASP8, and TERT are also associated with both TNBC and therisk of breast cancer in BRCA1 carriers (Fig. 1C and D;refs. 36, 3842). Of the known TNBC risk factors, only RAD51L1was not found to be a modier of BRCA1-related breast cancerrisk (Fig. 1D). Recent data also show that BRCA2 ER-negativetumors have pathologic characteristics similar to BRCA1 ER-negative tumors (10). Thus, further studies of BRCA1 andBRCA2 breast tumors, stratied by ER or triple-negative tumorstatus, may provide additional valuable insight into geneticsusceptibility to TNBC.

    Together with studies of overall breast cancer risk loci byER, PR, and HER-2 subtypes, these ndings suggest that TNBCand the other subtypes of breast cancer may have distinctgenetic risk factor proles. Although the 19p13.1 locus andMDM4 seem to be specic to TNBC, it is important to note thatthese loci were also signicantly associated with overall ER-negative breast cancer (Fig. 1B). Whether this overall associ-ation is driven by the inclusion of triple-negative or basaltumors or reects meaningful associations with other non-TNBC ER-negative tumors remains to be determined. On thisbasis, it will be important to continue to evaluate new breastcancer loci as candidate risk factors for TNBC and othersubtypes of breast cancer if a comprehensive understandingof genetic predisposition to breast cancer is to be attained.

    Future Directions and Implications ofUnderstanding TNBC Genetics

    The exact biologic mechanisms underlying TNBC geneticrisk loci are currently unknown, and additional ne-mapping,resequencing, and functional studies are necessary to deter-mine whether single or multiple variants at these loci affecttriple-negative risk through the dysregulation of nearby genesor though long-range genetic effects. One hypothesis is thatcausal variants at these loci directly initiate and promotedevelopment of a triple-negative tumor through pathways thatare specic to this hormone receptornegative subtype. Inter-estingly, 3 loci specic to TNBC contain genes (TERT, c19orf62,and MDM4) that encode proteins involved in DNA repair andthe preservation of genomic stability. The TERT gene encodesthe catalytic subunit of telomerase, which controls telomeremaintenance, andhas been associatedwith genomic instabilityand linked to tumorigenesis (43).MDM4 is a repressor of TP53and TP73 transcription and is important for cell-cycle regula-tion and apoptosis in response to DNA damage (44). C19orf62encodes the MERIT40 protein, which is integral to the local-ization of the BRCA1-A complex during DNA double-strandbreak (DSB) repair, through the recruitment and retention ofthe BRCA1-BARD1 ubiquitin ligase and the BRCC36 deubiqui-tination enzyme (45). Telomere maintenance, DSB repair, andDNA damage checkpoints have been linked as coordinatingfactors in genomic integrity, and the disruption of this path-way, resulting in genomic instability, has been implicated incancer (46, 47). Indeed, one proposed mechanism of sponta-neous telomere loss in cancer cells is a deciency in DSB repaircombined with oncogene-mediated DNA replication stress(46). In addition, evidence suggests that DNA damage

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  • checkpoint and DNA repair proteins have an essential role intelomere maintenance, by controlling the processing of telo-meric DNA and through other mechanisms that have yet to bedelineated (47). This highlights a potential common biologicpathway that may be specically associated with the develop-ment of TNBC. Focusing on these pathways involved in DNArepair and the preservation of genomic stability, as highlightedby the associations of TNBC with genetic variation in 19p13.1,MDM4, and TERT, may lead to the development of targetedprevention and/or therapeutic agents for patients with TNBC,analogous to PARP inhibitors and the homologous recombi-nation DNA repair pathway in BRCA1- and BRCA2-decientcarriers (48).

    An alternative hypothesis is that variants or even combina-tions of variants in the TNBC-associated risk loci may act tochange existing malignant breast lesions to a triple-negativephenotype during the formation of the tumor. This is partic-ularly intriguing considering the relevance of the ESR1 locus,which is directly involved in the estrogen signaling, to ER-negative and triple-negative breast cancer in addition to ER-positive breast cancer. While a particular locus such as ESR1may predispose breast epithelium to cancer in general, otherssuch as TERT and 19p13.1 may act further downstream aftertumorigenesis has begun to direct tumors towards the triple-negative phenotype. Thus, the identication of these TNBCgenetic loci offer exciting opportunities to better understandhow triple-negative tumors arise.

    Beyond gaining insight into the TNBC etiology, accuratelydening the spectrum of high-risk mutations in breastcancer susceptibility genes among women with TNBC hasthe potential to modify clinical practice. A recent study fromthe United Kingdom showed that up to a third of TNBCsfound to carry BRCA1 mutations would not have beenclinically tested for these mutations based on traditionalrisk proling (11) and would not have beneted from themodied clinical care associated with known cancer-pre-disposing mutations. By characterizing the associationbetween mutations in all high-risk susceptibility genes andfamily history of cancer, age of onset of cancer, and otherepidemiologic risk factors, improved breast cancer riskprediction models can be developed that more accuratelyidentify women at risk for TNBC.

    Similarly, identication of additional common genetic var-iants associated with the risk of TNBC will likely have use forbreast cancer risk prediction. The expectation is that inclusionof all 72 common breast cancer risk loci in the Gail model, inaddition to clinical and epidemiologic risk factors, will improverisk model performance (49), and the effectiveness of thesemodels will likely be further improved by tailoring them tospecic subtypes of breast cancer, including TNBC. On thebasis of the specicity of 19p13.1, TERT, and MDM4 for thissubtype, triple-negativespecic risk models may be feasible.Accurate risk prediction models for TNBC that incorporategenetic information from both rare, high-risk and common,low-risk susceptibility loci would argue for screening womenfor cancer at a younger age and may assist in identifying high-risk women earlier in life.

    Although we have made progress in understanding TNBCgenetics, it is clear that there is much to learn about thegenetic susceptibility to TNBC and that there is a scienticand clinical need to continue this line of work. We mustcontinue to combine high quality genetic, phenotypic, andpathologic data from large breast cancer studies and con-sortia to better dene genetic susceptibility to TNBC, par-ticularly considering that TNBC is a relatively rare subtype ofbreast cancer. Analyses that attempt to explain the complexbiology of human cancers are necessary to make progress inunderstanding the etiology of TNBC and to impact diseaseprevention and clinical care.

    Disclosure of Potential Conicts of InterestNo potential conicts of interest were disclosed.

    Authors' ContributionsConception and design: C.M. Vachon, F.J. CouchAnalysis and interpretation of data (e.g., statistical analysis, biostatistics,computational analysis): K.N. Stevens, F.J. CouchWriting, review, and/or revision of themanuscript: K.N. Stevens, F.J. CouchStudy supervision: F.J. Couch

    Grant SupportThis work was nancially supported by the National Institutes of Health (R01

    CA122340; R01 CA116167; R01CA128978; P50 CA116201), Komen Foundation forthe Cure, and the Breast Cancer Research Foundation.

    Received May 1, 2012; revised November 8, 2012; accepted December 3, 2012;published OnlineFirst March 27, 2013.

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