Phenotype-Genotype Correlation in Familial Breast Cancer

Phenotype-Genotype Correlation in Familial Breast Cancer

Ana Cristina Vargas & Jorge S. Reis-Filho &

Sunil R. Lakhani

Received: 25 February 2011 /Accepted: 1 March 2011 /Published online: 12 March 2011# Springer Science+Business Media, LLC 2011

Abstract Familial breast cancer accounts for a small butsignificant proportion of breast cancer cases worldwide.Identification of the candidate genes is always challeng-ing specifically in patients with little or no familyhistory. Therefore, a multidisciplinary team is requiredfor the proper detection and further management of thesepatients. Pathologists have played a pivotal role in thecataloguing of genotypic-phenotypic correlations in fam-ilies with hereditary cancer syndromes. These effortshave led to the identification of histological andphenotypic characteristics that can help predict thepresence or absence of germline mutations of specificcancer predisposition genes. However, the panoply of

cancer phenotypes associated with mutations of genesother than in BRCA1 is yet to be fully characterised; infact, many cancer syndromes, germline mutations andgene sequence variants are under investigation for theirpossible morphological associations. Here we review thecurrent understanding of phenotype-genotype correlationin familial breast cancer.

Keywords Familial breast cancer . Germline mutation .

Phenotype . Pathology

Introduction

Breast cancer is the commonest non-skin malignancy inwomen and it is estimated that over a million women willdevelop breast cancer each year [1]. Familial breast canceraccounts for approximately 7% of all breast cancers and aproportion of these cases are the result of germlinemutations in the BRCA1 and BRCA2 genes [2, 3]. Germlinemutations in other genes such as TP53, PTEN, CDH1 andATM also confer a high risk of breast cancer but theirmutation frequency only accounts for a small number ofinherited breast cancers. In addition, breast cancer geneticpredisposition may not be solely explained by the existenceof specific germline mutations of high risk genes. In fact, ithas been posited that a combination of low-penetrancevariants and/or single nucleotide polymorphisms (SNPs)may ultimately modify the risk in the general population orin patients with other mutations (e.g. BRCA1). Additionally,many of these patients do not have or do not record anyfamily history. Consequently, additional tools such asstandard morphological and immunohistochemical criteriamay allow us to predict the likelihood of a specificgenotype.

A. C. Vargas : S. R. LakhaniUQ Centre for Clinical Research, The University of Queensland,Brisbane, Australia

J. S. Reis-FilhoThe Breakthrough Breast Cancer Research Centre,Institute of Cancer Research,London, UK

S. R. LakhaniSchool of Medicine, The University of Queensland,Brisbane, Australia

S. R. LakhaniPathology Queensland, The Royal Brisbane & Women’s Hospital,Brisbane, Australia

S. R. Lakhani (*)The University of Queensland Centre for Clinical Research,Royal Brisbane & Women’s Hospital,Building 71 (918),Herston 4029 QLD, Australiae-mail: [email protected]

J Mammary Gland Biol Neoplasia (2011) 16:27–40DOI 10.1007/s10911-011-9204-6

BRCA1, BRCA2 and BRCAX

The BRCA1 gene, located on chromosome 17q, has a keyrole in DNA repair, cell-cycle regulation, transcriptionalregulation, chromatin remodeling, DNA decantenation andcontrol of multiple cell cycle checkpoints [4]. Functionsattributed to BRCA2, at 13q, are mainly restricted to DNArecombination and DNA repair through a regulating role inRAD51 activity [5–7]. Loss of BRCA1 or BRCA2 leads to adeficiency in the repair of DNA double-strand breaks byhomologous recombination (HR), leading to potentiallymutagenic repair of DNA lesions by alternative mecha-nisms such as non-homologous end-joining (NHEJ) andsingle strand annealing (SSA). Ultimately, genomic insta-bility is developed, contributing to the cancer predispositiongenerated by loss-of-function mutations in BRCA1 orBRCA2 [7]. Germline mutations in BRCA1 and BRCA2confer an estimated 65% and 45% cumulative lifetime riskof developing breast and an ovarian cancer risk of 39% and11%, respectively [8].

BRCA1

Patients with BRCA1 germline mutations usually develophigh grade Invasive Ductal Carcinomas of No Special Type(IDC-NST) with frequent medullary-like morphology [9,10] and often but not invariably, negative for oestrogenreceptor/ER, progesterone receptor/PR and HER2 over-expression or amplification (triple negative – TN; approx-imately 70%–75%, Fig 1). In multivariate analysis, Lakhaniet al. showed that morphological features predictive ofBRCA1 phenotype include pushing margins, lymphocyticinfiltrate and high mitotic count [10]. As for sporadic TNbreast cancer [11] BRCA1-associated tumours also clusterwithin the ‘basal-like’ intrinsic subtype of breast canceridentified by expression profiling [12, 13]. These tumoursare enriched by the expression of so-called ‘basal’ markersincluding high molecular weight cytokeratins (CK5/6,CK14, CK17 and/or Epidermal Growth Factor Receptor-EGFR/HER1) (Fig. 1) [14] and constitute in a significantproportion, TN tumours with basal-like phenotype (TNBL)[15]. Other myoeptihelial-related markers such as α-SMA,P-cadherin and Caveolins 1 and 2 are commonly expressedin TNBL tumours [16–19]. Basal-like tumours in bothBRCA1 and sporadic breast cancer tend to show higherexpression of p53, a distinct pattern of cell-cycle prolifer-ation markers (i.e. overexpression of cyclin E rather thancyclin D), neuroendocrine markers (chromogranin A andsynaptophysin), stem-cell-phenotype (CD44+/CD24-) andothers such as hypoxia-associated factor; CA9 and FHITprotein compared to TN-non basal-like cancers [20]. ER-associated genes such as BCL2 [21] and Cyclin D1 are

rarely if at all expressed in TNBL tumours (BRCA1 orsporadic) [22, 23] as are antiapoptotic and proapoptoticproteins, BCL2 and BAX, respectively [21, 24].

Increased expression of cell proliferation and cell cyclerelated markers is characteristic of BRCA1 tumours. Cellproliferation as determined by Ki-67 labelling index hasshown that these tumours are highly proliferative (Ki-67>65%) [25]. Van de Groep et al. [26] demonstrated that thecombination of high proliferation (Ki67 expression >25%)and EGFR positivity in women younger than 54 years ofage was predictive of BRCA1 mutation in 82% of the cases[26, 27]. Amplification of MYC also leads to proliferationand this is observed in up to 60% of BRCA1 tumours [25].Frequent over-expression of other cell cycle-related pro-teins such as Cyclin E, A, B1, p27, p16, p21, CDK4, CDK2and CDK1 [16, 28] is also a common feature of thesecancers.

BRCA1-related tumours exhibit TP53 truncating muta-tions in up to 100% of the cases, when detected bysequencing [29–32]. Although TP53 mutations have beenthought to correlate to BRCA1 mutation, recent evidencesuggests that the presence of TP53 mutations in factcorrelates with the ‘basal-like’ phenotype regardless ofBRCA-germline status. However, complex mutations (inser-tions and deletions) were shown to be more common inBRCA1-associated breast cancer than in sporadic TNBLcancers [33]. Similarly, BRCA1 of luminal subtype (i.e. ER+)also harbours a significant prevalence of TP53 mutations(53%), which is significantly higher than luminal non-BRCA1 tumours [33].

BRCA1 tumours can lose expression of luminal cytoker-atins [34] and a recent study has proposed that CK8/18negativity together with ‘basal-like’ phenotype and familyhistory can be used to predict BRCA1 germline mutationstatus [35]. In this study, absence or decreased CK8/18protein expression was independently associated withBRCA1-associated tumours compared to controls (43% vs94%; P<0.0001) [35].

BRCA1 tumours have also been evaluated for theexpression of stromal signature-related proteins. For in-stance, members of the Notch and TGF-β signallingpathways such as Jagged 1, TFG-β, osteopontin andosteonectin are higher in BRCA1-associated tumours [15,36]. The c-kit (CD117) reactivity in these tumours varies,ranging from 14.7% [37] to 48.1% of tumour cells [38]. c-kit has been widely used for the characterisation of stromaltumours. However, recent work suggests that it is a markerof luminal progenitor cells in the breast [38]. These stromalmarkers may provide interesting therapeutic avenues (e.g.imatinib as inhibitor for c-kit) for the management ofBRCA1 carriers [37].

Regarding the predictive value of BRCA1 phenotype,numerous studies have assessed the statistical power of

28 J Mammary Gland Biol Neoplasia (2011) 16:27–40

hormone receptor negativity, age of onset and positivefamily history. Farshid et al. showed that by using onlyhistopathological criteria in absence of any clinical infor-mation, pathologists were able to predict BRCA1–associat-ed breast cancer with high sensitivity and specificity (92%and 86%, respectively) [41]. In particular, ER negativity inearly onset breast cancer identified 29.6% of BRCA1mutations regardless of PR and HER2 status [42, 43].Eisinger et al. also reported that the combination of ERnegativity and high histological grade in early onset breastcancer was the only predictive feature of BRCA1 carrierstatus [44] but adding family history increases the BRCA1-mutation detection rate [25]. Similarly, triple negative and

basal-like phenotypes are highly predictive of germ-lineBRCA1 mutation [15, 45]. Lakhani et al. [15] showed thatthe addition of basal markers to ER negative tumoursincreases the specificity for detecting BRCA1 carriers.However, it must be emphasized that triple negativity withor without expression of basal markers will not identify allBRCA1 associated tumours. ER positive breast cancer, forinstance, comprises 5%–20% of BRCA1-associated breastcancer, in particular if the current ASCO/CAP definition ofER-positivity is adopted. In addition, HER2 amplification[46] and low-grade morphological variants (tubular carci-noma) [47] have been described in 3% and 3.6% of cases,respectively. Finally, the use of basal markers has not

Figure 1 a-b: High Grade In-vasive Ductal Carcinoma withbasal-like features (a) andMedullary-like breast cancer(b) are over-represented inBRCA1-, FANCN/PALB2- andLynch Syndrome-associatedbreast cancer (H&E). c-f: Im-munohistochemical expressionof basal markers. c: EGFR; d:CK14; e: CK5/6; andf: P63 (50X)

J Mammary Gland Biol Neoplasia (2011) 16:27–40 29

consistently proven to be predictive of BRCA1 phenotype[48]. Therefore, the presence of a TNBL breast cancer in ayoung patient can be very suggestive of BRCA1 germlinemutation, but an alternative phenotype would not excludethe possibility of a BRCA1 germ-line mutation.

It must be noted that BRCA1 pathway is frequentlydysfunctional in sporadic triple negative breast cancer. Lossof nuclear BRCA1 expression is present in approximately15% of sporadic breast cancer and is mainly due to BRCA1gene promoter methylation, ID4 epigenetic inactivation orposttranscriptional down-regulation (e.g.microRNA-182)[49–52]. Therefore, distinction must be made betweensporadic triple negative (Basal or non basal) breast cancerwith loss of BRCA1 due to methylation and BRCA1germline mutation. Regardless of the mechanism of BRCA1inactivation, patients with TNBL cancers are currentlymanaged with the same repertoire of systemic therapies[39, 40], and have a similar rate of pathological response toneoadjuvant chemotherapy [53–56] However, unlike spo-radic TNBL breast cancer, patients with BRCA1 germlinemutations must be identified to receive subsequent man-agement (i.e. risk prevention in the contralateral breast andovaries, screening of family members, genetic counseling,etc.) [57].

BRCA2

BRCA2-associated breast cancer is a very heterogeneousgroup [36, 58]. Although no specific phenotype is yetpredictive of BRCA2-associated tumours, ER+/HER2-tumours comprise the majority of these cases [36]. Inparticular, two morphological features are significant inBRCA2-associated breast cancer; pushing margins and lackof tubule formation [10]. Low and intermediate histologicalgrade is characteristic [24, 46, 58].

Bane et al. have shown that BRCA2-associated tumoursexpress genes involved in signal transduction, cell prolifer-ation, cell adhesion, and extracellular matrix remodelingwith activation of the MAPK signalling pathway [36].FGF1 (Fibroblastic Growth Factor 1) is involved in theMAPK and PI3K signalling activation [61] and increasedlevels of this protein and a related receptor, FGFR2(Fibroblastic Growth Factor Receptor 2) was observed inBRCA2 tumours. FGFR2 expression was observed in 30%of BRCA2 tumours compared to 6% of BRCA1, beinginversely correlated with basal-like phenotype [36].

A greater incidence of TP53 mutations (29%–63%) hasbeen described in BRCA2 tumours when compared tosporadic breast cancer. This is in agreement with thepotential role of TP53 in promoting tumourigenesis notonly in BRCA1 but also in BRCA2-associated breast cancer[62–64].

Loss of Heterozygosity (LOH) at the BRCA2 locushas been identified in a subset of high-grade lobularcarcinomas (pleomorphic variant) [66]. However, theassociation of BRCA2 germline mutation with the devel-opment of pleomorphic lobular carcinoma has not yetbeen studied.

The incidence of precursor lesions (e.g. DCIS) inpatients with BRCA1 and BRCA2 germline mutations hasproven controversial [67–71] but a recent study usingmammography, has described a higher proportion of DuctalCarcinoma In Situ (DCIS) in BRCA2-associated patients[47]. In that study, BRCA2 associated patients had fewerinterval cancers and favorable tumour size compared toBRCA1 patients [47].

BRCAX

BRCAX (non BRCA1/2)-associated breast cancer is a verydiverse group characterised by a similar proportion of ER+/HER2-, HER2+ and TNBL phenotypes [58, 59]. Nohistopathological features have been reproducible in thisgroup [60]. However, an association between invasivelobular carcinomas and BRCAX has been described [9, 65].

Unclassified Mutation Variants (UMVs)

UMVs are clinically challenging since presymptomatictesting is not possible and surveillance can only be basedon the family history [72]. As many as 30% and 50% of thegenetic variants in BRCA1 and BRCA2, respectively, fallunder the category of UMVs [73]. UMVs are mostlymissense sequence variations with not definite role incarcinogenesis [72], but deleterious mutations, may bepathogenic and clinically significant. Therefore, distinctionof patients with deleterious mutations who will benefit fromgenetic counselling is important [74].

Currently, pathological data have a restricted value inclassifying UMVs. Tumours arising in patients withgermline BRCA1/BRCA2-UMVs do not seem to havedistinctive features, with tumours being of high or lowgrade, ductal or mixed morphology with positive ornegative ER, PR and HER2 status [75–77]. However,some studies have highlighted the role of pathology inclassifying UMVs as pathogenic or non-pathogenic [74,78, 79]. By using LOH, family history of carriers and twopathological criteria (Grade 3 and ER negativity) Osorio etal. were able to classify an UMV as neutral or deleterious[74]. Furthermore, pathology has been applied to comparethe degree of inter and intra-familial concordance oftumour phenotype from multiple-case cancer BRCA1 andBRCA2 families [58]. Balleine et al. performed gene


expression profiling of BRCA1 and BRCA2 pathogenicmutations and UMVs. BRCA1 pathogenic mutationsclustered together but not family members, indicating thatno particular similarities exist between individuals. Aspecific clustering was not observed for BRCA2 tumours.This study demonstrated that breast cancer pathology isvariable even between individuals who carry the sameBRCA mutation [58].

Single Nucleotide Polymorphisms

Much of the genetic variability in breast cancer is notexplained by specific germline mutations, but may be dueto the combination of low-penetrance variants that tend tobe more frequently found in selected populations [80].

Three intronic polymorphisms in the FGFR2 gene,located at 10q26 (rs2981582, rs1219648, and rs2420946),clearly confer breast cancer risk not only in patients withBRCA-UMV or germline mutation carriers but also in thegeneral population [81]. FGFR2 encodes a receptor tyrosinekinase, which plays a role in mammary gland development[82] and is amplified and/or over-expressed in a smallproportion of breast cancer [83]. The SNP rs2981582 isassociated with breast cancer risk in BRCA2 mutationcarriers [84] and in agreement with the role of FGFR2 inER-related carcinogenesis, rs2981582 showed a strongerassociation with low grade ER-positive, node positivebreast cancer. This SNP was also associated with PRpositivity, but not independently from ER status [85]. TheFGFR2 SNP rs1219648 was also associated with ER-positive, node positive breast cancer in the generalpopulation, particularly in women with family history ofbreast cancer [80, 81].

Some other SNPs have been found to correlate with ERpositive breast cancer independently from PR status. SNPrs3803662 (TNRC9/TOX3, at 16q12) was significantlyassociated with ER positive breast cancer in both BRCA1and BRCA2 mutation carriers [84, 85]. The rs13281615located on 8q24 [85] and rs4415084 and rs10941679 on5p12 [86] also conferred risk for ER positive disease in thegeneral population. Interestingly, the MRPS30 gene locatedat 5p12 has been implicated in good outcome tamoxifen-treated patients [87]. None of these SNPs have beenassociated with other histopathological features or overallsurvival [80, 85].

Many other polymorphisms, such as rs13387042(2q35) [80], rs889312 (MAP3K1), rs3817198 (LSP1)[84, 85] and other BRCA1/BRCA2 modifiers such asCASP8 D302H (Caspase 8 coding variant) [88], RAD51135 G.C [89, 90] and the KRAS-variant, rs61764370 T > G[91] have not yet been linked to specific phenotypicalcharacteristics.

Lynch Syndrome and Breast Cancer

Lynch syndrome or Hereditary Non-Polyposis Colorectalcancer syndrome (HNPCC) is associated with germlinemutations in any of the mismatch repair (MMR) genes(MLH1, MSH2, MSH6, PMS2) [92, 93], resulting inmicrosatellite instability (MSI). The MMR pathway repairsbase substitution and insertion-deletion mismatches whicharise from replication errors. As a result, MMR-geneinactivation confers a mutator phenotype [94]. MSIinvolves length abnormalities in DNA microsatellites (shorttandem highly repeated DNA sequences) [95] and is usedas diagnostic marker to detect loss or dysfunction of theMMR genes [94, 96]. MSI in colorectal, as well as in breastcancer, is diagnosed when mutation in at least 1 of the 5NCI (National Cancer Institute)-recommended microsatel-lite sequences (BAT25, BAT26, D2S123, D5S346 andD17S250) [96–98] is present. Gene mutation in 1 or morethan 2 microsatellite sequences is called MSI-low (MSI-L)or MSI-high (MSI-H), respectively [94, 97, 99]. Inborderline cases, additional microsatellite markers must betested [100].

Although breast cancer was excluded in 2002 as partof the Lynch syndrome [101], some studies appear toconfirm the role of MMR germine mutations in thedevelopment of breast cancer in patients with Lynchsyndrome [102–106]. For instance, Shanley et al. foundthat 4 out of 29 individuals with breast cancer and Lynchsyndrome harboured MMR germline mutations [104].Furthermore, MMR gene-variant mutations have alsobeen shown to predispose to breast cancer. For instance,MSH6 rare variants have been identified in 10.3% amongfamilial breast cancer compared to 2% of the generalpopulation [107].

Breast cancer tumours associated with germline muta-tions of the MMR genes and Lynch syndrome can display adistinctive morphological appearance. These have beendescribed as IDC-NST with dense lymphocytic infiltrate[105, 108]. In addition, Walsh et al. [109] showed that 18out of 35 breast tumours from individuals with Lynchsyndrome were significantly more likely to be ER-/PR-,with high mitotic activity, solid growth pattern, confluentnecrosis and low frequency of adjacent DCIS whencompared to non-MMR gene mutation carriers. Thisphenotype, reminiscent of medullary-like breast cancerhas been previously linked to high MSI [110] (Fig. 1). Onthe other hand, tumour type, size, lymphovascular invasion,lymph node metastasis and P53 status were not significant-ly different in breast cancers arising in patients with Lynchsyndrome when compared to the general population.

The most sensitivity pathologic feature of MSI pheno-type in colorectal cancer is the presence of tumourinfiltrating lymphocytes and mucinous–signet ring cell


morphology [111, 112]. Tumour lymphocytes quantifica-tion has been suggested as a prognostic marker in colorectalcancer [94], which has been partially evaluated in medul-lary breast cancer [119]. Furthermore, unlike mucinouscolorectal carcinomas, mucinous breast cancer do notharbour MSI (as determined by PCR and IHC) [113].Immunohistochemistry (IHC) for MSI-associated breastcancer identifies loss of protein expression of the MMRaffected gene (MLH1, MSH2, MSH6 or PMS2) [104, 113,115]. However, as opposed to colorectal cancer [114], lackof immunohistochemical expression for these markersrarely occurs in breast cancer [113, 119].

Nevertheless, many other studies exclude MMR germlinemutations as responsible for the development of breast cancerin Lynch syndrome patients. Muller et al. [101] reported thatbreast cancer from Lynch syndrome families is sporadic,unrelated to MMR gene defects and Vansen et al. [116]suggested that MMR deficiency accelerates breast cancertumourigenesis in Lynch syndrome patients but is not theinitiating event [117]. Similarly, MSI is extremely infrequentin sporadic breast cancer (2%–3%) [113, 118, 119] with geneinactivation due to methylation as the main mechanism.

CDH1 Germline Mutations

CDHI germline mutations are associated with the autoso-mal dominant cancer-predisposition syndrome, HereditaryDiffuse Gastric Cancer (HDGC) [120], which is associatedwith increased susceptibility for the development ofinvasive lobular carcinoma of the breast. CDH1 encodesfor the E-cadherin protein, a cell-cell adhesion moleculethat has a fundamental role in adhesion, cell differentiation,and cellular signalling [121]. Inactivating mutations, dis-tributed throughout the gene, with no hot spots in anyparticular region, account for the majority of the cases[122]. CDH1 pathogenic variants are uncommon with afrequency of 1.3% in patients with family history of gastric/breast cancer [123]. Female mutation carriers have a 39%lifetime risk of breast cancer [120, 122, 124–126],particularly with lobular morphology (ILC) [127]. Familyhistory of gastric and/or breast cancer is present in thesecases, but can be absent [123]. In addition, family history ofbreast cancer of non-lobular histology (IDC-NST) can befound [128, 129]. In fact, both ILC as well as IDC can beobserved in CDH1 germ-line mutation carriers [120, 130].In these cases the possibility of sporadic ductal carcinomasarising in CDH1 mutation carriers cannot be excluded.

When lobular carcinomas arise inCDH1 mutation carriers,they show the same phenotype observed in sporadic cases,with loss of E-cadherin and β-catenin membranous expres-sion. As in sporadic ILC, E-cadherin aberrant staining [131]has been described. In a case report of an ILC and concurrent

diffuse gastric carcinoma, Zhu et al. showed that the tumourcells retained E-cadherin and β-catenin expression in asignificant proportion of cells. Interestingly, the gastriccarcinoma displayed the same aberrant E-cadherin/β-cateninreactivity observed in the breast tumour [130].

PTEN Germline Mutations

Cowden syndrome (CS) is an autosomal-dominant disorderchacracterised by multiple hamartomatous and neoplasticmucocutaneous lesions, CNS abnormalities and cancerpredisposition in multiple organs (Breast, colon, endome-trium and brain) [132, 133]. Germline mutations in thetumour suppressor gene, PTEN are responsible for CS.PTEN (phosphatase and tensin homologue) is located onchromosome 10q22.3 and encodes a lipid phosphatase witha regulatory role in the phosphoinositol 3-kinase and thePKB/Akt signalling pathways [134–136]. Diagnosis of CSis challenging because many of these patients do not meetthe criteria for diagnosis in the screening setting, includingthe lack of family history [137, 138].

Breast cancer is the most common malignancy in CS,occurring in 22% of women [139, 140], with a lifetime riskof 50% [137, 138]. CS-associated breast cancer usuallyoccurs in young women (mean age 40), but can occur inmen [139, 141] and is bilateral in 25% of the cases [142,143]. No consistent breast cancer phenotype has yet beendescribed for PTEN mutation carriers, but the majority ofthese tumours are of luminal phenotype, characterised byvariable expression of hormone receptors and negativeexpression for HER2, P53 and basal markers. Morpholog-ical type varies, but IDC-NST and mixed ductolobular[144] of low/intermediate histological grade with adjacentDCIS, account for most of the cases. Therefore, CS-associated breast cancer is regarded as favourable histologywith frequent lack of lympho-vascular invasion (LVI) andlymph node metastasis [137, 142, 143, 145, 146]. However,poor prognostic factors such as high histological grade,lymph node metastasis, squamous differentiation, triplenegative phenotype and interval carcinomas can also beenfound [142, 144, 147]. Benign breast lesions, such asfibrocystic disease [143], tubular adenomas and breasthamartomas [142, 148] are part of the spectrum of breastdisease. It must be noted that LOH of the PTEN locusoccurs in sporadic breast cancer [134, 149, 150].

PARP Inhbitors in BRCA and PTEN Familial BreastCancer

Based on the encouraging results of phase I and II clinicaltrials, Poly (ADP-ribose) polymerase 1 (PARP-1) inhibitors


(PARPis) are likely to play a major role in the treatment ofcancers in BRCA1 and BRCA2 germline mutation carriers[39, 40]. PARPis target Homologous Recombination (HR)deficiency in BRCA1/2 deficient cells. These are highlyselective due to the mechanism of synthetic lethality, whichrequires both, PARP and BRCA genes to be lost in thetumour cells.

PTEN-mutated cancer characteristically shows HR-deficient cells. Therefore, the role of PARPis is currentlybeing explored in this context [151, 152]. HomozygousPTEN mutations with significant truncations of the openreading frame are particularly sensitive to PARP inhibition.However, PTEN missense mutations have not shown suchsensitivity [152]. This may indicate that a proportion offamilial breast cancer associated with PTEN gemlinemutation, will greatly benefit from PARPis. Immunohisto-chemical expression for nuclear PTEN has been suggestedas predictor for tumour response to PARPis in tumour cellsbut further work is required [152].

Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is a rare autosomal disordercharacterised by an increased susceptibility for the devel-opment of malignant epithelial, mesenchymal and haema-topoietical neoplasms (i.e. breast cancer, sarcomas, braintumours, adrenocortical carcinoma, leukemia among others)[153, 154]. TP53 germline mutations account for thedevelopment of LFS [155] and Li-Fraumeni-like syndrome(LFL) [156] in 75% and 40% of the affected families,respectively [157]. Diagnostic criteria for LFS and LFL areconstantly being redefined because up to 30% of the TP53-mutated families develop tumours others than thoseincluded in the diagnostic criteria [156]. Although thereare over 450 germline mutations involving the TP53 gene,missense mutations of its coding region (exons 2–11) detect95% of LFS and LFL patients [158].

TP53 germline mutations account for approximately 1%of total breast cancer, which is the commonest epithelialneoplasm developed by women with LFS [159]. Thisfrequency increases up to 7% in women less than 30 yearsof age and up to 13% in selected populations [160]. LFSand LFL also account for a high proportion of bilateralbreast cancer (22%) in young women negative for BRCA1/BRCA2 genetic testing [160]. TP53 mutation carriers have alifetime risk for developing cancer of almost 100%, whichis in a significant proportion due to breast cancer [161].

Breast cancer phenotype in patients with TP53 germ-line mutation has been partially characterised in a recentstudy. Wilson et al. showed that HER2 overexpression oramplification was present in 83% of a small cohort (n=12)of breast cancers developed in TP53 mutation carriers,

compared to 19% HER2 amplification in the referencecohort. Regarding hormone receptor status, it was notedthat 42% of the TP53-mutated tumours were triple positive(ER+/PR+/HER2+) compared to only 8% of the referencecohort. No TN tumours were identified in the TP53-associated breast cancer cohort and this was statisticallysignificant. The authors hypothesised that TP53 mutationand HER2 overexpression/amplification may be coacti-vated in the same oncogenic pathway [162]. Despite thelimited data presented in this study, it can be concludedthat a HER2-amplified breast cancer in a very youngwoman (<30 years), especially when there is familyhistory of neoplasms in other organs may warrant TP53germline mutation testing, but more studies are necessaryto confirm these findings. Other breast malignancies, suchas malignant phyllodes have also been associated withLFS [163].

ATM Germline Mutations

Ataxia-telangiectasia is an autosomal recessive disordercharacterised by mutations in the ataxia telangectasiamutated (ATM) gene [164]. The ATM gene encodes a lipidkinase phosphatidylinositol 3-kinase (PI3K) that is involvedin DNA damage signalling, chromatin remodeling, tran-scriptional regulation and apoptosis [165, 166].

ATM is an intermediate-risk breast cancer susceptibilitygene, conferring 2- to 5-fold increased risk of breast cancerfor female relatives who are heterozygous carriers of ATMmutations [167, 168]. A large number of mutationsinvolving the ATM gene have been identified [169], whichare responsible for 2% of familial breast cancer [168]. ATMpolymorphic missense variants also confer a slight increasein breast cancer risk, specifically in patients with familyhistory and bilateral breast cancer [170, 171].

No distinctive histopathology has been associated withATM-associated breast cancer in mutation carriers [172].ATM protein is expressed in the normal breast epithelial cellswith reduced expression in BRCA1 and BRCA2-associatedbreast cancer as well as in sporadic triple negative tumours.No correlation has been found between decreased ATMexpression and other prognostic features such as P53expression [173]. ATM polymorphisms (rs637064) haveshown association with nodal metastasis [174].

Fanconi Anemia Pathway and Germline Mutations

The Fanconi anemia pathway (FA pathway) is comprisedof 13 genes involved in DNA damage response [175,176]. Mutations in genes pertaining to this pathway conferincreased susceptibility to chromosome breakage in


response to interstrand DNA cross-linking agents [177].Particularly, four Fanconi’s anemia genes (FANCD1,FANCN/PALB2, FANCJ/BRIP1 and FANCC) have beenshown to be intermediate risk breast cancer susceptibilitygenes [178, 179]. FANCN/PALB2 for instance, confers2.3-fold increased risk of breast cancer [180]. However,due to variable penetrance estimation for multiple-casefamilies, the real frequency of FANCN/PALB2 mutation isnot well defined [181]. The FANCD1 gene is in fact,identical to BRCA2 and considered by some authors as thesame gene [175].

Germline mutations as well as mutation variants andsingle nucleotide polymorphisms in the Fanconi anemia’sgenes have been linked to some phenotypical character-istics. For instance, FANCN/PALB2-associated tumours areusually ER and HER2 negative (58% and 93%, respective-ly) with 40% of all cases, being triple-negative phenotype(Fig. 1). Although this group of tumours shows similaritieswith BRCA1-associated breast cancer, it has reported toharbour gene copy changes (aCGH) similar to thoseobserved in BRCA2 tumours [180, 181]. Two FANCI SNPs(rs7168941 and rs8032440) were associated with presenceor absence of nodal metastasis, respectively [174]. Intronicnoncoding SNPs of the FANCJ/BRIP1 gene (rs7220740)and FANCN/PALB2 (rs447529) are associated with positiveexpression of progesterone, but not estrogen receptor [174].However, this last finding was not reproduced in anindependent study [182]. Association with overall survivalhas also been found for SNPs in FANCC (rs1045276) andFANCD1 (rs1801406) [174].

RAD51C, a tumour suppressor gene involved in homol-ogous recombination, [183] is a predisposing gene for aFanconi anemia-like disorder as well as for hereditary breastand/or ovarian cancer (monoallelic mutations) [176, 184,185]. RAD51 functions are regulated by BRCA1 and BRCA2in response to DNA damage. Mutations have been observedin 1.3% of probands from breast and ovarian cancer in apopulation-based study [186]. Although tumour phenotypein RAD51C mutation carriers has not been described,sporadic breast cancer of luminal B-type (ER+/PR-) wascharacterised by high RAD51 gene and protein expression.This was statistically associated with recurrence, distantmetastasis and overall survival [187].

CHEK2 Germline Mutation

The CHEK2 (Checkpoint kinase 2) protein is a cell cyclekinase that phosphorylates p53 and BRCA1 as a result ofDNA damage, inducing cell cycle arrest [188, 189]. Theframeshift mutation, 1100delC, is the most common andresults in loss of the CHEK2 kinase activity. It is associatedwith twofold breast cancer risk in carriers [190] and

increases up to 12.1% in women with bilateral breastcancer of selected populations [191]. For instance, in non-European populations this mutation does not seem to conferan increased in breast cancer risk [192, 193].

CHEK2 (110delC) mutation carriers usually develophigh-grade ductal carcinomas with positive expression ofhormone receptor (ER+/PR+). CHEK2 protein expressionis absent or significantly reduced in these cases [190]. Adifferent CHEK2 mutation (I157T] was reported to bestrongly associated with lobular carcinoma in a series fromPoland; this observation, however, was not reproduced indifferent populations [194, 195].

Summary

Since the identification of BRCA1 and BRCA2 genes,considerable work has been done to unravel thegenotypic-phenotypic correlations between mutations incancer predisposition genes and breast cancer. The stron-gest data are still for BRCA1-associated cancers but data arebeginning to emerge on the phenotypic characteristics ofcancers arising in families with mutations in other cancerpredisposition genes. The correlations do and will continueto play an important role in understanding biologicalfunction, in identification of patients at risk of carryinggermline mutations and in the development of therapeuticstrategies.

Acknowledgements ACV is a clinical fellow funded by the LudwigInstitute for Cancer Research (LICR). JSR-F is funded in part byBreakthrough Breast Cancer Research Centre. JSR-F is the recipientof the 2010 CRUK Future Leaders Prize.

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Phenotype-Genotype Correlation in Familial Breast Cancer