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Keywords:

  • prostate cancer;
  • germline genetics;
  • molecular biology

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE HERITABILITY OF PROSTATE CANCER
  5. RARE GENOMIC VARIATION AND PROSTATE CANCER
  6. COMMON GERMLINE VARIATION: GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND PROSTATE CANCER
  7. PHARMACOGENETICS, PHARMACOGENOMICS AND TREATMENT SELECTION
  8. TRANSLATING GENOMIC VARIATION INTO PROSTATE CANCER CLINICS
  9. CONCLUSION
  10. CONFLICT OF INTEREST
  11. REFERENCES

What's known on the subject? and What does the study add?

Prostate cancer is a heterogeneous disease and biomarkers to predict its incidence and subsequent clinical behaviour are needed to tailor screening, prevention and therapeutic strategies. Rare mutations in genes such as BRCA1, BRCA2 and HOXB13 can affect prostate cancer incidence and/or clinical behaviour. Genome wide association studies (GWAS) have identified more common genetic variations that explain an estimated 20% of familial prostate cancer risk.

In this review, we focus on the potential of germline genetic variation to provide biomarkers for prostate cancer screening, prevention and management. We discuss how germline genetics may have a role in treatment selection if reliable pharmacogenetic predictors of efficacy and toxicity can be identified. We have outlined possible mechanisms for including germline investigation in future prostate cancer clinical trials.

OBJECTIVES

  • • 
    Prostate cancer is a heterogeneous disease and biomarkers to predict its incidence and subsequent clinical behaviour are needed to tailor screening, prevention and therapeutic strategies.
  • • 
    In this review we focus on the potential of germline genetic variation to provide these biomarkers.

METHODS

  • • 
    We review the published literature on germline genetics in prostate cancer and examine the possibility of including germline genetic biomarkers in future prostate cancer clinical trials.

RESULTS

  • • 
    Rare mutations in genes such as BRCA1, BRCA2 and HOXB13 can affect prostate cancer incidence and/or clinical behaviour.
  • • 
    Genome-wide association studies (GWAS) have identified more common genetic variations that explain an estimated 20% of familial prostate cancer risk.
  • • 
    Germline genetics may have a role in treatment selection, if reliable pharmacogenetic predictors of efficacy and toxicity can be identified.

CONCLUSION

  • • 
    This rapidly emerging area of prostate cancer research may provide answers to current clinical conundrums in the prostate cancer treatment paradigm. We have outlined possible mechanisms for including germline investigation in future prostate cancer clinical trial design.

Abbreviations
DPD

dihydropyrimidine dehydrogenase

GWAS

genome-wide association studies

RR

relative risk

SNP

single-nucleotide polymorphism.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE HERITABILITY OF PROSTATE CANCER
  5. RARE GENOMIC VARIATION AND PROSTATE CANCER
  6. COMMON GERMLINE VARIATION: GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND PROSTATE CANCER
  7. PHARMACOGENETICS, PHARMACOGENOMICS AND TREATMENT SELECTION
  8. TRANSLATING GENOMIC VARIATION INTO PROSTATE CANCER CLINICS
  9. CONCLUSION
  10. CONFLICT OF INTEREST
  11. REFERENCES

Molecular characterisation of tumours and individuals promises an era of personalised cancer care but realising that goal will require a considerable translational effort. An individualised approach to cancer treatment will have both clinical and economic benefits at a population level. Technical advances have introduced tools into widespread use that facilitate unheralded biological discovery. Unfortunately, the rate of progress in understanding cancer biology has yet to be translated into clinical progress of equal magnitude. The USA Food and Drug Agency (FDA) attempted to address this discrepancy in 2004 when it established the ‘Critical Path Initiative’ and progress has been made.

The discovery of somatic (i.e. acquired) genetic mutations in certain tumour types has yielded novel therapeutic approaches. Some notable examples include ABL mutations in chronic myeloid leukaemia [1], KIT mutations in gastrointestinal stromal tumours [2], ALK rearrangements in lung cancer [3], and RAF mutations in melanoma [4].

Germline (i.e. inherited) mutations are now the focus of increased research. This inherited variation has the potential to predict both incidence and prognosis. Germline mutations may also be useful biomarkers in predicting which patients will benefit from a given therapy and indeed may serve as therapeutic targets themselves. This review focuses on the relevance of germline mutations in prostate cancer and on efforts to use this knowledge to yield a clinical benefit for patients.

THE HERITABILITY OF PROSTATE CANCER

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE HERITABILITY OF PROSTATE CANCER
  5. RARE GENOMIC VARIATION AND PROSTATE CANCER
  6. COMMON GERMLINE VARIATION: GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND PROSTATE CANCER
  7. PHARMACOGENETICS, PHARMACOGENOMICS AND TREATMENT SELECTION
  8. TRANSLATING GENOMIC VARIATION INTO PROSTATE CANCER CLINICS
  9. CONCLUSION
  10. CONFLICT OF INTEREST
  11. REFERENCES

Twin studies have suggested that 42% (95% CI 29–50%) of prostate cancer risk is directly attributable to hereditary factors [5], and epidemiological data provide further support for a hereditary component [6,7]. Until recently the study of cancer germline genetics focused on highly penetrant genes such as BRCA1/BRCA2 and associated rare cancer predisposition syndromes (hereditary breast ovarian cancer syndrome). However, despite strong evidence for the existence of prostate cancer susceptibility genes, family-based linkage studies have been unable to identify compelling candidates [8–25]. In Sweden, a population-based study suggested that ≈11.6% of all prostate cancer can be accounted for by familial factors alone [6]. A meta-analysis of 33 studies investigating familial clustering suggested that risk was greater for men with affected brothers (relative risk [RR] 3.4; 95% CI 3.0–3.8) than for men with affected fathers (RR 2.2; 95% CI 1.9–2.5). Second degree relatives (RR 1.7; 95% CI 1.1–2.6) conferred a lower risk than first-degree, and two or more first-degree relatives (RR 5.1; 95% CI 3.3–7.8) conferred increased risk compared with one (RR 2.6; 95% CI 2.3–2.8) [7]. Twin studies have further investigated this familial clustering and confirmed a strong genetic component with a concordance among monozygotic twins of 27% compared with 7.1% between dizygotic twins, resulting in the conclusion that 42% (95% CI 29–50%) of prostate cancer risk is due to hereditary factors [5].

RARE GENOMIC VARIATION AND PROSTATE CANCER

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE HERITABILITY OF PROSTATE CANCER
  5. RARE GENOMIC VARIATION AND PROSTATE CANCER
  6. COMMON GERMLINE VARIATION: GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND PROSTATE CANCER
  7. PHARMACOGENETICS, PHARMACOGENOMICS AND TREATMENT SELECTION
  8. TRANSLATING GENOMIC VARIATION INTO PROSTATE CANCER CLINICS
  9. CONCLUSION
  10. CONFLICT OF INTEREST
  11. REFERENCES

Many high penetrance prostate cancer candidate genes have been reported but few have been convincingly replicated, with the possible solitary exception of BRCA2 [26–28]. BRCA1 and BRCA2 are involved in double-strand DNA repair and the maintenance of genomic integrity, and germline mutations in these genes are inherited in an autosomal dominant fashion. BRCA2 mutations confer a 35–40% lifetime risk of developing prostate cancer and carriers have an up to 23-fold increased risk of developing early onset disease over the general population [27,29,30]. The impact of BRCA1 mutations on prostate cancer incidence appears less pronounced with one large study involving 11 847 mutation carriers suggesting a 3–8% lifetime risk with a modestly elevated incidence of prostate cancer before the age of 65 years (RR 1.82; 95% CI 1.01–3.29) but no increased risk in older men [30].

Furthermore BRCA1 and BRCA2 mutations are associated with a more aggressive clinical course. Mutation carriers are more likely to have high-grade prostate tumours and are more likely to relapse and die from their disease [31]. BRCA-associated prostate cancer may therefore require a tailored clinical approach, and may represent a subset of the disease that would benefit from a specific prevention and/or early detection strategy.

The unique biology of BRCA-associated prostate cancer may also warrant a specific therapeutic approach. BRCA-associated breast, ovarian, and prostate cancer are particularly sensitive to platinum-based chemotherapy, suggesting that molecular variation of the host in addition to that of the tumour can predict response to therapy, and indicating that platinum-based treatment is worthy of further investigation in this disease. There is also evidence that BRCA-associated prostate cancer responds to poly-ADP ribose polymerase (PARP) inhibition, again illustrating how germline variation may impact treatment selection [32].

BRCA1/2 mutations therefore serve as an example of how germline mutations can affect the incidence, behaviour and treatment of prostate cancer. Recent work by Ewing et al.[33] has identified germline mutations in HOXB13 as increasing prostate cancer risk (RR 20.1, 95% CI 3.5–803) and this genetic mutation was found to be more common in men with familial and/or early onset disease. However, highly penetrant germline genetic mutations, such as those in BRCA1, BRCA2 and HOXB13, are rare. Even in patients with familial prostate cancer, BRCA2 mutations are present in <5% of cases [34–36]. Next generation sequencing technology has improved our ability to detect rare genetic variants and, as shown by the example of HOXB13, may identify additional rare variants that impact on prostate cancer incidence and biology [33].

COMMON GERMLINE VARIATION: GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND PROSTATE CANCER

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE HERITABILITY OF PROSTATE CANCER
  5. RARE GENOMIC VARIATION AND PROSTATE CANCER
  6. COMMON GERMLINE VARIATION: GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND PROSTATE CANCER
  7. PHARMACOGENETICS, PHARMACOGENOMICS AND TREATMENT SELECTION
  8. TRANSLATING GENOMIC VARIATION INTO PROSTATE CANCER CLINICS
  9. CONCLUSION
  10. CONFLICT OF INTEREST
  11. REFERENCES

Roughly 99.9% of DNA sequence is identical across different individuals but given the vast size (3.2 billion base pairs) of the human genome, even this small discrepancy results in millions of potential variations [37]. The most common variations are single base-pair changes called single-nucleotide polymorphisms (SNPs) [38]. Common genomic variation is a term used to describe this genomic variability and SNPs with a minor allele frequency >5% are termed common variant alleles. GWAS refers to case-control studies that search for associations between a given disease and common variant alleles at >500 000 loci throughout the genome [39]. The advent of high-throughput genotyping, together with the completion of the HapMap and Human Genome Projects has facilitated this approach. The identified SNP is commonly a surrogate for another locus within a linkage disequilibrium block that is biologically responsible for the association. Identification of this locus through fine mapping of the surrounding genomic region may reveal a stronger signal and a biologically plausible genetic association. GWAS are often referred to as ‘agnostic’ meaning there is no a priori assumption made about the likely significance of any one SNP. In contrast to the candidate gene approach, the agnostic approach has the advantage of being completely unbiased and has the ability to lead us to heretofore undiscovered biological mechanisms of disease.

GWAS to assess the impact of common genomic variation on human traits and disease have not explained as much population variation as the scientific community had hoped they would. For example, GWAS have only explained 3% of the population variation in height and 2% of variation in body mass index [40,41]. In the field of cancer genetics, GWAS have found common variant alleles to explain ≈5% of the inherited risk of breast cancer and 6% in colorectal cancer [42,43]. Even alleles with the strongest association with these cancers had a relatively weak overall effect on incidence (RR 1.26 and 1.2, respectively) [38]. This is understandable in the context of evolutionary biology because alleles that strongly increase cancer risk are less likely to be passed on to future generations and therefore unlikely to become ‘common variant alleles’. Increased ability to measure common variation may lead to the discovery of even more risk alleles and ‘less common’ variant alleles (those with minor allele frequencies of 0.5–5%). However, it seems unlikely that these improved techniques will make major advances on what has already been achieved using common genomic variation to explain population variation [39].

Prostate cancer GWAS have identified >30 common variant alleles that increase prostate cancer risk (Table 1) [44–56]. These explain an estimated 20% of inherited prostate cancer risk, which is relatively large when compared with breast and colon cancer. The 8q24 region has been repeatedly associated with prostate cancer risk, initially in linkage and admixture studies, and more recently through GWAS [44]. This association is consistent with the chromosomal gains identified in early cytogenetics studies of this region, and fine mapping of 8q24 has now identified at least five distinct prostate cancer susceptibility regions [44]. Despite the proximity of the proto-oncogene C-MYC and a putative functional link between the two, the role played by this predisposition region in prostate cancer biology remains unexplained [57].

Table 1. Germline variants associated with prostate cancer risk in GWAS performed to date
LocusChromosomeSNPPAFPer allelle ORPReference
  1. PAF, published allele frequency; OR, odds ratio.

ITGA62rs126212780.941.39 × 10−23Eeles et al. (2009) [50]
2p152rs7210480.191.158 × 10−9Gudmundsson et al. (2008) [48]
THADA2rs14656180.231.082 × 10−8Eeles et al. (2009) [50]
2q372rs22928840.251.144.3 × 10−8Schumacher et al. (2011) [56]
3p123rs26607530.111.183 × 10−8Eeles et al. (2008) [45]
3q21.33rs109348530.281.123 × 10−10Gudmundsson et al. (2009) [49]
TET24rs76796730.551.093 × 10−14Eeles et al. (2009) [50]
PDLIM54rs170219180.661.14 × 10−15Eeles et al. (2009) [50]
PDLIM54rs125004260.461.081 × 10−11Eeles et al. (2009) [50]
6q256rs93645540.291.175.5 × 10−10Eeles et al. (2008) [45]
7q217rs64656570.461.121 × 10−9Eeles et al. (2008) [45]
JAZF17rs104865670.771.121 × 10−7Thomas et al. (2008) [51]
8p218rs29286790.421.057 × 10−8Eeles et al. (2009) [50]
NKX3.18rs15122680.451.183 × 10−30Eeles et al. (2009) [50]
8q248rs6208610.611.285 × 10−8Al Olama et al. (2009) [44]
8q248rs100869080.71.258 × 10−8Al Olama et al. (2009) [44]
8q248rs4451140.641.145 × 10−10Gudmundsson et al. (2009) [49]
8q248rs169020940.151.216 × 10−15Gudmundsson et al. (2009) [49]
8q248rs69832670.51.269 × 10−13Yeager et al. (2007) [52]
8q248rs14472950.11.623 × 10−11Amundadottir et al. (2006) [53].
8q248rs169019790.032.13 × 10−15Gudmundsson et al. (2007) [46]
CTBP210rs49624160.271.173 × 10−8Thomas et al. (2008) [51]
MSMB10rs109939940.41.259 × 10−29Eeles et al. (2008) [45]/Thomas et al. (2008) [51]
11p1511rs71279000.21.223 × 10−33Eeles et al. (2009) [50]
11q1311rs79313420.511.162 × 10−12Eeles et al. (2008) [45]/Thomas et al. (2008) [51]
12q1312rs9027740.151.174.7 × 10−9Schumacher et al. (2011) [56]
HNF1B17rs44307960.491.241 × 10−11Gudmundsson et al. (2007) [47]
HNF1B17rs116497430.81.282 × 10−9Sun et al. (2008) [54]
17q24.317rs18599620.461.253 × 10−10Sotelo et al. (2010) [55]
KLK2/KLK319rs27358390.851.21.5 × 10−15Eeles et al. (2008) [45]
19q13.219rs81024760.541.122 × 10−11Gudmundsson et al. (2009) [49]
22q1322rs57591670.531.166 × 10−29Eeles et al. (2009) [50]
Xp11Xrs59456190.361.191.5 × 10−9Eeles et al. (2008) [45]/Gudmundsson et al. (2008) [48]

Other prostate cancer predisposition loci lie within plausible candidate genes, and while location within a gene does not define a functional role, it increases this likelihood. Variation within MSMB which encodes microseminoprotein-β has identified this key constituent of seminal fluid as a potential tumour suppressor gene [45]. Variants within genes that encode other secretory products of the prostate, e.g. KLK2 (which encodes human kallikrein-related peptidase 2) and KLK3 (which encodes PSA), have also been associated with prostate cancer risk [45].

Although less widely studied, the question of whether GWAS can be used to predict the incidence of aggressive or lethal prostate cancer may be even more clinically relevant than their use to predict any form of prostate cancer. One study reported an association between rs7920517, rs10993994 and PSA recurrence after prostatectomy, and others have identified germline predictors of biochemical recurrence, development of castrate-resistance metastases and prostate cancer specific mortality, but in general this is an area which would benefit greatly from further research [58,59].

PHARMACOGENETICS, PHARMACOGENOMICS AND TREATMENT SELECTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE HERITABILITY OF PROSTATE CANCER
  5. RARE GENOMIC VARIATION AND PROSTATE CANCER
  6. COMMON GERMLINE VARIATION: GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND PROSTATE CANCER
  7. PHARMACOGENETICS, PHARMACOGENOMICS AND TREATMENT SELECTION
  8. TRANSLATING GENOMIC VARIATION INTO PROSTATE CANCER CLINICS
  9. CONCLUSION
  10. CONFLICT OF INTEREST
  11. REFERENCES

The identification of predictive signatures, which guide the selection of appropriate therapy, is an area of heightened interest due to the emergence of novel therapeutic approaches for prostate cancer [60–63]. The terms pharmacogenetics and pharmacogenomics, like genetics and genomics, are commonly used interchangeably to describe this field. While the former refers to a specific gene and the latter to more global genomic architecture, in this manuscript they will be used interchangeably to describe how an individual's germline genetic profile dictates response to medications.

The field of pharmacogenetics is not as developed as the genome wide investigation of predisposition to disease described in the previous section. A recent systematic review reported that the significant majority of publications in this field have been reviews and opinion pieces (ratio of reviews to primary research articles, 25:1) that have generated excitement about the possibility of personalised medicine with a dearth of conclusive evidence to support this goal [64], and concordantly few pharmacogenetic tests have been approved for clinical use. Most reports have used the candidate gene approach and sample sizes have been small, but nonetheless the few successes provide proof of concept for this approach. The FDA ‘Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels’ lists a growing number of medications whose prescription may be altered by genomic information, including a number of agents used in cancer care (http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm) (Table 2). As mentioned in our introduction, somatic mutations within tumours are used to guide the prescription of imatinib, crizotinib and other drugs. Several germline variants may also be used to direct prescribing in medical oncology patients, e.g. dihydropyrimidine dehydrogenase (DPD) deficiency (fluorouracil and capecitabine), UGT1A1 variants (irinotecan and nilotinib). Despite this, few oncologists order a DPD test before prescribing a fluoropyrimidine or a UGT1A1 test before prescribing irinotecan, showing the difficulty in translating even true positive findings into the clinical setting. These variants all predict toxicity, and perhaps the identification of germline predictors of efficacy would be more likely to influence clinical practice.

Table 2. Germline variants that can affect the efficacy/tolerance of drugs frequently prescribed by medical oncologists. Adapted from the FDAs ‘Table of Valid Pharmacogenetic Tests in the Context of Approved Drug Labels’ (Available at: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm)
BiomarkerDrug
  1. G6PD deficiency, glucose-6-phosphate dehydrogenase.

CYP2C19 variantsOmeprazole
Pantoprazole
Esomeprazole
Diazepam
Rabeprazole
CYP2C9 variantsCelecoxib
CYP2D6 variantsTamoxifen
Venlafaxine
Risperidone
Atomoxetine
Fluoxetine
Olanzepine
Tramadol+acetaminaphen
Thioridazine
Protriptyline HCl
Codeine sulphate
DPD deficiencyFluorouracil
Capecitabine
G6PD deficiencyRaspuricase
TPMT variantsAzathioprine
Thioguanine
Mercaptopurine
UGT1A1 variantsIriniotecan
Nilotinib

Panels of germline markers or single, highly significant associations may prove to be clinically applicable. However, the example of tamoxifen and CYP2D6 in breast cancer shows the challenges of translating promising findings into the clinic. CYP2D6 metabolises tamoxifen to more active forms and this metabolism can be inhibited when women carry variant alleles or take other drugs that inhibit CYP2D6 function [65]. The hypothesis that CYP2D6 inhibition might modify the effectiveness of tamoxifen was first proposed in 1991 [66], and almost 20 years later the only accepted clinical practice modification is that potent inhibitors of CYP2D6 should be avoided in individuals on tamoxifen [65]. Due to inconsistent epidemiological data, no consensus guidelines currently recommend germline CYP2D6 testing for women who would otherwise benefit from tamoxifen [67]. The difficulty interpreting clinical data relating to this pharmacogenetic example illustrates the importance of carefully incorporating promising pharmacogenetic biomarkers into prospective studies. With the exception of abacavir for the treatment of HIV/AIDS [68], no germline pharmacogenetic test has yet been adopted into routine medical practice. For UGT1A1 and irinotecan, CYP2D6 and tamoxifen, and VKORC1, CYP2C9 and warfarin, limited or absent prospective data has prevented widespread acceptance of predictive testing. The apparent strong association between prostate cancer and common genetic variation may yield germline biomarkers of clinical significance and lessons from the translation of these previous associations must be heeded if patients with prostate cancer are to benefit.

As yet, there have been few germline pharmacogenetic studies in prostate cancer. All have used the candidate gene approach with few clinically meaningful reports. RFC1 G80A genotype was not associated with response in a phase II study of pemetrexed in castration-resistant prostate cancer [69]. Variants in ABCB1 do not predict response to taxanes [70]. Interestingly, in view of the data supporting a preventive role for finasteride and dutasteride [71,72], germline variants in 5α-reductase type II may alter the activity of the drugs although replication of a single report is required [73]. Trinucleotide repeat length in the androgen receptor has been investigated as a predictor of response to androgen-deprivation therapy, but both longer [74] and shorter [75] repeats have been associated with better response, diminishing the interest in pursuing this approach. Another hypothesis generating report suggested that germline variants in three genes involved in the androgen axis can be used to predict response to androgen-deprivation therapy [76]. Preclinical data suggests that response to taxanes requires functional BRCA1, which activates the mitotic checkpoint and induces apoptosis [77,78]; although in a small subset of BRCA mutation carriers responses to docetaxel-based therapy were seen [79].

Through the establishment of groups such as the Pharmacogenetics Research Network the scientific community has recently adopted an organised and collaborative approach that proved successful in risk prediction and will hopefully produce similar success in response and toxicity prediction.

TRANSLATING GENOMIC VARIATION INTO PROSTATE CANCER CLINICS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE HERITABILITY OF PROSTATE CANCER
  5. RARE GENOMIC VARIATION AND PROSTATE CANCER
  6. COMMON GERMLINE VARIATION: GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND PROSTATE CANCER
  7. PHARMACOGENETICS, PHARMACOGENOMICS AND TREATMENT SELECTION
  8. TRANSLATING GENOMIC VARIATION INTO PROSTATE CANCER CLINICS
  9. CONCLUSION
  10. CONFLICT OF INTEREST
  11. REFERENCES

Genomic variation has the potential to inform prostate cancer management, and to guide clinical decision making at many points in the prostate cancer clinical states model; however, the translation of rapidly emerging preclinical data is challenging. Ultimately, it may be possible to perform smaller clinical trials of genetically homogenous study populations that may yield a more productive and less costly clinical trial system. An imperative first step in achieving this goal is the molecular definition of the natural history of prostate cancer. This requires the establishment of clinically annotated databases of patients with prostate cancer who have achieved clinically meaningful endpoints, such as prostate cancer-specific death. This resource would then facilitate the discovery and validation of relevant biomarkers.

Biomarker discovery could be initiated retrospectively. When analysing germline variation stratification of patients by gender, race and environmental factors would be important because a gene that is significant in one population may not be in another [80]. Furthermore, such stratification may give clues as to how different genes interact with these factors to affect the disease. Once identified, a genetic biomarker could be prospectively investigated using an appropriately designed clinical trial. This approach was used in the Tailor X trial of patients with breast cancer to prospectively validate a retrospectively defined somatic, prognostic and predictive genetic signature [81]. This approach has also been proposed by the Cancer Research UK Biomarker Roadmap Initiative as the most efficient way of identifying and validating biomarkers for future use in oncology patients (http://www.cancerresearchuk.org). A composite germline and somatic genetic signature may prove to be more powerful that either one alone. An illustrative example of how such a germline genetic signature could be defined and validated to help treatment decisions in early prostate cancer is shown in Figs 1 and 2.

image

Figure 1. Flow diagram showing the steps to translate germline biomarkers into clinical practice.

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image

Figure 2. Example of a hypothetical prospective, randomised controlled trial evaluating the clinical utility of a germline risk prediction test in managing patients with early stage prostate cancer.

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The emergence of multiple new systemic therapies for advanced prostate cancer in recent years [60–63] has resulted in efforts to define the optimal sequence of treatments. It is uncertain for example whether cabazitaxel, abiraterone or MDV3100 should be first choice for docetaxel-refractory prostate cancer. Germline variants affecting the metabolism of these drugs may help predict response and toxicity and assist such clinical decision making.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE HERITABILITY OF PROSTATE CANCER
  5. RARE GENOMIC VARIATION AND PROSTATE CANCER
  6. COMMON GERMLINE VARIATION: GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND PROSTATE CANCER
  7. PHARMACOGENETICS, PHARMACOGENOMICS AND TREATMENT SELECTION
  8. TRANSLATING GENOMIC VARIATION INTO PROSTATE CANCER CLINICS
  9. CONCLUSION
  10. CONFLICT OF INTEREST
  11. REFERENCES

Germline genetic variation is stable, accurate and amenable to high throughput analysis. Technical advances have simplified measurement of inherited genomic variation to the point that a simple blood test in clinic could feasibly predict disease outcome, and as such it may represent an ideal biomarker candidate. This potential has not yet been investigated and it is essential that germline DNA be ascertained in biological specimen procurement protocols to ensure that future investigation is feasible. Once pre-clinical knowledge has advanced to the point that clinically valid tests are available, a novel clinical trial structure will be required to test their clinical utility. After showing the net health benefits, economic and ethical issues must also be considered before introducing the test into clinical practice. This will require thoughtful dissemination to ensure adequate comprehension of the implications and appropriate interpretation of the results. Prostate cancer appears to be a logical disease in which to establish this paradigm. It is a common, late onset disease disproportionately arising from common genetic variation when compared with other cancers, and its increasingly complicated clinical management would benefit from a novel biomarker at many points in the disease states model. Widespread PSA screening has led to more overtreatment of indolent disease and reliable biomarkers would identify a subset of men with localised disease for surveillance. The emergence of novel systemic treatments has increased therapeutic options in prostate cancer and molecular characterisation of individuals may guide appropriate treatment selection. If successful, this approach would rationalise therapeutic strategies and strengthen our clinical trial system. There would be savings in terms of efficacy and morbidity for patients, cost and efficiency for the healthcare system and medical research field, and ultimately the pace of scientific and clinical progress may be re-aligned.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. THE HERITABILITY OF PROSTATE CANCER
  5. RARE GENOMIC VARIATION AND PROSTATE CANCER
  6. COMMON GERMLINE VARIATION: GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND PROSTATE CANCER
  7. PHARMACOGENETICS, PHARMACOGENOMICS AND TREATMENT SELECTION
  8. TRANSLATING GENOMIC VARIATION INTO PROSTATE CANCER CLINICS
  9. CONCLUSION
  10. CONFLICT OF INTEREST
  11. REFERENCES