Background
Next generation sequencing technologies such as whole genome sequencing (WGS) have enhanced the speed and reduced the cost of seeking genetic mutations predisposing to conditions such as hereditary cancer syndromes [
1]. There has, however, been intense debate about the appropriateness of using these technologies to screen individuals who do not meet traditional testing criteria. Arguments against population testing include uncertainty about the balance of benefit versus harm of interventions for high risk gene carriers without a strong family history of disease as well as other ethical, technical and cost concerns [
2‐
6].
Internationally, clinical approaches to testing for and reporting secondary genomic findings, defined as findings that are actively sought by a practitioner but are not the primary target of investigation [
7], vary widely. In the United Kingdom, the approach taken to secondary findings in the 100,000 Genomes Project–a flagship research project that aims to sequence 100,000 whole genomes from NHS patients by 2017 [
8]–will act as a blueprint for future NHS practice. It is crucial therefore that the impact of using WGS for germline genetic testing on population health, clinical and laboratory services is appropriately considered.
In the 100,000 Genomes Project, deleterious alleles in 16 genes detected on whole genome analysis will be reported back to participants regardless of test indication [
8]. These include the genes
BRCA1 and
BRCA2, implicated in hereditary breast and ovarian cancer syndrome. In contrast, usual clinical practice is to undertake
BRCA1 and
BRCA2 testing based on results of risk scores calculated using factors such as age, family history and personal cancer history [
9,
10]. Germline genetic testing for high risk cancer genes aims to provide the best possible estimate of an individual’s cancer risk to inform decisions about undergoing risk-lowering interventions. In the absence of a family history, the disease risk for mutations identified and therefore the clinical utility of testing, is likely to differ from that seen in multi-case families and may be poorly estimated.
In this study we aimed to model the likely outcomes of testing for medically-actionable gene mutations in unselected populations undergoing WGS, using the example of BRCA1 and BRCA2. We considered the clinical validity of such testing and implications for individuals, laboratory and clinical services.
Discussion
Using the example of pathogenic
BRCA1 and
BRCA2 mutations we demonstrate the type of process that should be undertaken when considering likely outcomes of testing for secondary genomic findings in unselected populations. We estimated that WGS would detect 75.5-77.5 % of pathogenic
BRCA1 and
BRCA2 mutations, with the majority of undetected mutations comprising CNVs. This is well below the 95 % sensitivity threshold recommended for clinical genetic diagnostic tests [
13]. In a hypothetical UK population of 100,000 women, this would result in 244 identified for further interventions, potentially preventing around 132 cases of breast cancer. This would also result in unnecessary inteventions for 112 women with mutations predicted not to develop cancer, although this is in line with current practice [
10]. We note that outside the context of WGS, routine
BRCA1 and
BRCA2 testing is neither recommended nor advocated at population level [
9,
10,
24].
Key areas of uncertainty include limitations to current knowledge of the prevalence, spectrum and penetrance of pathogenic mutations associated with a variety of hereditary diseases, including those currently recommended for routine examination on WGS by Genomics England. In hereditary breast cancer, estimates of penetrance have frequently been derived from studies conducted in multi-case families as population estimates do not exist, and it may not be appropriate to apply such estimates to unselected populations undergoing WGS. For mutations in other genes conferring a lower risk of disease, there is uncertainty about the threshold for clinical action and thus the level of absolute disease risk at which secondary findings should be fed back.
Care pathway factors should also be considered when implementing this approach. Currently WGS has sub-optimal sensitivity for detecting certain types of mutation, in particular CNVs and some indels. Concerns have been raised about potential inconsistencies between laboratories in assuring quality of data generated by WGS and its interpretation [
25]. The risk of false positives, although low, would be increased if laboratories did not undertake a confirmatory step. The number of pre-symptomatic mutation carriers identified across a range of genes tested for secondary findings is unknown so there is a lack of assurance that clinical services will be able to manage the extra work volume generated. For
BRCA1 and
BRCA2 mutation carriers this would include enhanced radiologic surveillance, chemoprophylaxis and/or prophylactic surgery to mitigate risk. In addition the cost effectiveness of such interventions is uncertain although recent data suggest that screening of generally healthy individuals using next generation sequencing may not currently be cost effective [
26].
Globally there is divergent policy around secondary genomic findings: in 2013 the American College of Medical and Genetics and Genomics (ACMG) controversially recommended routine examination of 56 potentially actionable genes and types of variants whenever clinical exome or genome sequencing is undertaken [
27] (although an opt out clause has since been added) [
28]; the European Society of Human Genetics in contrast suggests using a targeted testing or reporting strategy where possible to minimise the risk of genetrating unsolicited findings [
29]. In the UK the 16 genes recommended for routine examination in the 100,000 Genomes Project are based on the ACMG list plus ‘subsequent expert opinion’ [
7]. In unselected populations, however, it is unclear how well this approach to secondary genomic findings allows quantification of an individual’s absolute disease risk, which is essential to making valid judgements about risks and benefits of clinical intervention.
Conclusions
In summary, we use a simple model to highlight issues that hinder the utility of actively seeking secondary findings using WGS, even for relatively well-characterised genes. Applying this method to other gene-disease combinations is likely to reveal further gaps. It is therefore imperative that robust processes are in place for managing and understanding these complex data and appreciating the levels of uncertainty around clinical validity and clinical utility of testing positive for a cancer risk gene. Detailed evaluation of developing practice and research will be essential to enable effective clinical implementation of this approach to secondary genomic findings in unselected populations.
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Competing interests
All authors declare that they have no competing interests.
Authors’ contributions
CWG reviewed literature, developed models, analysed data and wrote the manuscript. MK, HB and PP conceived the study, provided academic supervision and critically revised the manuscript. All authors read and approved the final version.