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Cancer Genomics: From Diagnosis to Treatment


The first publication of cancer genome sequencing was in 2006, whereby more than 13,000 genes involved in breast and colorectal tumours were studied. Shortly after, in 2008, the first whole cancer genome was sequenced, which was derived from a bone marrow cancer, also called cytogenetically normal acute myeloid leukaemia (CN-AML). The first breast cancer tumour was later sequenced in 2009 and the first lung cancer tumour was sequenced the following year.

Today, genomics is transforming the way we understand cancer. It is helping clinicians to provide precise oncology treatments for patients and to detect resistance to therapies. Moreover, the application of cancer genomics has the potential to enable early diagnosis and predict treatment failures. Ultimately, harnessing the power of genomics in cancer care will drastically improve patient outcomes and make this deadly group of diseases more treatable.

For a more in-depth view of the cancer genomics field and the precision oncology space, check out the Cancer Genomics report. It includes exclusive panelist interviews and up-to-date information about relevant enabling technologies. Download it for free here:

What is Cancer Genomics?

One in two people will develop cancer at some point during their lifetime.

An ageing population is one of the leading causes for the rising prevalence of cancer. Nevertheless, ongoing research efforts over the last 40 years have resulted in the UK’s cancer survival rate doubling, and around half of patients now surviving the disease for more than a decade.

Much of this life-saving research has focused on cancer’s genetic basis. Put simply, this is because cancer is a disease of the genome. It occurs when changes in a person’s DNA cause cells to grow and divide uncontrollably. These mutations can be inherited from a parent, which are called germline variants, or acquired at some point during a lifetime, named somatic variants.

Cancer genomics aims to understand the genetic basis of tumour cell proliferation and the evolution of the cancer genome. Knowledge can be gained whilst the cancer is under selection by the body’s environment, the immune system and therapeutic interventions. In recent years, the combination of next-generation sequencing (NGS) and advanced computational data analysis approaches has revolutionised our understanding of the genomic underpinnings of cancer development and progression.

A Brief History of NGS

Although it is clear that genomics has the potential to significantly enhance our knowledge about the molecular drivers behind tumour growth, and subsequently improve our treatment options, challenges remain in pushing genomics to the core of cancer care. Overcoming these barriers relating to cancer genomics will be crucial for opening the next era of precision medicine and, ultimately, for improving patient outcomes.

How can Cancer Genomics Improve Diagnosis?

Today, cancer diagnosis remains largely focused on national screening programmes, which mainly consist of medical imaging and physical examinations. Once a tumour is detected, a biopsy is taken to help inform the diagnosis. The tissue undergoes molecular testing for cancer-specific biomarkers and the genetic information gained is then used to select therapies and monitor the effects of treatment.

However, the biopsy procedure is often uncomfortable for the patient and in some cases can be difficult due to the location of the tumour. Moreover, once a patient has been matched to a therapy, a proportion of patients still do not show a sustained response or respond at all. Essentially, many cancer treatments are ineffective, and unfortunately, this cannot usually be determined right away. Therefore, large research efforts have been carried out using genomics and other molecular technologies to improve the cancer diagnosis process.

Liquid biopsy

A liquid biopsy is a non-invasive diagnostic test conducted on bodily fluids, most commonly blood. It is used to detect biomarkers called circulating tumour cells (CTCs) and cell-free tumour DNA (ctDNA), which have been shown to be clinically relevant for many cancer types.

Essentially, the hope is that once the clinical utility of liquid biopsies has been proven through a series of trials, different types of cancers at various locations in the body will be detected from a simple blood sample. Then, the information gained from the diagnostic test can be used to match patients to the best drugs. Additionally, during treatment, regular liquid biopsies can be taken to reveal the persistence or increase of CTCs or ctDNA, quickly indicating resistance to the chosen therapy. In this case, patients would be offered a more effective treatment before the tumour became incurable. Periodic liquid biopsies have the potential to monitor patients at high risk of cancer relapse.

Advantages of using liquid biopsies

  • Non-invasive: The procedure can be carried out outside of a hospital setting, without the need for senior medical supervision. This means that the tests can act as a complimentary screening method in lower-income countries where access to healthcare is limited.
  • Repeat testing: The non-invasive nature of the test means that repeat testing is not detrimental to the patient. This means that the technique is ‘real-time’ and can be used to monitor the molecular changes of a tumour over sustained periods.
  • Early detection: Tumour-derived material can be identified in the bloodstream at the beginning stages of tumour formation, allowing for early detection of cancer.
  • Shifting treatments: Detecting treatment resistance early can halt the use of ineffective therapies quickly. This is especially significant for unpleasant treatments like chemotherapy, where unnecessary side-effects can be avoided.
  • Detect relapse: Liquid biopsies can measure minimal residual disease, which is when cancer persists after treatment but can no longer be detected using medical imaging. This can help to detect relapse early.

Disadvantages of using liquid biopsies

  • Not standard procedure: Today, liquid biopsies are not considered a standard testing procedure. Instead, the use of these assays is primarily to compliment a tissue biopsy, which may undermine most of their advantages. Further validation through clinical trials is needed to test their utility and value in medical settings.
  • Potentially biased: It remains unclear as to whether liquid biopsies provide representative sampling of all genetic variants, or if they are bias to specific regions of a tumour. Therefore, more studies are needed to test their accuracy and ability to identify different cancer types.
  • Test sensitivity: CTCs and ctDNA are relatively rare compared to the number of other haematological molecules found in a blood sample. Therefore, there are difficulties surrounding the sensitivity of liquid biopsies and the test’s ability to reliably detect cancer.

The extent to which liquid biopsies will replace standard biopsies remains unclear. Perhaps they will provide a reliable alternative for diagnosing primary tumours or determining the stage of metastatic lesions in tissues where extracting a sample is difficult. It is probable that they will also prove useful for monitoring purposes, such as throughout treatment and identifying relapse.

But to push liquid biopsies into widespread use, more interventional clinical trials are required that include diverse groups of participants. Moreover, an algorithm that locates appropriate circulating biomarkers needs to be developed by combining all the relevant data for researchers to obtain a complete and precise tumour profile. This will require huge collaboration between the industry and policymakers.

Additional molecular profiling

It is thought that the profiling of cancer patients could be strengthened by adding further molecular information at diagnosis. This would enable the development of more precise diagnostic tests that truly reflect an individual’s tumour biology and could be used to benefit clinical decision making.

For example, proteogenomics is the integration of proteomic and genomic profiles. Clinicians could use this to help inform the diagnosis and management of cancers because it could provide insight into genetic changes occurring within the tumour. However, proteomic profiling is particularly difficult due to the challenges presented when handling proteins.

The Clinical Proteomic Tumour Analysis Consortium (CPTAC), run by the National Cancer Institute, is an effort to accelerate the understanding of the molecular basis of cancers through the application of proteogenomics. It was launched in 2011 and has since pioneered the integrated proteogenomic analysis of colorectal, breast and ovarian cancers. The continuous progress of CPTAC has enabled the creation of the Applied Proteogenomics OrganizationaL Learning and Outcomes (APOLLO) network and the International Cancer Proteogenome Consortium (ICPC), both of which aim to make studying proteins within a patient’s tumour part of routine care.

A Guide to Proteomics

How can Cancer Genomics Enhance Treatment Choices?

Precision oncology

Since the advent of genomic sequencing, targeted therapies that are specific to the genetic drivers of cancer have been developed. Precision oncology is the provision of targeted treatment for an individual’s cancer, based on its genetic and molecular profile. The practice also considers patients unique characteristics when matching them to the most accurate treatment, including their proteome, epigenome, microbiome, lifestyle and diet. Knowledge about cancer genomics is vital at various stages of precision oncology to successfully deliver targeted treatments. This can be from clinical trials and throughout the patient management process.

Many precision oncology efforts have been successful, including the FDA approval of using dabrafenib and trametinib collectively to treat non-small cell lung cancer with the BRAF V600E mutation. However, there is currently no drug available capable of targeting every specific mutation identified. In fact, NGS studies have shown that most patients do not have ‘actionable’ mutations, like BRAF V600E. Moreover, cancers are often hugely complex and have several driver mutations, making treatment choices difficult.

Nevertheless, precision oncology and cancer therapeutics have continued to make rapid advances. For example, the European Society for Medical Oncology (EMSO) published a Precision Medicine Glossary in the Annals of Oncology in 2017. Papers like this are important for creating standardised communication between oncologists, researchers and patients. Moreover, several new drugs and immunotherapies that target protein kinases, which are increasingly being recognised as hallmarks of tumour development, have recently been accelerated or granted approval.

To read an exclusive panelist discussion about the promises and pitfalls of precision medicine in clinical trials, check out the Cancer Genomics report. It includes contributions from experts in the precision oncology field and highlights the latest research in the cancer genomics space. Download it here:

Drug rediscovery

Not only can large-scale genetic profiling of tumours identify potentially actionable molecular variants associated with approved anticancer drugs, but it can also help to discover variants that could be treated outside of typical and currently available therapeutic options. The Drug Rediscovery Protocol was initiated in 2016 as an adaptive trial that aimed to identify signals of activity in cancer patients treated with drugs outside of their approved label. The study was set up to enable the successes and failures of these unconventional therapies to be systematically collected and shared for the first time.

To be eligible for the scheme, patients had to have a cancer with potentially actionable variants for which no approved anticancer drugs were available. Overall, the protocol was shown to have a clinical benefit for 34% of patients who took part. This illustrated that the use of approved drugs outside of their labels could improve outcomes for people with rarer cancer types. Following on from this initiative, it is important to create publicly available repositories that contain data on different uses of anticancer drugs. Exploring outside of approved drug labels will guide future decision making and accelerate clinical improvements through new insights gained from exploring outside of approved drug labels.

Tracking cancer evolution

After a cancer-causing mutation occurs, there are several biological repair systems in the body that attempt to destroy the diseased cells. However, if unsuccessful and the cancer cells evade the immune system, it allows the disease to proliferate and spread to distal organs. Fortunately, the cancer genome leaves clues about its evolution through ongoing mutations that can be tracked to understand cancer development. Identifying the genomic evolution of cancer cells can be of great importance when evaluating treatment options, because it can provide insight into how drug-resistant clones render some treatments ineffective.

TRACERx was set up in 2014 to observe the relationship between phenotypic variation caused by cancer evolution and patient outcomes in a clinical setting. This project enables researchers to track the evolutionary processes within a tumour from early to late stages of cancer as well as throughout therapy. In fact, by integrating longitudinal and multiregional sampling, researchers have already detailed the evolutionary processes of the tumour and immune microenvironment of non-small cell lung cancer and clear-cell renal cell carcinoma.

The Cancer Gene Directory

Cancer Genomics Technologies

Genomic technologies have emerged as incredibly valuable tools in cancer research during recent years. In particular, NGS platforms have provided oncologists with a growing body of knowledge that has contributed to more effective drug design, better patient treatment options and more accurate disease prognoses. The choice of sequencing approach depends on several factors, including the research purpose, available budget and desired throughput.

Whole genome sequencing

Whole genome sequencing provides information about all the DNA in a tumour. The approach has helped to identify millions of changes in tumour genomes, from localised changes like point mutations and indels, to large structural variations, including the translocation of DNA between chromosomal regions. Such information can be used to predict the prognosis of a patient’s cancer and identify the most effective treatment. The main advantage of whole genome sequencing is that it gives such a comprehensive view, enabling previously unknown regions to be explored. This makes it unlikely to miss key mutations.

Whole exome sequencing

Many oncogenic variants are found within exons, or protein coding regions, which make up around 1% of the genome. Exome sequencing is often the method of choice for large cancer research projects, due to the many advantages that targeted techniques have over whole genome approaches. For example, whole exome sequencing narrows the scope of a sequencing project significantly, in turn reducing the data analysis burden, cost per sample and turnaround time. This means that deep sequencing can be performed, which is critical for locating rare mutations.

Focused sequencing panels

Focused sequencing panels are used to target specific mutations in a sample. They are particularly useful for detecting somatic mutations at a low frequency. Focused panels contain a select set of genes, or gene regions, that are suspected to be associated with disease. Targets can include oncogenes, tumour suppressor genes, mutation hotspots, copy number variants, RNA fusions, splice variants and gene expression changes. The sequencing panels produce a smaller and more manageable dataset than broader approaches, making analysis easier and less time consuming.

RNA sequencing

RNA sequencing enables researchers to understand the functional effects of genomic mutations. This allows the detection of gene fusions and other cancer-associated transcriptome variations. RNA research data can help to inform cancer treatment choices and support the development of diagnostics and biomarkers. Moreover, RNA sequencing has been used in studies on cancer evolution, drug resistance, cancer neoantigens and the cancer immune microenvironment.

ChIP sequencing and bisulphite sequencing

Cancer progression is often caused or influenced by epigenetic changes that alter gene expression. Chromatin immunoprecipitation sequencing (ChIP-seq) and bisulphite sequencing can be used to investigate the role of epigenetic factors in tumour growth. ChIP-seq has been used to study the genome-wide chromatin structure in human cancer cell lines and bisulphite sequencing has been utilised to investigate genome-wide  DNA methylation changes in cancer.

DNA Sequencing: How to Choose the Right Technology

For more information about the enabling technologies that are being utilised by researchers to make breakthroughs in precision oncology, check out the Cancer Genomics report. It includes perspectives from experts in the field and various relevant case studies. Download it for free here:

Challenges Facing Cancer Genomics

Unfortunately, today, not all cancer genomes hold the key for prolonging life. This is due to an array of reasons, such as a lack of targeted therapy or because the genomic alteration is too poorly understood. Nevertheless, each genomic mutation that is studied in a cancer could lead to identifying a future drug target.

Rare genetic alterations

The genetic abnormalities found within a single type of cancer are hugely diverse. Moreover, these alterations vary greatly between patients, meaning that identifying which genetic changes initiate tumour growth and drive cancer development is extremely difficult.

Moreover, only a subset of tumours contain specific actionable alterations, whereby clinical data can directly influence the choice of therapy. Furthermore, only a minority of patients with these actionable mutations are currently enrolled in relevant cancer genomics studies.

High-quality samples

Acquiring biological samples that are of high enough quality for genomic studies is challenging. This is especially true for tumour types that are rare or those that have not been primarily treated by surgery. Liquid biopsies are overcoming some of these obstacles, but as mentioned earlier, they are yet to be fully utilised. Additionally, modelling rare subtypes presents difficulties as developing cell lines and animal models that represent the diversity of human cancer is still lacking. Therefore, rare cancer subtypes are currently under-represented in research.

Managing big data

Analysing the vast amount of data involved in cancer genomic research presents a challenge for the field. Unless properly managed, this will become a growing issue due to the extra data associated with combining different molecular layers. The involvement of data expertise across multi-disciplinary teams and the training of bioinformaticians will inevitably be required to tackle the management of cancer genomics data.

Potentially high costs

Approaches such as whole-genome, whole-exome and whole-transcriptome sequencing typically have higher computational requirements and longer workflow times compared to more targeted alternatives. These factors ultimately translate into higher costs. This is why tumour profiling by selecting regions of interest, followed by genomic DNA enrichment, has been adopted by the majority of clinical and research laboratories instead.

Opportunities of Cancer Genomics

The field of cancer genomics is evolving rapidly and so predicting its future is difficult, both from a research and clinical perspective. But, with continuously advancing technologies, genomics will certainly play an increasingly significant role in cancer care in the future.

Genomic data repositories

More genomic databases focused on cancer care are crucial. The Human Genome Project has allowed scientists to establish what a ‘normal’ human genome looks like. Therefore, it is now possible to determine what genomic changes have taken place with regards to cancer. Now, large projects, such as The Cancer Genome Atlas in the US and the Catalogue of Somatic Mutations in the UK, have determined the genome sequences of many cancer types. These projects have helped in the discovery of many cancerous mutations and added to scientists’ knowledge about the molecular mechanisms driving them.

Cancer Genomics Projects: The Collection

Additional molecular layers

Although genomics has been extremely informative for the characterisation of tumours and the identification of patients who may be eligible for targeted therapies, the landscape of cancer is highly complex. For example, nearly all common tumours have mutations of unknown significance. Therefore, it could be argued that relying exclusively on genomics for the diagnosis and treatment of cancer is insufficient. Improvements in technologies are expected to enhance the collection of richer phenotypic data, particularly with regards to the incorporation of additional molecular layers.

Multi-omics studies will enable a more in-depth picture of cancer and increase the likelihood of discovering more effective treatments. Combining proteomic data with genomic and transcriptomic data could help to better represent the complex biology of cancers. While proteogenomic profiling has been deemed useful in research settings, challenges remain in terms of its clinical use. Current difficulties include the need for biopsy scale sample sizes and the requirement for effective data sharing between collaborators to inform diagnosis and treatment choices.

Single cell multi-omics

Single cell sequencing has already made a huge impact on cancer research, particularly in terms of improving the understanding of the tumour microenvironment. Increasing the capabilities within the single cell space, in combination with multi-omics, will present huge opportunities for scientists to gain a better biological reflection of the molecular interactions that occur within cancer growth. By utilising single cell multi-omics, researchers will be able to obtain the richest datasets possible and provide additional granularity to cancer studies. Effectively integrating these datasets, however, will present the next challenge.

Choose the Right Single Cell Multi-Omics Protocol

Genomics education

Another shift that has already begun, and is likely to continue, is the education of the healthcare workforce about the importance of genomics in cancer care. The Genomics Education Programme was founded by the Health Education England in 2014. It aims to enable both future and current healthcare professionals to harness the power of genomic medicine for patient benefit. The initial £20 million four-year scheme was launched to ensure that the 1.2 million NHS workers had the knowledge, skills and experience to enable the UK to drive the genomics revolution in healthcare. Since then, the programme has been extended and continues to develop resources for a wide range of cancer professionals and provide training in genomics.

For more information about the future directions of precision oncology, check out the Cancer Genomics report. It includes perspectives from experts in the field and case studies of real-world cancer genomics research. Download it for free here:

Resources for Cancer Genomics

Cancer Genomics Online – July (Webinar series)

Cancer Genomics Online – April (Webinar series)

Liquid Biopsy: Current Status and Future Directions (Report)

Image credit: Breastlink

Don’t forget to follow Front Line Genomics for more information about how genomics is being used to benefit patients.