Genomics and cancer research
Since the human genome was sequenced in 2000, much progress has been made with cancer research. In a review article published this week in the New England Journal of Medicine, McDermott et al., (2011) stated that:
“The identification of an essentially complete set of protein-coding genes, coupled with the discovery of novel transcribed elements such as microRNAs, has fostered an explosion of investigation using array-based approaches into patterns of gene expression in most cancer types.”
In most cancers, histology still drives diagnosis, which I always thought of as a rather crude method of differentiation. The ones that have begun to advance beyond this?
- Breast cancer: where expression profiling has led to the identification of different molecular subtypes of basallike, positive for human epidermal growth factor receptor 2 (HER2), normal breastlike, luminal A, and luminal B.
- Acute and chronic myeloid leukemias, where molecular subtyping helps in diagnosis and also to determine outcomes and in some cases, when to change therapy as new mutations are acquired.
In CML, basic and clinical research may be far advanced in Academic practice on both sides of the pond, but sadly often community clinical practice in the US is lagging in basic routine monitoring of patients with CML in terms of regular cytogenetic and molecular testing to evaluate responses to treatment or acquired resistance developing. In AML, many molecular subsets have been identified, but we still don’t know which are key drivers or mere passengers. There is a long way to yet in practical day to day terms.
The impact of the research in breast cancer has demonstrated that different subtypes exhibit very different clinical and biologic features, including patient survival. Essentially this means taking a very heterogeneous disease and identifying more homogenous subgroups that behave more consistently. That said, the authors note:
“In routine clinical practice, however, classification is still based on conventional histologic analysis, coupled with immunohistochemical staining for estrogen receptor (ER), progesterone receptor (PR), and HER2, which when combined can reconstruct most of the subclasses defined by mRNA expression.”
Gradually, though, new treatments are evolving for each subtype as well and this will continue to develop as new, more targeted therapies emerge based on a deeper understanding of the biology and how it all fits together. Systems biology is very much at the heart of breast cancer research.
The review highlighted several areas where advances may emerge:
- Prognostic indicators
- Optimising use of therapeutics
- Development of new therapeutics
- Acquired resistance to therapy
- Monitoring of disease burden and early recurrence
- Genomics in the design of early clinical trials
- Susceptibility to cancer
Of course, as the article notes,
“The technologies that are research tools today are primed to become the diagnostics of tomorrow.”
One of the cool things about this article was an interactive graphic looking at the assay of tumor DNA to detect recurrence and early after resection using non-small cell lung cancer (NSCLC) as an example. Unfortunately, the article appears to be subscriber only, not open access, so if your institution takes this journal I highly recommend checking it out {HT to Edward Winstead of the NCI Cancer Bulletin, this article is indeed open access for anyone to read}.
I’ll leave you with the final observation from the review to ponder and debate:
“The rapid development of next-generation sequencing technologies seems likely to be transformative. Within a few years, a complete cancer genome sequence will be obtainable for a few hundred dollars or less. As the number of informative genetic abnormalities to be searched for in an individual cancer continues to increase, it may ultimately be more parsimonious to sequence the whole genome rather than do a large battery of directed tests.
However, in order to exploit the full clinical potential of information within the cancer genome, it will first be necessary to incorporate analysis of the genome and transcriptome more widely into clinical trials, generating new and unexpected predictors of drug responsiveness and prognosis.”
References:
Feero, W., Guttmacher, A., McDermott, U., Downing, J., & Stratton, M. (2011). Genomics and the Continuum of Cancer Care New England Journal of Medicine, 364 (4), 340-350 DOI: 10.1056/NEJMra0907178
2 Responses to “Genomics and cancer research”
Great post, Sally. Do you know if there’s any work being done to translate the work being done at the Broad Institute’s Molecular Signatures Database into clinically validated tests? I suspect that main reason we don’t see more use of MDx in a clinical setting, is the lack of validation and FDA approval. Without that, no clinician is going to recommend tests that insurance won’t pay for.
No I don’t Mark, good observation re: Broad Institute.
There’s a fair amount of evidence for molecular diagnostics eg EGFR mutations, cytogenetics in CML etc, all approved and the relationship with outcomes well established. Granted, others still need clinical evidence from trials to emerge, eg CTC’s are approved but their relationship to survival less well established… with the forthcoming data expected from the abiraterone trials in prostate cancer we may well see things changing.
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