The largest studies performed on the genomes of breast cancer tumors to date have revealed that the disease is much more complicated than previously thought.
Three recent studies, all published in the journal Nature, investigated the genetic basis of breast cancer and suggest that the genetics of the disease is more complicated than previously thought. The studies discovered ten different subtypes of the disease and a continuum of mutations that cause it.
The first study, conducted by researchers at various institutions including Cancer Research UK (London, UK), the Wellcome Trust (London, UK), British Columbia Cancer Research Centre (BC, Canada), the University of British Columbia (BC, Canada) and the University of Cambridge (Cambridge, UK), studied both DNA and RNA from almost 1000 tumors to evaluate both the genome and transcriptome of breast cancer.
The results suggested that there are ten genetically distinct subtypes of breast cancer, and that these subtypes correlate with different clinical presentations of the disease. Hopefully, this will mean that in the future, doctors will know how best to treat each individual based on the subtype of their breast cancer.
Carlos Caldas, one of the researchers from Cancer Research UK, explains that; “essentially, we‘ve moved from knowing what a breast tumor looks like under a microscope to pinpointing its molecular anatomy.” He believes that future research following these results will mean that “eventually we‘ll know which drugs [breast cancer] will respond to.”
In addition, this study highlighted new genes linked to breast cancer, and implicated cellular signaling pathways involved in the pathogenesis of the disease, which have already been characterized; two results that could lead to the development of new treatments.
The second study, which included researchers from multiple countries, including Belgium, the UK, Canada, The Netherlands and Norway, found nine new genes that are linked to breast cancer. The study also offered new insights into the complexities of disease-causing mutations.
By analyzing 100 tumors, researchers were able to identify driver mutations that cause cancer in 40 genes, including nine that had not been previously linked to breast cancer: AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. The researchers also noted that the numbers of driver mutations varied, from a single driver in many tumors, to some with as many as six. In the set of tumors studied, more than 75 combinations of mutations were found.
Andy Futreal, from the Wellcome Trust Sanger Institute (Cambridge, UK), commented on the importance of these findings for the treatment of breast cancer: “one of the most striking things about breast cancer is how it progresses differently in each patient and how each patient responds differently to therapy. Our results can help us to understand these differences.” The ultimate goal is to use knowledge of these differences to develop new treatments for breast cancer.
The third study was conducted at the BC Cancer Agency (BC, Canada), and investigated the genomes of triple-negative breast cancer, currently the most difficult breast cancer to treat. The study, led by Sohrab Shah, found that triple-negative breast cancer is much more genetically variable than previously thought.
Steven Jones (BC Cancer Agency), a coauthor of this study, explains the significance of the results: “the genetic diversity of these tumors, even though they‘re clinically similar, probably explains why they are so difficult to treat.” Jones continues, “these findings prove the importance of personalizing cancer drug treatment so that it targets the genetic make up of a particular tumor rather than presuming one therapy can treat multiple, similar-looking tumors.”
Taken together, these studies emphasize the need for personalized medicine in breast cancer treatment, and take the field further towards this goal. Caldas hopes that these results will “pave the way for doctors in the future to diagnose the type of breast cancer a woman has, the types of drugs that will work and those that won‘t, in a much more precise way than is currently possible.”
– Written by Alisa Crisp
Sources: Curtis C, Shah SP, Chin ST et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature doi:10.1038/nature10983 (2012) (Epub ahead of print); Stephens PJ, Tarpey PS, Davies H et al. The landscape of cancer genes and mutational processes in breast cancer. Nature doi:10.1038/nature11017 (2012) (Epub ahead of print); Shah SP, Roth A, Goya R et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature, doi:10.1038/nature10933 (2012) (Epub ahead of print).
A hospital in London has announced that it will be the first in the UK to use the Spartan RX™ (Spartan Bioscience Inc., ON, Canada) point-of-care genetic test to screen patients for genetic resistance to clopidogrel.
The Spartan RX is the first sample-to-result point-of-care DNA testing system to identify individuals who carry the CYP2C19*2 allele (estimated to be 30% of the world‘s population) and are therefore genetically less responsive to clopidogrel administration. The difference in metabolism can lead to a higher risk of clotting following cardiac stent implantation and lead to an increase in recurrent heart issues.
“This is an exciting development in terms of improving the risk profiling of cardiac patients and has the potential to allow improved tailoring of therapy.” Commented Charles Knight at BMI the London Independent Hospital, London, UK.
Currently, genetic tests take place in a laboratory and can take up to 7 days. Point-of-care systems such as the Spartan RX are designed to be operated in a clinical environment by nurses and can deliver results 1 h after the cheek swab. Discussing the implications of point-of-care genetic testing, Knight added “Most complications of coronary stenting occur in the first 24–48 h postsurgery so having results in 1 h is a significant development.”
– Written by Louise Rishton
Source: Spartan RX™: www.spartanbio.com/products/spartan-rx
This August, the University of Ljubljana, Slovenia will serve as the backdrop for the first European Society of Pharmacogenomics and Theranostics-organized summer school. The event will take place between 21 and 26 August 2012, and will provide students and health professionals with comprehensive training and updated knowledge in the multidisciplinary field of pharmacogenomics and theranostics.
The summer school, which will be cochaired by Janja Marc (University of Ljubljana) and Pharmacogenomics Editorial Board member Vangelis Manolopoulos (Democritus University of Thrace, Greece), will be based on an integrated approach incorporating all facets of ‘New Genetics‘ and aims to encourage interaction between young students and specialists in the field. The program is designed for graduate and postgraduate students, but also for medical doctors and researchers from various fields interested in pharmacogenomics.
The summer school will consist of lectures, held by distinguished international faculty, workshops and student presentations. Talks by Pharmacogenomics Editorial Board members include:
| ▪ | Clinical Pharmacology: History, definitions, dimensions, role in drug development: Vangelis Manolopoulos | ||||
| ▪ | Adverse drug effects: Munir Pirmohamed, University of Liverpool, UK | ||||
| ▪ | Pharmacogenomic discovery using cell-based models: David Gurwitz, Tel-Aviv University, Israel | ||||
| ▪ | Population pharmacogenomics: Adrian Llerena, Hospital Universitario Infanta Cristina, Spain | ||||
| ▪ | Pharmacogenomics and pharmacoepigenomics in oncology: Ingolf Cascorbi, University Hospital Schleswig-Holstein, Germany | ||||
| ▪ | Pharmacogenetics of breast cancer: Ron van Schaik, Erasmus University Medical Center, The Netherlands | ||||
Participants will also have a unique opportunity to discuss their work with invited professors during the ‘Meet the professor session‘ and will be able to introduce themselves and their work to their peers on a one-to-one basis, during the ‘speed dating session‘.
– Written by Natalie Harrison
Source: ESPT summer schools: http://schools.esptnet.eu
Using preclinical models and patient tumor samples, researchers at The University of North Carolina at Chapel Hill (UNC; NC, USA) have discovered, for the first time, a link between intrinsic molecular subtypes of lung adenocarcinoma (LAD), genomic alterations and patient therapy response. The findings serve to advance the understanding of LAD etiology and nominate patient subgroups for future evaluation of treatment response. The results are published in the 10 May 2012 online edition of the journal Public Library of Science One.
Using statistical methods and published cohorts, the researchers tested LAD molecular subtypes (bronchoid, squamoid and magnoid) for association with gene mutations and DNA copy number alterations. Mutation rates of EGFR, KRAS, STK11 and TP53, chromosomal instability, regional copy number and genome-wide DNA methylation were found to be significantly different among tumors of the molecular subtypes.
The team, who first defined and reported on the three lung cancer molecular subtypes in 2006, compared the bronchoid, squamoid and magnoid subtypes by integrated alterations and patient outcomes; different subtypes were found to be associated with specific gene alterations. In addition, subtypes were also found to be associated with tumors with concurrent mutant genes, such as KRAS-STK11 with magnoid. The authors went on to discover that these mutations may have independent predictive value for therapeutic response as patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes.
Commenting on the results of the study in the context of the current status of the field, senior author, Neil Hayes, associate professor of medicine at UNC explains: “It has been known for about a decade of using gene-expression arrays that ‘molecular subtypes‘ exist. These subtypes have molecular ‘fingerprints‘ and frequently have different clinical outcomes. However, the underlying etiologies of the subtypes have not been recognized. Why do tumors form subtypes?”
The UNC Lineberger Comprehensive Cancer Center researcher continues: “Our study shows that tumor subtypes have different underlying alterations of DNA as part of the difference. These differences are further evidence of the importance of subtypes and the way we will use them. For example, the mutations are different, which may imply much more ability to target than previously recognized.”
Hayes concludes by highlighting the fact that researchers are beginning to gain clues that suggest that these subtypes may reflect different cells of origin that rely on different cancer pathways, which he believes will further unlock the diversity of this complex disease.
– Written by Natalie Harrison
Source: Wilkerson MD, Yin X, Walter V et al. Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation. PLoS ONE 7(5), e36530 (2012).