Research Demonstrates a Mutation Associated with Aggressive Prostate Cancer Occurs Earlier than Previously Believed
New research has highlighted the involvement of a known genetic mutation in whether prostate cancer will progress to the aggressive form in later life and whether relapses will occur after hormone therapy.
Prostate cancer is newly diagnosed in over 40,000 individuals annually, it is the most common cancer in males in the UK. Treatment options are varied if the cancer is diagnosed early and can range from hormone-withdrawal therapy to ‘watchful waiting‘. In order to determine how aggressive the prostate cancer may be and to be able categorize those men diagnosed into low- and high-risk groups, more indicators of the cancers aggressiveness are needed. This may allow for the earlier implementation of life-extending therapy in those who are likely to develop fatal prostate cancer.
Jeremy Clark (University of East Anglia, Norfolk, UK) one of two lead researchers on the present study reports that, “By the age of 60, the majority of men will have signs of prostate cancer. However, only a small proportion of men will die of the disease. The question is – which of these cancers are dangerous and which are not? Deciding which cancers are going to progress and kill the patient is key to effective patient treatment.”
Hormone-withdrawal therapy does result in remission, however, it will likely relapse with the more resistant form of the cancer, a third of these relapses are identified as being caused by an increase in the copy number of the androgen receptor (AR) gene. The present investigation examined biomarkers, using a tissue microarray series, prior to hormone-withdrawal therapy, of almost 596 prostate cancer patients. The researchers screened chromosome X for copy number alterations specific to the AR-gene locus.
“Our research has shown that an early form of this hormone-gene boosting is present in a number of prostate cancers that have never been treated with hormone reduction therapy. We think that it is these cancers that will grow and kill the patient,” comments Clark. Colin Cooper of the University of East Anglia also took the lead on this investigation, which was funded by the Association for International Cancer Research (Fife, UK).
The research identified that this mutation, which increases the copy number of the AR gene, can occur before hormone-withdrawal therapy, whereas previously this mutation was thought to occur in response to the therapy. With men normally only having one copy of the AR gene, as it occurs on the X chromosome, the increase in AR gene copies impacts the progression of prostate cancer. It has this effect as prostate cancer is particularly responsive to male hormones, but if it has more copies of the AR gene, the cancer growth is enhanced and enabled to become therapy resistant.
The methodology used in the study was time consuming and labor intensive, therefore in order for this identification method to be useful to categorize the aggressive cancer types in the clinic, more rapid methodology needs to be developed. This is what the researchers at the University of East Anglia are currently investigating.
Clark concludes, “This discovery can be used to identify these killer cancers in patients much earlier than is currently possible. Patients could then be selected for more aggressive therapy before the cancer has developed full immunity.”
– Written by Elizabeth Webb Illustrated by Amy O‘Donnell
Sources: Merson S, Yang ZH, Brewer D et al. Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer. Br. J. Cancer 110(6), 1655–1662 (2014); University of East Anglia press release: www.uea.ac.uk/mac/comm/media/press/2014/February/prostate-cancer-advance
A Panel of 55 Genes may Predict Poorer Survival in Breast Ductal Carcinoma in situ
A recent study, published in PLoS ONE, identified a genetic panel that may determine the future invasiveness of breast cancers and therefore poorer survival.
The 55 gene panel proposed by researchers from a variety of institutions contains a number of genes that are affected by the loss of a specific protein. The panel represents the loss of SYK, an important tumor suppressor gene that encodes the Syk protein, and genetic alterations in 51 other genes that are affected by the absence of Syk.
Susette Mueller (Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA) and colleagues utilized tissue from breast ductal carcinoma in situ (DCIS). This cancer can invade and morph the tissue surrounding it but is contained within the ducts of the breast. Tissue from DCIS was used to examine for the absence of SYK, invasive ductal carcinoma was demonstrated to be nearby in tissue samples presenting with a loss of one copy of SYK. Of the normal breast tissue samples, 100% did not present with a loss of SYK.
“Without SYK, the protein it makes, and genetic disruption in a set of genes thought also to be controlled by SYK, cancer invades and metastasizes,” comments Mueller. “This was the first time that a loss of a SYK gene was found in DCIS breast tissue, but we needed information about the outcomes of these cases to determine the significance of this finding.
The investigators then used The Cancer Genome Atlas (from the NIH, MD, USA) to determine the disease outcomes of the patients. The Cancer Genome Atlas documents gene mutations and sequences of invasive cancer patients and includes their outcomes. By pairing the outcomes and the 55 gene panel it was reported that the panel predicted the DCIS patients who presented with better outcomes. After 18 years follow-up, as completed in this study, approximately 20% of those who presented with alterations in the genetic panel were still alive, in comparison it was estimated that 80% of the patients who did not present with genetic alterations survived.
“Survival was much better in the invasive ductal carcinoma patients who did not have any change in the 55 genes,” comments Mueller. “The panel is not ready for use as a prognostic tool in the clinic, and much work is required to test it in that way,” she concludes.
– Written by Elizabeth Webb
Sources: Blancato J, Graves A, Rashidi B et al. SYK allelic loss and the role of Syk-regulated genes in breast cancer survival. PLoS ONE 9(2), e87610 (2014); Georgetown University Medical Center press release: http://explore.georgetown.edu/news/?ID=74635&PageTemplateID=295
Cancer Profiling Genomic Tests Launched
The release of cancer profiling tests for 22 different types of tumor has been announced.
NeoGenomics Inc. (FL, USA), a clinical laboratory specializing in cancer-focused genetic and molecular testing services, recently announced the launch of a series of cancer profiling tests. The NeoTYPE™ Cancer Profiles cover 22 different hematologic and solid cancers, with each test being custom-designed for a specific tumor type.
Scientists developed the technology to identify key driver genes that are central to therapy decisions, prognosis and clinical research. Only 8–18 genes are investigated per patient or tumor type, including brain, lung, breast, stomach and thyroid. The mutations are investigated using multiple techniques, including Sanger sequencing, FISH and fragment length analysis.
Maher Albitar, NeoGenomic‘s Chief Medical Officer and Director of Research and Development, commented, “Classifying cancers based on their morphology and site of origin is no longer adequate for the practice of evidence-based medicine. Our molecular profiling testing is a reliable and concise approach to subclassifying these tumors based on their underlying driving biology.” Albitar added, “This enables clinicians to better manage and treat their patients.”
Doug VanOort, Chairman and Chief Executive Officer of NeoGenomics, commented on the practicalities of this new technology, “Precision medicine requires precision testing. Our targeted tests are responsive to the need for both comprehensive testing in complex cases and the need to be cost sensitive for patients and insurance companies. Therefore, we are launching these tests on both a ‘comprehensive‘ and a ‘concise‘ basis. We believe this flexibility will meet the needs of the scientific community and our clients.”
– Written by Kasumi Crews
Source: NeoGenomics launches 22 new cancer genomic tests designed for actionable profiling of various hematologic and solid cancers: http://ir.neogenomics.com/releasedetail.cfm?ReleaseID=822075
New assay for Detecting ALK Rearrangements in Non-Small-Cell Lung Cancer may be Superior to Established Techniques
Researchers have developed a novel method of detecting rearrangements of the ALK gene in non-small-cell lung cancers (NSCLCs), one they describe as more sensitive and easier to carry out than the tests currently utilized. Detection of such genetic changes is vital for identifying individuals with the disease who are most likely to benefit from treatment with ALK inhibitors. Further details of the study appear in the March issue of the Journal of Thoracic Oncology.
FISH is currently the only method approved for use in the detection of ALK mutations clinically. However, it represents a complex and low-throughput assay that in actuality is difficult to use in diagnostic practice. Other routine methods that are able to detect rearrangements in this gene include immunohistochemistry and reverse transcription (RT)-PCR. These methods are also noted for their pitfalls, such as weak and variable immunoreactivity in immunohistochemistry and the need for high-quality RNA for RT-PCR.
Lead author Claudia Kalla and team (Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany) developed this new technique based on quantitative RT-PCR (qRT-PCR) techniques adapted for use with RNA isolated from routine formalin-fixed, paraffin-embedded material. When applied to 652 NSCLC patient samples, the qRT-PCR assay detected unbalanced ALK expression indicative of a gene rearrangement in 24 (4.6%), and full-length ALK transcript expression in six (1.1%) of 523 interpretable tumors. The reliability of this technique to detect ALK dysregulation was further demonstrated by comparison with FISH and immunohistochemistry.
“The qRT-PCR technique reliably detects ALK-rearranged tumors independently of the fusion partner and also identifies tumors with full-length transcript expression of the gene that is not detectable by FISH but may be relevant for ALK inhibitor therapy as well,” commented Kalla. “The technique seems to be a sensitive, easy-to-perform, and high-throughput method suitable for the routine diagnosis of ALK activation not only in lung cancer, but also in other tumor entities where rearrangements with alternative fusion partners or transcriptional upregulation are prevalent.”
– Written by Emily Brown
Source: Gruber K, Horn H, Kalla J et al. Detection of rearrangements and transcriptional upregulation of ALK in FFPE lung cancer specimens using a novel, sensitive, quantitative reverse transcription polymerase chain reaction assay. J. Thorac. Oncol. 9(3), 307–115 (2014); International Association for the Study of Lung Cancer press release: www.iaslc.org/articles/novel-assay-developed-detecting-alk-rearrangement-nsclc