Genetic alterations are important diagnostic, prognostic, and predictive biologic markers in cancer and can help tailor individual cancer treatment. Researchers in the field of cancer genetics have been studying genetic alterations in tumour tissues to categorize cancer by gene mutations to facilitate development of personalized cancer therapies. Here is an summary of two research papers on two different cancers, leading to the same conclusion – moving away from a ‘one size fits all’ approach will help identify treatment options specific to the patient.
Scientists at UCLA’s Institute of Urologic Oncology and Department of Urology have studied Renal Cell Carcinoma (RCC), the most common type of kidney cancer in adults, at the genetic and molecular level and have identified new kidney-cancer subtypes in a recent publication1. Renal cell carcinoma is counted among the most resistant tumours to chemotherapy and radiotherapy with partial or radical surgery used for treatment of local disease. Being able to predict whether the tumour cells will remain localized to be surgically removed or be more aggressive and spread through the body, would influence the treatment.
Traditionally, pathologists have observed sections of the tumour under a microscope and attempted to predict the way the tumours will behave depending on the way they look, with mixed results. Tumours which look similar under the microscope can develop differently making the cancer more difficult to treat.
“Pathologists can give us some important information, but similar-appearing tumours often can and do behave differently,” said Dr. Allan Pantuck, director of genitourinary oncology at UCLA’s Jonsson Comprehensive Cancer Center and senior author of the publication in the journal Cancer.
The scientists initiated a cytogenetic analysis of 288 clear cell RCC samples1. The objective of the study was to evaluate the loss of the short arm of chromosome 3 (3p) which harbours a tumour suppressor gene (VHL), and also of the long arm of chromosome 14 (14q) where the hypoxia-inducible factor 1a (HIF-1a) gene is located, on cancer free survival.
Loss of chromosome 3p (the VHL gene) was found to be associated with improved survival in patients whereas loss of chromosome 14q (the HIF-1a gene) was associated with worse outcomes. Patients with tumours in which both 3p and 14q were deleted had much worse outcomes.
“The results of this study support the hypothesis that the HIF1 alpha gene functions as another important tumour-suppressor gene,” Dr. Pantuck said2. “With this finding, we can now decide to treat these patients with more aggressive therapies.”
“These findings have important implications to the surgical and medical treatment of kidney cancer. It is one important step to individualize kidney cancer therapy and move away from the ‘one size fits all’ approach.” said Dr. Arie Belldegrun, director of UCLA’s Institute of Urologic Oncology2.
A similar sentiment was echoed by Dr Timothy Ley of Washington University in St. Louis about treatment options for Acute Myeloid Leukemia (AML). AML is the most common leukemia affecting adults. AML patients with good prognosis can be treated with chemotherapy while those with a poorer prognosis need bone marrow transplant, an expensive, difficult and risky treatment.
Using special staining methods and microscopic observations, researchers had discovered that in half the cases of AML, chromosomes in the leukemia cells were broken off and lost or reattached incorrectly, while in the other half they were normal. They knew that some chromosomal alterations were associated with a good prognosis and others with a bad one but no definitive way to decide if chemotherapy would benefit the patients.
“It was a huge conundrum,” said Dr. Ley of Washington University in St. Louis “For patients who cannot be cured with chemotherapy, we have a potentially curative therapy. But picking the right patients for a bone marrow transplant was very difficult3.”
Scientists at The Cancer Genome Atlas Research Network led by Dr Timothy Ley and Dr Richard Wilson of Washington University in St. Louis analyzed the genomes of 200 cases of AML4. They reported in the New England Journal of Medicine that 23 genes were significantly mutated with patterns of interaction among mutations, including cooperation i.e. mutations seen together more commonly than would be expected and mutual exclusivity i.e. mutations seen together less frequently than expected. These observations give researchers a new foundation for assessing which cancers will be lethal unless the patient gets a risky bone marrow transplant and which can be treated with chemotherapy alone. Knowing which genes are mutated will also help researchers investigate drugs that target specific genes.
“Within two or three years, risk assessment (of AML) may be dramatically better,” Dr. Ley said3. “It certainly sets the stage for the next era of therapy.”
- Kroeger N et al. Deletions of chromosome 3p and 14q molecularly subclassify clear cell renal cell carcinoma. Cancer 2013; 119:1547
- UCLA researchers ID new kidney cancer subtypes (2013, April 17) SciTechDaily
- Kolata G (2013, May 1) Cancer shares gene patterns, studies affirm. The New York Times
- The Cancer Genome Atlas Research Network. May1 2013. DOI: 10.1056/NEJMoa1301689