A new study analyzing the genetic basis of osteosarcoma, a common bone cancer, could make treatment more effective. Graduate student Ivan Pasic along with David Malkin, a U of T professor and senior scientist at Sick Kids Hospital, have discovered a new chromosomal region that may be an important factor in osteosarcoma tumour development, the disease Terry Fox famously battled.
The study observed 49 different tumours with high-resolution cameras, capturing images of gene clusters within the tumours. The previously unidentified gene mutation was found on chromosome 3, where a particular gene responsible for tumour suppression is missing. “[The gene is a] tumour suppressor whose normal behavior is like the brake of a car—it stops cancer cells from growing,” explains Malkin. When the tumour suppressor gene is absent, the tumour is more aggressive and causes greater damage.
Scientists believe that gene abnormality occurs because osteosarcoma tumours have an unstable genome. While the cause of this gene instability is not fully understood, DNA and cell production within this chromosomal region occur rapidly, thus errors are frequent and not as easily repaired. The high-velocity replication therefore induces genetic instability in the region.
The discovery of this new regional hotspot for gene abnormalities was largely due to high-resolution technology used to observe chromosomes. Previous technologies such as the CGH array for detecting copy number variation provided only a basic chromosomal map. This is analogous to searching for a house (in this case the particular chromosome) and a street using a city map. With the CGH array, “you may be able to find the street but you couldn’t really see the house,” explains Malkin. “The new technology is like Google Maps with Street View where you can see individual cars and houses.” The new technology refined the earlier model by identifying smaller chromosomal and individual clusters rather than larger regions.
The new treatment allows for more specified osteosarcoma treatment. The new discovery can induce cell differentiation or genesis between treatments. The presence of this abnormality demonstrates, even in the early detection stages, signals to doctors that the patient should undergo aggressive treatment. Says Malkin: “If the patient does not have this abnormality, we would anticipate better prognosis, providing them a lighter treatment, preventing long-term complications of therapy.”
In order to identify whether the individual possessed this specific gene abnormality, clinicians perform a tumour biopsy, whereby they extract and sequence a small portion of tumour DNA. Comparing the sequenced pattern with the pattern previously identified in the study shows whether the tumour is threatening or if it is nonaggressive, and helps prescribe treatment.
Additionally, through observation and understanding of individual gene function, new drugs target and engage specific abnormalities and may be able to reverse abnormal effects.
Osteosarcoma is the most common bone tumour in humans, with 2.8 per million children diagnosed annually. While this may not count as a significant portion of the child and youth population (who are the most susceptible to osteosarcoma), the 40 per cent mortality rate of tumour patients shows the cancer’s severity.
In the future, this study will expand to include a larger sample of bone cancer tumours, not only to verify that the same gene mutations occur within other tumours, but also to understand why the alterations occur and if the specific genes possess additional functions and characteristics that could be targeted in the development of osteosarcoma therapies.
The project was funded by the Canadian Institute of Health Research and was published in 2009 in Cancer Research. The novel research technology offers a practical clinical approach capable of treating individual patients in a short time period. “The most important thing is [that] we are studying things that we foresee as having immediate potential help to patients,” said Malkin.
