Building on trailblazers’ work: How the impact of cancer genetics is being realized today

Dr. David Malkin is Senior Staff Oncologist, Senior Scientist and Director of the Cancer Genetics Program at SickKids. He is also Professor in the Department of Paediatrics and the Department of Medical Biophysics, the School of Graduate Studies at the University of Toronto.

Until recently, it had been thought that cancer was only rarely a ‘hereditary’ disease. With the advent of powerful new DNA sequencing technologies together with greater attention paid to accurate descriptions of family cancer histories, it is emerging that heredity does, in fact, play an important part in cancer. Remarkably, this new knowledge was foreshadowed at least 50 years ago by two brilliant physician-researchers at the National Cancer Institute in Bethesda, MD. In 1969, Frederick P. Li and Joseph Fraumeni, Jr. identified four families from a database of over 400 in whom a child diagnosed with a rare muscle tumour, called rhabdomyosarcoma, had at least one first degree relative and several other more distant relatives with various other types of cancer.

The syndrome they described became known as Li-Fraumeni syndrome (LFS) and over the next two decades they and other researchers identified a few dozen more such families around the world. What is particularly remarkable is that Drs. Li and Fraumeni suggested these constellations of cancers were caused by some abnormal gene being inherited from generation to generation almost a decade before it was possible to sequence genes, and during a time when most people thought that cancer was caused almost entirely by exposure to various carcinogens.

We take a look back at the impact that Li and Fraumeni had on our current understanding of the relationship between our genes and cancer predisposition in the May 27 issue of Science.

Unfortunately, many challenges still exist for LFS patients: we cannot prevent cancers from forming, treatments for the cancers that do occur are infrequently successful, patients may develop multiple cancers in their lifetime, and their lifetime risk to develop cancer approaches 100 per cent. Fortunately, we have also made important strides; we developed a surveillance protocol (the Toronto protocol) to closely monitor patients in order to detect cancers as early as possible. By so doing we demonstrated improvements in survival and reduction in treatment-related morbidity.

We and others have also built on Li and Fraumeni’s original findings, discovering new genes associated with an ever-increasing number of other cancer predisposition syndromes, and applying the principles of early tumour detection to improve their outcomes. At the same time, great effort is being expended to develop novel approaches to therapy; time will tell whether these pay off.

This revolution in cancer predisposition research has enormous societal, psychosocial, ethical, medical and scientific implications – all of which must be carefully addressed in ongoing and future studies.  Despite the challenges, we are optimistic that this research will result in improved outcomes for all these patients. As we state in our paper, it is the Li-Fraumeni syndrome families themselves that motivate and inspire us to continue our work in the dynamic field of hereditary cancer. We owe it to them, and to the dedicated trailblazing work of the forefathers of the field, to make a difference.