International research team links gene to cancer susceptibility


Study identifies those with gene variant as more at risk for breast and ovarian cancer

By Kristina Charania

Dr. Angela Brooks-Wilson, SFU biomedical physiology and kinesiology associate professor, is one scientist among 448 others who have collaborated on an international study linking variations in a particular gene to increased susceptibility to breast and ovarian cancers.

“This paper is a huge success in terms of international cooperation. That’s what’s really remarkable about this research,” says Brooks-Wilson, who is also head of a cancer genetics laboratory at Canada’s Michael Smith Genome Sciences Centre.

Published online in the journal Nature Genetics, the group’s work is comprised of 140 smaller studies conducted globally as part of the Collaborative Oncological Gene-Environment Study (COGS) consortium. Each study looks at genes, the differences in gene sequences between individuals, and the effects its diversity has on a disease of choice.

Brooks-Wilson acted as the genetic investigator for a small research group of epidemiologists and biostatisticians conducting OVAL BC (Ovarian Cancer in Alberta and British Columbia Study), one of the many studies examining the link between ovarian cancer and several genetic and environmental variables.

“Several groups in COGS were interested in the TERT gene,” said Brooks-Wilson. “Several groups chose genetic markers in that gene. When that happened, the agreement was that researchers would share the analysis with each other, and the writing of this paper.”

The TERT gene encodes an enzyme called telomerase reverse transcriptase, a molecular helper that is essential to the formation of telomeres, the DNA repeat sequences that cap the ends of chromosomes and protect them as cells replicate.

“Telomeres are like molecular clocks for cells, because each time a cell divides, they’ll shorten a little bit. When you examine the telomeres of older people, they are shorter than those of younger people,” says Brooks-Wilson. “When your telomeres become too short and the cell works properly, the cell is supposed to go into a senescent state where it won’t divide anymore but still do its cellular job to some extent. If senescence fails to happen, you will encounter problems like cancer.”

Because up to 80 per cent of telomere length is genetically determined, analyzing the independent variants in the TERT gene is essential to understanding the science behind hereditary increases and decreases in cancer susceptibility and forecasting who is more likely to be afflicted.

To examine if differences in TERT loci affected cancer predisposition, the COGS collaboration evaluated 104,000 women in breast cancer studies, 40,000 women in the ovarian cancer studies, and 12,000 people carrying BRCA mutations that cause hereditary breast cancer.

In the breast cancer groups, susceptibility to the disease was sampled from the general population having these cancers and a special set of women who were carriers of known BRCA mutations.

“In some circumstances and particularly with these types of studies, you really have to pool together with the community,” says Brooks-Wilson. “Think about all of the background checking and past research needed in order to characterize women who are BRCA mutant carriers. It’s a lot of work, and you need really high numbers of cases and controls to examine factors that are this small.”

The results found an approximate cancer risk increase of 10 per cent with a handful of TERT variants. Although this is only a small difference from the general population, the group’s numbers are conclusive thanks to their large sample numbers.

“When people band together, they gather results that are far more conclusive than they would be if you had conducted experiments alone,” says Brooks-Wilson. “It would be so confusing if you had our 52 breast cancer studies produce 52 small, inconclusive papers. With large-scale studies, you get much more convincing data that is more definite and trustworthy than it would be in smaller studies.”