21 July 2019
Thirty years of investigations into the genetic causes of colorectal cancer have identified 14 genes that, when mutated, are associated with an increased risk of the disease. Now, a Saudi-US research collaboration has found two more genes, greatly improving the ability of clinicians to identify at-risk individuals, while indicating potential therapeutic options for chemotherapy-resistant patients.
Colorectal cancer is a critical health concern in Saudi Arabia alongside much of the developed world. Despite a predicted 30 percent of colorectal cancer risk being attributable to inherited factors, the known genetic risk factors explain only five to ten percent of cases.
“This is what’s known as ‘missing heritability,’” says Saud AlDubayan, who co-authored the collaboration’s study, published in The American Journal of Human Genetics. AlDubayan describes seeing many members of the same family developing colorectal cancer without having any of the known mutated genes that indicate hereditary risk.
With a clear need to identify more sources of cancer heritability, AlDubayan’s team compared the DNA of almost 4,000 colorectal cancer patients to more than 27,000 healthy individuals. The results showed two heritable genetic mutations in the genes ATM and PALB2 that were more common in cancer patients, suggesting a causal link. “The diagnostic yield increased by 20 percent when we included these two genes in genetic screening for colorectal cancer risk. This is huge,” says AlDubayan.
Not only does this discovery enable the identification of those at risk of colorectal cancer, but a positive result can also inform relatives of their own potential risk.
Perhaps the most exciting revelation is that ATM and PALB2 are both involved in a biological pathway, known as homologous recombination (HR), that mediates the repair of double-stranded DNA breaks. “This particular pathway is very targetable,” explains AlDubayan. “We already have FDA-approved medications for chemo-resistant patients with mutations to genes involved in the HR pathway.” AlDubayan expects these particular patients to be “exceptionally responsive” to the drugs and that this will give some hope to people enrolling in clinical trials after initial chemotherapy has failed.
AlDubayan credits the decreasing costs and increasing capabilities of genetic sequencing as driving forces behind the team’s discovery, alongside a global collaborative sharing of genetic data.
The team now plans to use its methods to identify other pathogenic mutations within DNA pathways and are preparing to publish their discovery of a gene mutation that’s associated with a four-fold risk of developing egg or sperm cell cancers.
AlDubayan, S., Giannakis, M., Moore, N. D., Han, C., Reardon, B. et al. Inherited DNA-repair defects in colorectal cancer. The American Journal of Human Genetics 102, 401-414 (2018). | article