12 August 2018
The gene that confers sensitivity to chemotherapy
Published online 21 February 2017
A gene mutation could make colorectal cancer patients resistant to chemotherapy.
Genetic analyses of Saudis with colorectal cancer show recurrent mutations in a gene, called MED12, which cause resistance to chemotherapy treatment.
Researchers from King Faisal Specialist Hospital and Research Center in Riyadh conducted genetic analyses on tissue samples from 427 Saudis with colorectal cancer and identified recurrence of mutations in the gene MED12 in 2.8% of the cases1. Although apparently a small percentage, this is comparable to other genes that are known to be involved in this type of cancer.
“We show that MED12 somatic mutations are often associated with other well-known ‘driver’ mutations in known cancer genes,” says geneticist Khawla Alkuraya. “This means that MED12 mutations may not drive the initial cancer transformation but contribute to its evolution into a more aggressive form.”
MED12 is found on the X chromosome. Further analyses of female patients, who normally have one active and one inactive X chromosome, showed that the mutated gene was present on the active allele. “This is a particularly exciting finding because reactivation of a ‘silenced’ X chromosome may, in theory, reset MED12 and potentially help with treatment,” says Alkuraya.
The team tested the response of various colorectal cancer cell lines to treatment with the chemotherapeutic drug fluorouracil. They found that cancer cells that over-expressed MED12 responded well to chemotherapy, whereas those with negligible MED12 expression were resistant to the drug. Silencing the gene also led to chemotherapy resistance, and forcing its expression in cancer cells deficient with MED12 led to sensitization to fluorouracil treatment.
Using genome sequencing to identify MED12 mutations in colorectal cancer patients could predict resistance to chemotherapy, the researchers say. The findings also add another biomarker to help diagnose the disease, says Alkuraya.
The team next plans to investigate epigenetic changes and genomic deletions that could lead to loss of MED12.
- Siraj, A. K. et al. MED12 is recurrently mutated in Middle Eastern colorectal cancer. Gut http://dx.doi.org/10.1136/gutjnl-2016-313334 (2017).