BioWorld International Correspondent
LONDON - The time when patients with cancer have chemotherapy tailored to the genetic make-up of their tumors is fast approaching.
Researchers in Switzerland have identified a gene which, when lost from a tumor, reduces the success of a specific type of chemotherapy. Their discovery will provide clues about the genetic basis of drug resistance in cancer.
Jean-Louis Boulay, a geneticist in the department of research at University Hospital in Basel, Switzerland, where the research was carried out, said: "In the future, testing people for the gene at the time of diagnosis could help doctors to make the right decisions about which treatments to use, improving survival while sparing some patients from drugs which will not do them any good."
Boulay and his collaborators studied the loss of the SMAD4 gene in colorectal cancers. The protein product of SMAD4 is involved in signaling by transforming growth factor beta, a pathway that can lead both to apoptosis and to tumor proliferation. SMAD4 lies in the chromosomal region 18q21, which is commonly deleted in colorectal cancer.
The physiological functions of SMAD4, together with the frequent deletion of 18q21 in colorectal tumors, led Boulay and his colleagues to hypothesize that SMAD4 may have a role in suppressing colorectal carcinogenesis. They report the results of their investigations in the Sept. 3, 2002, issue of the British Journal of Cancer, in a paper titled "SMAD4 is a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer."
Boulay told BioWorld International, "Our discovery also provides an additional clue that to induce apoptosis with a cytostatic agent, the cell needs to have a functional way to proceed to apoptosis. It will now be important to evaluate different pathways involved in apoptosis, in a range of tumors. This may allow doctors in the future to refine patients' therapies, depending on the status of these different pathways, and switch to more appropriate drugs."
The group tested tumor samples from 202 patients who had undergone curative resection for colorectal cancer, to find out if these tumors had lost one or both copies of SMAD4. One hundred and thirty-five out of the 202 (67 percent) demonstrated such a deletion.
Analysis showed that there was no statistically significant relationship between genotype and the risk of death and relapse. When the team examined the relationship between loss of SMAD4 and disease-free survival following treatment with 5-fluorouracil (5-FU), however, they found that the risk of death and relapse among patients treated with 5-FU who had SMAD4 deletion was 2.9 times greater than that for patients who had retained both copies of SMAD4 and had been treated with 5-FU. A similar result was found for overall survival. Both results were of borderline statistical significance (p = 0.045 and p = 0.056, respectively).
In their paper, Boulay and his colleagues conclude: "This suggests SMAD4 as a predictive marker for 5FU/mitomycin adjuvant chemotherapy."
The finding, the authors point out, is consistent with a previous observation that patients who retained the chromosomal region 18q21 in their colorectal tumors had a threefold greater benefit from 5-FU-based chemotherapy than those who had lost this section of the chromosome.
Christoph Rochlitz, associate professor of internal medicine at the University of Basel, who led the study, told BioWorld International that it would be very important for an independent group to replicate the findings. "We are currently trying to find someone who would be willing to collaborate with us on such a study," he said.
He is planning further work to test for loss of SMAD4 in a large collection of samples of breast tumors, to find out the correlation, if any, with the type of chemotherapy received and patients' disease-free survival time. "It is very important to find out if the same thing holds true in other cancers, and if it is dependent on the type of chemotherapy used. It may be different for different types of chemotherapy," he said.