Mutation of the COX2 gene can double or treble a woman's risk of ovarian cancer

Researchers in Portugal have discovered that a specific mutation of the COX2 gene seems to play a role in the onset of ovarian cancer, increasing women's susceptibility to developing the disease.

The discovery raises the possibility that, if the findings are confirmed by further studies, it might be possible to use non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, which are used already for other conditions, to prevent ovarian cancer developing in women with the COX2 mutation.

Dr Ana Carina Pereira told the European Cancer Conference (ECCO 14) in Barcelona, that the COX2 gene is responsible for the production of the enzyme COX-2, which plays a crucial role in prostaglandins production; prostaglandins cause inflammation, pain and fever, as well as mediating a wide range of other physiological processes. “Although the causes of ovarian cancer are not fully understood yet, inflammation is known to play an important role in the onset of both ovarian and invasive cervical cancer,” she said. “COX-2 has an important role in the inflammatory process, as well as in key steps in tumour development.”

Dr Pereira, who is a junior scientist in the molecular oncology group at the Portuguese Institute of Oncology, Oporto, Portugal, said that one mutation, the -765G>C COX2 polymorphism, had been associated with the development of a number of diseases such as cancers of the stomach, oesophagus and prostate, and asthma, heart attacks and stroke. So she and her colleagues decided to investigate the role it played in ovarian and invasive cervical cancer.

They analysed the DNA in blood samples from 727 women; 150 had ovarian cancer, 351 had cervical lesions, including 291 with cervical cancer, and the remaining 226 women had no cancer and were the control group.

Although they found no evidence that the -765G>C COX2 polymorphism played a role in cervical cancer, they found that particular versions of it doubled the risk of developing ovarian cancer and, in women aged 53 or younger, it trebled the risk.

Dr Pereira looked at the distribution and frequency of three different types (genotypes) of the -765G>C COX2 polymorphism: the GG, GC and CC genotypes. An individual genotype is composed of two distinct parts, the inherited sequences from the maternal and paternal genomes. Therefore, for every genotype, there are two copies of the sequence and these copies are called alleles. Alleles may be identical or different.

Dr Pereira explained: “The C and G are alleles that can be inherited, one from each parent. As everyone carries two alleles, their genotypes could be a CC, GC or GG genotype. The G allele is the most common, while the CC genotype is rare; therefore, it is usual to pool the GC and CC genotypes together and we call people with these genotypes C allele carriers.

“Our results demonstrated that C allele carriers had a nearly two-fold (1.8) increased risk of developing ovarian cancer. This was even more evident when we stratified our analysis into two groups based on the average age of the patients; the women aged 53 or under had a nearly three-fold (2.8) increased risk of developing ovarian cancer.”

She said the polymorphism could enhance the expression of the COX2 gene, thereby inhibiting apoptosis (programmed cell death) and promoting tumour proliferation, metastasis and angiogenesis (the formation of new blood vessels needed to supply a growing tumour). The reason why the same effect was not observed in cervical cancer was probably due to the different causes of the two cancers.

“The biological mechanism involved in the carcinogenesis of different organs is not always similar. In the case of cervical cancer we know that the trigger mechanism is an oncogenic virus, HPV (human papillomavirus) and that in ovarian cancer, although not as clearly understood, inflammation and hormonal regulation are credited with playing a role in its development.”

She continued: “Although our findings are very interesting and this polymorphism seems to play an important role in cancer development, these are only preliminary results which need to be confirmed with more complete studies, nor only in the Portuguese population but also in other populations.

“The interesting clue from these results is the importance of this COX-2 enzyme and the therapeutic drugs that may inhibit its activity (such as aspirin and other NSAIDs). Former studies involving NSAIDs and risk for ovarian cancer were not strongly conclusive because the individual variability in the response to preventive drugs was not taken into account. Now we need studies that will confirm whether giving NSAIDs to women with this polymorphism might be of value in both preventing and treating ovarian cancer.

“Identifying the molecular epidemiologic profile of individuals may open new windows for the development of preventive strategies and for the individualisation of therapies for patients. It would be possible to anticipate the patient's response to therapy, increasing treatment efficacy and decreasing the incidence of adverse reactions to drugs.”

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