Can genes predict oxaliplatin-associated nerve damage?

The authors aimed to identify genetic indicators of severe peripheral neuropathy (nerve damage) resulting from oxaliplatin-based chemotherapy.

Oxaliplatin (Eloxatin)-based chemotherapy is widely used as adjuvant (used in addition to initial treatment) therapy for stage III and selected high-risk stage II colon cancer patients. However, this type of chemotherapy can be associated with peripheral neuropathy. Peripheral neuropathy is weakness, numbness and pain, usually in the hands or feet, as a result of nerve damage.

Single nucleotide polymorphisms are the most common type of genetic variation among people. Each single nucleotide polymorphism represents a difference in a single DNA building block, called a nucleotide (A,C,T or G). For example, in a given stretch of DNA a single nucleotide polymorphism may replace C with T, which will result in a different or mutated protein being formed from that stretch of DNA. This can affect the way a body responds to or breaks down a drug.

The aim of this study was to identify single-nucleotide polymorphisms that can predict oxaliplatin-associated peripheral neuropathy among colon cancer patients.

Genomic DNA was extracted from samples of 206 high-risk stage II and stage III colon cancer patients receiving oxaliplatin-based adjuvant chemotherapy (discovery group). Genotyping was carried out for 34 single-nucleotide polymorphisms in 15 genes. The average follow-up was 51.4 months. A second group of 181 patients were used for validation of the results and were followed for an average of 49.7 months.

23.3% of the discovery group and 39.77% of the validation group experienced severe oxaliplatin-induced neuropathy during treatment. The average time to onset was 119 days in the discovery group and 112 days in the validation group.

In the discovery group, severe oxaliplatin-induced neuropathy was associated with the cyclin H rs2230641 and the ABCG2 rs3114018 single nucleotide polymorphisms. The rs numbers help to identify the positions of the single nucleotide polymorphisms.

Patients with the cyclin H rs2230641 C/C genotype had 5 times the odds of experiencing severe neuropathy compared to those with C/T or T/T genotypes. In those with the C/C genotype the rate of neuropathy was 57.15% compared to 23.8% for those with the C/T genotype and 21.7% for those with the T/T genotype.

Patients with the ABCG2 rs3114018 A/A genotype trended towards 2.67 times the odds of experiencing severe neuropathy compared to those with an A/C or C/C genotype. In those with the A/A genotype the rate of neuropathy was 35.42% compared to 21.7% in those with the A/C genotype and 16.7% in those with the C/C genotype.

Overall, those patients harbouring the cyclin H rs2230641 C/C genotype and/or the ABCG2 rs3114018 A/A genotype had 2.37 times the risk of experiencing severe neuropathy. This was also validated in the validation group.  The presence of these unfavourable genotypes was the only factor significantly associated with the development of severe oxaliplatin-induced neuropathy.

The authors declared that combined genotype analysis of cyclin H rs2230641 and ABCG2 rs3114018 may help to decide which patients are suitable or unsuitable for oxaliplatin-based chemotherapy.

The study concentrated only on single nucleotide polymorphisms discussed in the literature, and therefore did not cover all potential single nucleotide polymorphisms.