Susceptibility Locus Predicts Prostate Cancer Radiotherapy Risk

Genetic testing could predict which prostate cancer patients will develop radiotherapy side effects

medwireNews: Scientists have identified a genetic marker that may help clinicians predict the likelihood of late radiotherapy side effects in men with prostate cancer.

The susceptibility locus for radiotherapy toxicity at chromosome 2q24.1 includes the TANC1 Gene, which is thought to play a role in the fusion of differentiated muscle cells in response to local tissue injury.

Therefore “it is biologically possible that TANC1 is involved in the regeneration of radiation-induced muscle damage”, explain Ana Vega, from the Universidade de Santiago de Compostela in Spain, and co-workers.

Writing in a letter to Nature Genetics, the researchers suggest: “The identification of carriers of the TANC1 risk allele would allow for consideration of treatments with similar outcomes that are not associated with this toxicity, such as surgery, in the cases in which these individuals are treated for prostate cancer.”

The genome-wide association stage of the study was performed in 741 Spanish prostate cancer patients who were treated with external beam radiotherapy and followed up for acute effects through the RADIOGEN study. Late toxicity, defined as side effects occurring at least 2 years after treatment, was also monitored in 417 of the cohort.

Analysis identified 117 and 612 Single nucleotide polymorphism (SNP) associated with early and late toxicity, respectively, and these were assessed in a further 579 UK prostate cancer patients from the RAPPER study. In all, 29 SNPs were associated with early toxicity and 61 SNPs with late toxicity in this cohort.

The best candidate locus, at 2q24.1, was then further examined in a third cohort of 270 US participants of the Gene-PARE study and meta-analysis of the three analyses indicated a significant association between late radiation-induced toxicity and the TANC1 gene.

In particular, SNP rs264663 was identified as the most likely candidate to alter TANC1 expression and each copy of the allele was associated with a significant increase in the toxicity associated with radiation exposure.

The researchers emphasise that this finding must be confirmed in a large cohort, but further analysis of their data suggested that patients heterozygous for the risk allele were around six times more likely to experience late radiation toxicity than those without the allele.

They now plan to examine whether the risk allele alters the risk of radiotoxicity in patients with other types of cancer. The team also suggests that the true causal variant at the locus should be defined, to determine whether the functional variant alters TANC1 expression directly or regulates another gene.

Reference

Fachal L, Gómez-Caamaño A, Barnett G, et al. A three-stage genome-wide association study identifies a susceptibility locus for late radiotherapy toxicity at 2q24.1. Nat Genet 2014; Published online 29 June. doi:10.1038/ng.3020

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