Role of DFNA5 in hearing loss and cancer – a comment on Rakusic et al

Abstract

Dear editor We would like to comment on the paper published by Rakusic et al about sudden bilateral hearing loss in gastric cancer as the only symptom of disease.1 The authors state that “Inactivated DFNA5, otherwise described in hereditary bilateral deafness, perhaps favors the development of deafness in patients with gastric cancer”.1 We believe this conclusion is erroneous. Although DFNA5 has been implicated in both hearing loss and cancer, the underlying molecular mechanisms are different and completely opposite (Figure 1). In 1998, we identified the first DFNA5 mutation in a Dutch family, as a cause for a specific form of progressive, sensorineural, and non-syndromic hearing loss.2 This type of hearing loss is inherited in an autosomal dominant manner. Afterward, other families were reported with hearing loss due to DFNA5 mutations.3–8 Although all these DFNA5 mutations are different on DNA level, they all result in skipping of exon 8 on mRNA level, and have an identical effect on the protein.9 The DFNA5 mutation leading to hearing loss is thought to be an activating, gain of function mutation. As the DFNA5 protein has an apoptosis inducing capacity, the effect is expected to be an increase in apoptosis, possibly leading to hearing loss by apoptosis of cells crucial for hearing, such as cochlear hair cells (Figure 1).10 Since 1998, a number of papers on DFNA5 have been published, pointing toward an involvement in cancer.9–20 Here the molecular mechanism is different. DFNA5 becomes inactivated through DNA promotor methylation. Because of the inactivation, DFNA5 loses its capacity to induce apoptosis and most likely contributes to tumorigenesis in this manner (Figure 1). In conclusion, a very specific gain of function mutation in DFNA5 leads to hearing loss, while inactivation of DFNA5 on the epigenetic level (DNA methylation) plays a role in cancer. Therefore, in our opinion, the observed sudden bilateral deafness in the 60-year-old woman is not caused by inactivation of DFNA5. Akino et al showed that DFNA5 is methylated in 52% of primary gastric cancers and was correlated with positivity for Epstein–Barr virus and the absence of metastasis.14 In patients with metastasized gastric cancer the incidence of DFNA5 methylation was 16.7% (2/12).14 The observation that DFNA5 is inactivated in this woman is thus not exceptional and in agreement with the literature. However, as described above, inactivation of DFNA5 is very unlikely to be the cause of the observed hearing loss.