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

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          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.

          Most cited references21

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          Nonsyndromic hearing impairment is associated with a mutation in DFNA5.

          Nonsyndromic hearing impairment is one of the most heterogeneous hereditary conditions, with more than 40 loci mapped on the human genome, however, only a limited number of genes implicated in hearing loss have been identified. We previously reported linkage to chromosome 7p15 for autosomal dominant hearing impairment segregating in an extended Dutch family (DFNA5). Here, we report a further refinement of the DFNA5 candidate region and the isolation of a gene from this region that is expressed in the cochlea. In intron 7 of this gene, we identified an insertion/deletion mutation that does not affect intron-exon boundaries, but deletes five G-triplets at the 3' end of the intron. The mutation co-segregated with deafness in the family and causes skipping of exon 8, resulting in premature termination of the open reading frame. As no physiological function could be assigned, the gene was designated DFNA5.
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            Aberrant promoter methylation and tumor suppressive activity of the DFNA5 gene in colorectal carcinoma.

            To identify novel methylated gene promoters, we compared differential RNA expression profiles of colorectal cancer (CRC) cell lines with or without treatment of 5-aza-2'-deoxycytidine (5-aza-dC). Out of 1776 genes that were initially 'absent (that is, silenced)' by gene expression array analysis, we selected 163 genes that were increased after 5-aza-dC treatment in at least two of three CRC cell lines. The microarray results were confirmed by Reverse Transcription-PCR, and CpG island of the gene promoters were amplified and sequenced for examination of cancer-specific methylation. Among the genes identified, the deafness, autosomal dominant 5 gene, DFNA5, promoter was found to be methylated in primary tumor tissues with high frequency (65%, 65/100). Quantitative methylation-specific PCR of DFNA5 clearly discriminated primary CRC tissues from normal colon tissues (3%, 3/100). The mRNA expression of DFNA5 in four of five colon cancer tissues was significantly downregulated as compared to normal tissues. Moreover, forced expression of full-length DFNA5 in CRC cell lines markedly decreased the cell growth and colony-forming ability whereas knockdown of DFNA5 increased cell growth in culture. Our data implicate DFNA5 as a novel tumor suppressor gene in CRC and a valuable molecular marker for human cancer.
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              Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer.

              Epigenetic gene inactivation plays a key role in the development of various types of cancer. Using methylated CpG island amplification coupled with representational difference analysis to identify genes inactivated by DNA methylation in gastric cancer, we identified seven DNA fragments corresponding to the 5' CpG islands of the affected genes. One of the clones recovered was identical to the 5' flanking region of DFNA5, a gene previously shown to be associated with deafness and induced by DNA damage. Further analysis revealed that DFNA5 is expressed in normal tissues but is down-regulated in gastric cancer cell lines due to methylation of the region around its transcription start site. Treating gastric cancer cells that lacked DFNA5 expression with a methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the gene's expression. Methylation of DFNA5 was detected in 50% of primary gastric tumors, and was correlated with positivity for Epstein-Barr virus and the absence of metastasis. Moreover, introduction of exogenous DFNA5 into silenced cells suppressed colony formation. Taken together, these data suggest that the silencing of DFNA5 occurs frequently in gastric cancer and may play a key role in development and progression of the disease.
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                Author and article information

                Journal
                Onco Targets Ther
                Onco Targets Ther
                OncoTargets and Therapy
                OncoTargets and therapy
                Dove Medical Press
                1178-6930
                2015
                15 September 2015
                : 8
                : 2613-2615
                Affiliations
                [1 ]Center of Medical Genetics (CMG), Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
                [2 ]Center for Oncological Research (CORE), Department of Medicine, University of Antwerp, Antwerp, Belgium
                [1 ]Department of Oncology, University Hospital Center Zagreb, Zagreb, Croatia
                [2 ]Fidelta Ltd. for Research and Development, Zagreb, Croatia
                [3 ]Department of Pathology, University Hospital Center Zagreb, Zagreb, Croatia
                Author notes
                Correspondence: Lieselot Croes, University of Antwerp, Center of Medical Genetics (CMG) and Center for Oncological Research (CORE), Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium, Tel +32 3 275 9781, Email lieselot.croes@ 123456uantwerpen.be
                Correspondence: Zoran Rakusic, Department of Oncology, University Hospital Center Zagreb, Kispaticeva 12, 10 000 Zagreb, Croatia, Email zrakusic@ 123456kbc-zagreb.hr
                Article
                ott-8-2613
                10.2147/OTT.S91168
                4592022
                7d11fbb4-6c92-4ce9-a65a-fdbc7807a118
                © 2015 Croes et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Oncology & Radiotherapy
                Oncology & Radiotherapy

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