Breast Cancer and Smell: Hints from Epigenetic and Functional Alteration of the Olfaction

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Abstract Purpose: Olfactory receptors are G protein coupled surface receptors (GPCRs) of which their ectopic expression is currently of mounting interest to the development and metastasis of malignancies. These genes having a direct contact with the environment may probably be stimulated by various factors which can bring about methylation aberrations, including DNA hypo and hyper-methylation. Here we gather clues from epigenetic and phenotypic data in order to further our understanding of the potential association of the olfaction with oncogenesis.Methods: Whole methylome dataset of breast cancer series generated by Illumina Infinium Human Methylation 450 Bead Chip was interrogated for differentially methylated genes and further subject to network analysis using various search tools. Analysis of putative phenotypic trait in olfaction function was performed using smell detection and smell identification tests and data was analyzed using Mann-Whitney test.Results: Sixty-eight differentially methylated ORs were enriched mainly on chromosomes 1q23, and 11p15, specifically 1q44 (P value 6.867e-20). Amongst the disease signatures of these hypomethylation events was breast cancer itself (P value 0.004437). Network analysis suggests the interaction of differentially hypo and hyper methylated olfactory receptor genes might be pivotal in stimulating several important biological pathways including circadian genes and pathways potentially associated with metastasis. Phenotypic smell test shows a generalized impairment of smell capability in breast cancer patients as compared to controls (Mann-Whitney Test P=0.0001), an effect that is independent of chemotherapyConclusions: The olfaction appears as a crucial element in carcinogenesis, evident by both phenotypic and genotypic (epigenetic) data in a well characterized breast cancer subset.

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