Inverse comorbidity is a lower-than-expected probability of disease occuring in individuals who have been diagnosed with other medical conditions. Emerging evidence points to inverse cancer comorbidity in people with certain CNS disorders. In this Opinion article, we discuss the evidence for this intriguing association and possible underlying mechanisms. We believe that this association is an invaluable opportunity to gain insight into the pathogenesis of these diseases, and understanding why certain individuals with CNS disorders are protected against many different types of cancer could help to develop new and improved treatments.
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This article was supported in part by grants received by R.T.-S. from the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III, CIBERSAM, INCLIVA, Generalitat Valenciana (PROMETEO11/2011/042), and Alicia Koplowitz Foundation. We would like to thank J. M. Valderas, A. Valencia, K. Ibáñez, J. Climent, B. Crespo-Facorro, V. Balanzá-Martínez, S. Martínez, E. Vieta, M. Gómez-Beneyto, F. Catalá-López and A. Balmain for their helpful advice on previous versions of the manuscript. We also thank B. Normanly, E. Tormo, C. Amézcua, M. Suárez and P. Suárez for their excellent editorial and technical assistance.
The authors declare no competing financial interests.
Number of genes and pathways common to cancer and schizophrenia. (PDF 208 kb)
List of genes involved in schizophrenia, breast cancer, prostate cancer, melanoma and all cancers, and list of cancer genes related with schizophrenia (PDF 355 kb)
List of KEGG pathways (ID) involved in schizophrenia, breast cancer, prostate cancer, melanoma and all cancers, and list of KEGG cancer pathways related with schizophrenia. (PDF 201 kb)
Construction of a network showing the overlap of genes and pathways common to schizophrenia and cancer. (PDF 224 kb)
- Cell division plane
A mitotic cell divides into two daughter cells along the division plane. When the two daughter cells both become progenitors, the division plane is perpendicular to the neuropeithelium. When one daughter cell becomes a progenitor and the other becomes a neuron, it is parallel to the neuroepithelium.
- Mammalian target of rapamycin
(mTOR). The protein kinase mTOR regulates several critical intracellular and extracellular signals. The mTOR pathway has a crucial role in cancer and is frequently activated in many cancers, mainly as a result of alterations of regulators such as phosphoinositide 3-kinase–AKT activation, phosphatase and tensin homologue (PTEN) loss or dysregulation of mTOR-negative regulators (for example, tuberous sclerosis complex 1 (TSC1) and TSC2). At present, major CNS disorders such as autism spectrum disorders are also associated with dysregulation of mTOR signalling.
- Paraneoplastic neurological syndromes
(PNSs). Examples of PNSs include limbic encephalitis, encephalomyelitis and chronic gastrointestinal pseudo-obstruction and are frequent in patients with several types of cancer (and antedate its diagnosis), including ovarian teratoma, small-cell lung and breast cancer. The cause is probably an immune response against neuronal proteins expressed by the tumour (for example, antibodies against cell-surface or synaptic proteins).
- Tuberous sclerosis complex
(TSC). TSC is an autosomal dominant inherited disorder that is characterized by benign tumours (hamartomas) that form during development in various organs; for example, in the brain (known as tubers). These brain lesions are associated with epilepsy, cognitive disability and autism. TSC is caused by mutations in either of the two tumour suppressor genes TSC1 (which encodes hamartin) and TSC2 (which encodes tuberin). TSC1 and TSC2 are negative regulators of mammalian target of rapamycin.
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Tabarés-Seisdedos, R., Rubenstein, J. Inverse cancer comorbidity: a serendipitous opportunity to gain insight into CNS disorders. Nat Rev Neurosci 14, 293–304 (2013). https://doi.org/10.1038/nrn3464
A study of gene expression by RNA-seq in patients with prostate cancer and in patients with Parkinson disease: an example of inverse comorbidity
Molecular Biology Reports (2021)
Interpreting molecular similarity between patients as a determinant of disease comorbidity relationships
Nature Communications (2020)
Acta Neuropathologica (2019)
Antiproliferative activities of the second-generation antipsychotic drug sertindole against breast cancers with a potential application for treatment of breast-to-brain metastases
Scientific Reports (2018)