A genomic approach to study down syndrome and cancer inverse comorbidity: untangling the chromosome 21.

Jaume Forã©S-Martos,Raimundo Cervera-Vidal,Joan Climent,Enrique Chirivella,Alberto Ramos-Jarero

doi:10.3389/fphys.2015.00010

Jaume Forã©S-Martos, Raimundo Cervera-Vidal + Show 3 more

Open Access

https://doi.org/10.3389/fphys.2015.00010

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Journal: Frontiers in Physiology	Publication Date: Feb 4, 2015
Citations: 21	License type: cc-by

Affiliation: INCLIVA Health Research Institute

Abstract

Down syndrome (DS), one of the most common birth defects and the most widespread genetic cause of intellectual disabilities, is caused by extra genetic material on chromosome 21 (HSA21). The increased genomic dosage of trisomy 21 is thought to be responsible for the distinct DS phenotypes, including an increased risk of developing some types of childhood leukemia and germ cell tumors. Patients with DS, however, have a strikingly lower incidence of many other solid tumors. We hypothesized that the third copy of genes located in HSA21 may have an important role on the protective effect that DS patients show against most types of solid tumors. Focusing on Copy Number Variation (CNV) array data, we have generated frequencies of deleted regions in HSA21 in four different tumor types from which DS patients have been reported to be protected. We describe three different regions of deletion pointing to a set of candidate genes that could explain the inverse comorbidity phenomenon between DS and solid tumors. In particular we found RCAN1 gene in Wilms tumors and a miRNA cluster containing miR-99A, miR-125B2 and miR-LET7C in lung, breast, and melanoma tumors as the main candidates for explaining the inverse comorbidity observed between solid tumors and DS.

Highlights

Down syndrome (DS) was first described and named by the British physician John Langdon Down about 150 years ago
We hypothesized that the third copy of genes located in HSA21 may have an important role on the protective effect that DS patients show against most types of solid tumors
In particular we found RCAN1 gene in Wilms tumors and a miRNA cluster containing miR-99A, miR-125B2 and miR-LET7C in lung, breast, and melanoma tumors as the main candidates for explaining the inverse comorbidity observed between solid tumors and DS

Summary

Introduction

Down syndrome (DS) was first described and named by the British physician John Langdon Down about 150 years ago. Professor Jerome Lejeune discovered a century later that the cause of this disorder was the presence of an extra chromosome 21 (HSA21) (Mégarbané et al, 2009). The Down phenotype is caused by a complete or partial trisomy (TS21) of human chromosome 21 (HSA21) acquired essentially by meiotic non-disjunction events during gametogenesis. In the past two decades, substantial advances in exploring the human genome, together with the exponential growth of bioinformatics, have permitted a better understanding of the functional links between the extra copy of HSA21 and the variations in the different phenotypes of DS individuals (Letourneau and Antonarakis, 2012; Letourneau et al, 2014). The sequencing of HSA21 and the experimental research done with models of DS have allowed the scientific community to connect specific genomic regions and sets of genes to different clinical conditions and syndrome phenotypes. Nowadays, based on data provided by large-scale studies, the HSA21 gene number is estimated to be around 534 from a total of 2176 gene transcripts (Scarpato et al, 2014)

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