Alterations in new regions of non-coding DNA may lead to cancer growth and progression

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In an unprecedented pan-cancer analysis of whole genomes, researchers at the Ontario Institute for Cancer Research (OICR) have discovered new regions of non-coding DNA that, when altered, may lead to cancer growth and progression.

The study, published today in Molecular Cell, reveals novel mechanisms of disease progression that could lead to new avenues of research and ultimately to better diagnostic tests and precision therapies.

Although previous studies have focused on the two per cent of the genome that codes for proteins, known as genes, this study analyzed mutation patterns within the vast non-coding regions of human DNA that control how and when genes are activated.

Cancer-driver mutations are relatively rare in these large non-coding regions that often lie far from genes, presenting major challenges for systematic data analysis,” says Dr. Jüri Reimand, investigator at OICR and lead author of the study.

“Powered by novel statistical tools and whole genome sequencing data from more than 1,800 patients, we found evidence of new molecular mechanisms that may cause cancer and give rise to more-aggressive tumours.”

The research group analyzed more than 100,000 sections of each patient’s genome, focusing on the often-overlooked non-coding regions that interact with genes through the three-dimensional genome.

One of the 30 key regions discovered was predicted to have a significant role in regulating a known anti-tumour gene in cancer cells, despite being more than 250,000 base pairs away from the gene in the genome.

The group performed CRISPR-Cas9 genome editing and functional experiments in human cell lines to explore the cancer-driving properties of this non-coding region.

“We characterized several non-coding regions potentially involved in oncogenesis, but we’ve just scratched the surface,” says Reimand.

“With our algorithms and the rapidly growing datasets of patient cancer genomes and epigenetic profiles, we look forward to enabling future discoveries that could lead to new ways to predict how a patient’s cancer will progress and ultimately new ways to target a patient’s disease or diagnose it more precisely.”

Reimand’s research group developed the statistical methods behind this study and made them freely available for the research community to use. These methods have been rigorously tested against other algorithms from around the world.

“Looking into the non-coding genome is really important because these vast sections regulate our genes and can switch them on and off. Mutations in these regions can cause these regulatory switches to act abnormally and potentially cause – or advance – cancer,” says Helen Zhu, student at OICR and co-first author of the study. “We’ve shown that our method, called ActiveDriverWGS, can excavate these regions and pinpoint specific areas that are important to cancer growth.”

“Although these candidate driver mutations are rare, we now have the first experimental evidence that one of the mutated regions regulates cancer genes and pathways in human cell lines,” says Dr. Liis Uusküla-Reimand, Research Associate at The Hospital for Sick Children (SickKids) and co-first author of the study.

“As the research community collects more data, we plan to look deeper into these regions to understand how the mutations alter gene regulation and chromatin architecture in specific cancer types to enable the development of new precision therapies to patients with these diseases.”


Neuroblastoma

Neuroblastoma is a type of peripheral sympathetic nervous system cancer, affecting mostly infants and young children (95% of which are under the age of 5, and occurring 13% more frequently in males), which alters the growth and proliferation of neural crest cells (precursor nervous system cells) [1]. Neuroblastoma has a diverse clinical response to current treatments across the patient population and is quite rare, making research difficult.

In Europe, alone, the annual incidence rate is recorded to be six cases/million [2]. Some children respond well to treatment and eventually are deemed cured of their cancer, while some children’s cancer spontaneously regresses on its own, but others develop a strong resistance to treatments and a poor prognosis remains [3,4,5,6].

Infants have the best prognosis of all age groups, with a 5-year survival rate of 91%. However, the 5-year survival rate decreases with age of onset, with a 56% survival rate for children 10–14 years of age [7,8]. Most often, neuroblastoma originates within either the adrenal glands, the paravertebral ganglia, and/or the neck as a solid tumor, and can potentially spread, although it is normally caught prior to widespread malignancy [2].

Surgery, chemotherapy, and radiotherapy are all current options for treatment depending upon the characteristics of the tumor’s presentation and behavior; however, chemotherapy is currently the main treatment option [1].

It was discovered that an amplification of the MYCN (v-myc myelocytomatosis viral related oncogene, neuroblastoma derived(avian)) gene in Neuroblastoma patients was correlated with an increased aggressive behavior of the tumor, leading to a poor prognosis [9,10]. Currently, research is focused on new therapies aimed at attempting to target and inhibit both the MYCN amplification process, as well as the tumorigenesis of the cancer [11].

Transcribed-Ultra Conserved Regions

Bezarano et al. were the first to discover ultra-conserved regions (UCRs), using a bioinformatics approach from the genome [11]. UCRs are 481 elements longer than the 200 base pairs that are 100% conserved, without any deletions or insertions, between the orthologues regions of human, rat, and mouse genomes.

Protein-coding genes represent anywhere from 1% to 2% of the human genome; therefore, the scientific community was ignoring the rest of 98% of the genome, referred to as “junk DNA.”

Recently, a group led by Axel Visel described the functional role of non-coding DNA elements in mice. Authors used genome editing technology to create knockout mice lacking individual or a group of ultra-conserved elements. Mice with deletions of ultra-conserved elements showed neurological abnormalities, including structural brain defects [12].

UCRs represent a small portion of the “junk DNA” and are likely to be involved in different biological pathways. Based on their localization, UCRs are classified into five groups: exonic, partly exonic, exon-containing, intronic, and intergenic, as shown in Figure 1 [13].

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Types of ultra-conserved regions (UCRs). A schematic representation of the different types of UCRs as per their genomic location with respect to their protein-coding genes.

he transcripts that are transcribed from UCRs are called Transcribed-Ultra Conserved Regions (T-UCRs), which can either be “sense” (transcribed in the same orientation) or “anti-sense” (transcribed in the opposite direction). If the T-UCRs are transcribed towards the host gene, they are called sense direction, whereas they are called anti-sense direction in the opposite direction of the host gene.

T-UCRs are defined as a novel class of long, non-coding RNAs. Furthermore, the presence of cancer-specific mutations in UCRs raises the question of their potential role in cancer biology [14]. In addition, UCRs are located within cancer-associated genomic regions, suggesting a role in cancer biology [15].


More information: Helen Zhu et al, Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks, Molecular Cell (2020). DOI: 10.1016/j.molcel.2019.12.027

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