www.oncotarget.com Oncotarget, 2019, Vol. 10, (No. 40), pp: 3982-3984 Editorial The non-random landscape of somatically-acquired uniparental disomy in cancer Pau Erola, Keyvan Torabi, Rosa Miró and Jordi Camps Uniparental disomy (UPD) was first described common that these models fail to analyze many samples in 1980 by Engel and was defined as the occurrence of or return low confidence predictions. More recently, some inheriting a pair of homologous chromosomes from tools have been proposed for next-generation sequencing the same parental origin. Such event, also known as data. While whole-exome sequencing lacks an even constitutional UPD, is caused by segregation errors mostly coverage of the genome and heterozygous positions, in meiosis and leads to the development of several genetic leading to a potential lower accuracy, whole-genome disorders through the gain or loss of imprinted regions, sequencing data promise highly precise estimates of allele- or the presence of two identical copies of an abnormal specific copy number profiles and a better integration with gene [1]. The great advance in molecular genetics in the mutational status and epigenetic marks. last two decades, especially with the development of Recent reports have shown that aUPD events are single nucleotide polymorphism (SNP) arrays and next- non-randomly distributed across cancer types, pointing generation sequencing, has provided the opportunity to out common genomic profiles of aUPD in a tumor-type systematically identify regions of somatic UPD in cancer, specific manner, which typically coincide with regions of commonly known as somatically-acquired UPD (aUPD) genomic losses, both in solid tumors and hematological or copy-neutral loss of heterozygosity (cnLOH) [2, 3]. malignancies [5, 6]. In addition, the identification of The detection of allele-specific copy number cancer-specific minimal regions of aUPD has led to the aberrations in tumor cells relies strongly on bioinformatic discovery of inactivating mutations in cancer-related tools that were initially developed for SNP array genes, which might increase the functional relevance of technologies. These methods are strongly dependent on such events in the development of cancer. In fact, several each technology-associated signal and noise characteristics, studies have provided evidence that aUPD could act as tumor ploidy, the cellularity of the samples, variant the “second hit” in the Knudson hypothesis and inactivate allele bias in heterozygous loci, and the tumor type [4]. tumor suppressor genes. Examples of this phenomenon Moreover, allele-specific copy number analysis requires are the inactivation of well-known tumor suppressor genes heterozygous SNP markers, which represent on average such as APC in colorectal cancer, RB1 in retinoblastoma, less than 1/3 of the covered positions. Altogether, it is ARID1A in colorectal and stomach carcinoma, and Figure 1: Circos plots depicting genomic profiles of aUPDs (green), copy number losses (blue) and gains (red) in (A) esophageal squamous cell carcinomas (ESCC) and (B) colon adenocarcinomas (COAD). Data was obtained from The Cancer Genome Atlas (TCGA) through the NCI Genomics Data Commons (GDC) portal. In the outer ring, the most frequently mutated genes involved in aUPD events are indicated for each tumor type. (Adapted from Torabi et al., 2019). www.oncotarget.com 3982 Oncotarget inactivation of TP53 in several cancer types, including ACKNOWLEDGMENTS glioblastoma, diffuse large B cell lymphoma, and colorectal carcinoma, among others [7]. Moreover, some We would like to thank the Instituto de Salud Carlos studies have identified aUPD in colorectal pre-malignant III and co-funded by the European Regional Development adenomas, mostly affecting APC and SMAD4, two tumor Fund (ERDF) [CPII18/00026, PI14/00783], the Agència suppressor genes known to be involved in early colorectal de Gestió d’Ajuts Universitaris i de Recerca, Generalitat carcinogenesis [8]. Likewise, aUPD also occurs in de Catalunya [2017 SGR 1035, 2017 SGR 21, 2017 SGR genomic regions including proto-oncogenes such as KRAS 1796], and the CRUK [C18281/A19169] for funding at 12p, indicating that aUPD also plays a crucial role in the support. activation of oncogenes (Figure 1). The mechanisms by which aUPD is generated Pau Erola: CRUK Integrative Cancer Epidemiology remain elusive. aUPD events are either caused by Programme, MRC Integrative Epidemiology Unit, chromosome segregation errors in mitosis, leading to University of Bristol, Bristol, BS8 2BN, UK whole-chromosome aUPD, or by mitotic recombination, Keyvan Torabi: Gastrointestinal and Pancreatic Oncology which acts as a repairing double strand break mechanism Group, Institut D’Investigacions Biomèdiques August Pi i and might lead to segmental aUPD. In fact, segmental Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), aUPD is commonly identified in tumors with impaired Barcelona, Catalonia, 08036, Spain chromosome repair mechanisms, such as MUTYH- associated polyposis colon carcinomas [9]. It might Rosa Miró: Unitat de Biologia Cel·lular i Genètica Mèdica, be plausible to rationalize that mitotic recombination- Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, associated segmental aUPD might imply two features: Bellaterra, Catalonia, 08193, Spain (i) genomic sites of high sequence homology, which coincide with sites of meiotic recombination as seen for Jordi Camps: Gastrointestinal and Pancreatic Oncology Group, Institut D’Investigacions Biomèdiques August Pi i chromosome 5q breakpoints [10], and (ii) a physical Sunyer (IDIBAPS), Centro de Investigación Biomédica en proximity of homologous chromosomes that would Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), increase the chances of mitotic recombination events, Barcelona, Catalonia, 08036, Spain especially in aneuploid tumors where the higher-order Correspondence to: Jordi Camps, genome organization might be altered. email: jcamps@clinic.cat Several questions remain to be answered to further Keywords: somatically-acquired uniparental disomy, uni- understand the role of aUPD in cancer. The higher parental disomy, copy-neutral loss of heterozygosity, copy prevalence of aUPD in certain chromosomal regions number alterations, cancer compared with the frequency of genomic losses (e.g., Received: May 08, 2019 chromosome 5q in colorectal cancer), suggests that tumor Published: June 18, 2019 cells need to preserve such chromosomal regions in two or more copies in order to maintain cellular fitness, most REFERENCES likely due to the presence of haploinsufficient genes or genomic regions under negative selection in a tissue- 1. Engel E. Am J Med Genet. 1980; 6:137–43. https://doi. specific manner. At the functional level, the transcriptional org/10.1002/ajmg.1320060207. [PubMed] consequences of aUPD, as well as the gene dysregulation 2. Tuna M, et al. Trends Mol Med. 2009; 15:120–28. https:// due to the disruption of imprinted gene clusters during doi.org/10.1016/j.molmed.2009.01.005. [PubMed] the carcinogenesis, prevail largely unknown. Lastly, the 3. Makishima H, et al. 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