Patterns of somatic uniparental disomy identify novel tumor suppressor genes in colorectal cancer

Abstract

Colorectal cancer (CRC) is characterized by specific patterns of copy number alterations (CNAs), which helped with the identification of driver oncogenes and tumor suppressor genes (TSGs). More recently, the usage of single nucleotide polymorphism arrays provided information of copy number neutral loss of heterozygosity, thus suggesting the occurrence of somatic uniparental disomy (UPD) and uniparental polysomy (UPP) events. The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs and CNAs in sporadic CRC. Our results indicate that regions showing high frequencies of UPD/UPP mostly coincide with regions typically involved in genomic losses. Among them, chromosome arms 3p, 5q, 9q, 10q, 14q, 17p, 17q, 20p, 21q and 22q preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. Several regions affected by recurrent UPDs/UPPs contain well-known TSGs, as well as novel candidates such as ARID1A, DLC1, TCF7L2 and DMBT1. In addition, VCAN, FLT4, SFRP1 and GAS7 were also frequently involved in regions of UPD/UPP and displayed high levels of methylation. Finally, sequencing and fluorescence in situ hybridization analysis of the gene APC underlined that a somatic UPD event might represent the second hit to achieve biallelic inactivation of this TSG in colorectal tumors. In summary, our data define a profile of somatic UPDs/UPPs in sporadic CRC and highlights the importance of these events as a mechanism to achieve the inactivation of TSGs.

Quantitative analysis of somatically acquired and constitutive uniparental disomy in gastrointestinal cancers

“…In particular, we could show that STAD, EAC and ESCC carried significantly different patterns of aUPD compared to COAD and READ, thus suggesting the existence of cancer‐specific landscapes of aUPD across GI cancers. As observed for CNAs, aUPD profiles in the COAD cohort matched with those identified in READ samples, which is in agreement with previous reports . Remarkably, the high rate of segmental aUPD in STAD and ESCA suggests higher levels of structural CIN in these cancer types compared to COAD and READ, which agrees with a previous study showing more focal amplification events in the upper than in the lower GI tract .…”

“…Finally, 20 colorectal adenocarcinomas provided by the Hospital Clínic of Barcelona/IDIBAPS Biobank were included in a tissue microarray (TMA). Clinical features of each patient were previously described . All patients signed the corresponding informed consent and the sample collection was approved by the institutional review board of the hospital.…”

“…Out of all paired samples examined in our study, only those that presented less than 300 segments were considered for further analyses. Details on data analysis have been previously published . Moreover, in order to identify the global ploidy of a previously reported dataset (GSE64114) and TCGA samples, we used the recommended pipeline of the Allele‐Specific Copy Number Analysis of Tumors (ASCAT) method .…”

“…Similar to genomic losses, the mutational status of genes located at recurring regions of aUPD can provide evidence to determine the extent to which a certain aUPD event is a driver alteration if biallelic inactivation is achieved. In fact, UPD events have been already associated with driver genes in several cancer types . Moreover, some authors have also reported gain‐of‐function of homozygous mutations affecting oncogenes in regions of aUPD .…”

Comparison of Results between Cytogenetic Technique and Molecular Genetic Technique in Colorectal Carcinoma Patients

“…(47∼57%) and 22q (37∼40%), respectively, which is shown a similar result with previous reports [17]. The matching rate between CGH and LOH was 94.4% (85/90), similar to that reported in other countries (94.5%) [18].…”