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

Abstract

Somatically acquired uniparental disomies (aUPDs) are frequent events in solid tumors and have been associated with cancer‐related genes. Studies assessing their functional consequences across several cancer types are therefore necessary. Here, we aimed at integrating aUPD profiles with the mutational status of cancer‐related genes in a tumor‐type specific manner. Using TCGA datasets for 1,032 gastrointestinal cancers, including colon (COAD), rectum (READ), stomach (STAD), esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), we show a non‐random distribution of aUPD, suggesting the existence of a cancer‐specific landscape of aUPD events. Our analysis indicates that aUPD acts as a “second hit” in Knudson's model in order to achieve biallelic inactivation of tumor suppressor genes. In particular, APC , ARID1A and NOTCH1 were recurrently inactivated by the presence of homozygous mutation as a consequence of aUPD in COAD and READ, STAD and ESCC, respectively. Furthermore, while TP53 showed inactivation caused by aUPD at chromosome arm 17p across all tumor types, copy number losses at this genomic position were also frequent. By experimental and computationally inferring genome ploidy, we demonstrate that an increased number of aUPD events, both affecting the whole chromosome or segments of it, were present in highly aneuploid genomes compared to near‐diploid tumors. Finally, the presence of mosaic UPD was detected at a higher frequency in DNA extracted from peripheral blood lymphocytes of patients with colorectal cancer compared to healthy individuals. In summary, our study defines specific profiles of aUPD in gastrointestinal cancers and provides unequivocal evidence of their relevance in cancer.

Copy neutral loss of heterozygosity (cnLOH) patterns in synchronous colorectal cancer

“…In this study, we employed SNP-A to assess cnLOH profiles in SCRC among all cases and by subgroup classification in order to better understand etiologies underlying sporadic colorectal carcinogenesis. Previous reports have analyzed cnLOH profiles across diverse gastrointestinal tumors and revealed the lowest level of regions with cnLOH (3 per sample) for colon cancers by tumor type [10]. Nevertheless, compared with previous results, our specific interrogation of SCRCs revealed a higher frequency of regions altered by cnLOH (median of 7.5 events per sample).…”

“…Nevertheless, compared with previous results, our specific interrogation of SCRCs revealed a higher frequency of regions altered by cnLOH (median of 7.5 events per sample). We also observed that SCRCs showed a distinct pattern of cnLOH events compared with cases with one primary invasive CRC [10]. It is important to note that while previous studies have leveraged similar techniques and cnLOH criteria, the biospecimen type (e.g.…”

“…Recent studies have proposed cnLOH as a "second hit" to inactivate TSGs as well as to activate oncogenes [7,10]. In order to study cnLOH in SCRC, we explored associations between the presence of cnLOH and genomic landscape of commonly altered SCRC genes.…”

Genes copy number variation in colorectal cancer patients as a marker of the disease clinical outcome and response to therapy

“…Применение CGH предоставило доказательства того, что геномный дисбаланс ответственен за прогрессирование опухоли от диспластических поражений до инвазивного заболевания. Позже ДНК-микрочипы позволили одновременно измерить количество копий многих полиморфных локусов в геноме, что привело к обнаружению с высоким разрешением LOH, обычного явления в онкогенезе [27].…”

The non-random landscape of somatically-acquired uniparental disomy in cancer

“…Recent reports have shown that aUPD events are non-randomly distributed across cancer types, pointing out common genomic profiles of aUPD in a tumor-type specific manner, which typically coincide with regions of genomic losses, both in solid tumors and hematological malignancies [5, 6]. In addition, the identification of cancer-specific minimal regions of aUPD has led to the discovery of inactivating mutations in cancer-related genes, which might increase the functional relevance of such events in the development of cancer.…”