Cell Models for Chromosome 20q11.21 Amplification and Drug Sensitivities in Colorectal Cancer

Abstract

Background and objectives: The chromosome locus 20q11.21 is a commonly amplified locus in colorectal cancer, with a prevalence of 8% to 9%. Several candidate cancer-associated genes are transcribed from the locus. The therapeutic implications of the amplification in colorectal cancer remain unclear. Materials and Methods: Preclinical cell line models of colorectal cancer included in the Cancer Cell Line Encyclopedia (CCLE) collection were examined for the presence of amplifications in 20q11.21 genes. Correlations of the presence of 20q11.21 amplifications with gene essentialities and drug sensitivities were surveyed on salient databases for determination of therapeutic leads. Results: A significant subset of colorectal cancer cell lines in the CCLE (12 of 63 cell lines, 19%) bear amplifications of genes located at 20q11.21. Cancer-associated genes of the locus include ASXL1, DNMT3B, BCL2L1, TPX2, KIF3B and POFUT1. These genes are all amplified in the 12 cell lines, but they are variably over-expressed at the mRNA level, compared to non-amplified lines. 20q11.21 amplified cell lines are sensitive to various tyrosine kinase inhibitors and are resistant to chemotherapy drugs targeting the mitotic apparatus and microtubules. CRISPR and RNAi dependencies screening revealed, besides the β-catenin and KRAS genes, a few recurrent gene dependencies in more than one cell line, including YAP1 and JUP. Conclusions: Cell line models of colorectal cancer with 20q11.21 gene amplifications display dependencies on the presence of specific genes and resistance or sensitivity to specific drugs and drug categories. Observations from in vitro models may form the basis for clinical drug development in this subtype of colorectal cancer. Genetic lesions conferring synthetic lethality to certain drugs or categories of drugs could be discovered with this approach.

Oncogenic miR‐1825 promotes head and neck carcinogenesis via targeting FREM1

“…Previous studies illustrated that miR‐1825 acts as a cancer‐promoting microRNA in numerous cancers, 16,21,43 however, the carcinogenic functions of miR‐1825 in HNSCC have not been ascertained yet. It has been shown that the 20q11.21 locus contains cancer‐associated genes with potential oncogenic properties, and amplification detected in this region in colorectal cancer leads to genomic instability and recurrent genetic abnormalities and contributes to cancer pathogenesis 44,45 . Jo et al found that copy number variation in the 20q11.21 region led to increased migration capacities, metastatic potential, aberrant differentiation tendencies, cell proliferation, and decreased sensitivity to apoptosis in many types of cancers and human pluripotent stem cells 46 .…”

“…It has been shown that the 20q11.21 locus contains cancerassociated genes with potential oncogenic properties, and amplification detected in this region in colorectal cancer leads to genomic instability and recurrent genetic abnormalities and contributes to cancer pathogenesis. 44,45 Jo et al found that copy number variation in the 20q11.21 region led to increased migration capacities, metastatic potential, aberrant differentiation tendencies, cell proliferation, and decreased sensitivity to apoptosis in many types of cancers and human pluripotent stem cells. 46 Given the facts that miR-1825 resides within 20q11.21 chromosomal region, where has been notified as a recurrent gain of function abnormality in human embryonic and induced pluripotent stem cells 13,14 and that 20q11.21 amplification in human embryonic stem cells resulted in acquisition of a geneexpression signature enriched for cancer-related genes, 16,17 we suggested that miR-1825 might promote cellular phenotypes related to cancer progression in HNSCC as well.…”

Therapeutic Landscapes in Colorectal Carcinoma

“…CRISPR and RNAi dependency analysis identified YAP1 and JUP as recurrent gene dependencies in cell lines. Therefore, amplified 20q11.21 gene cell line models of CRC with resistance or sensitivity to various drug categories could be adopted within in vitro models to favor clinical drug development in this tumor [ 15 ].…”