Deletions in metastatic colorectal cancer with chromothripsis
DOI:
https://doi.org/10.32471/exp-oncology.2312-8852.vol-41-no-4.13841Keywords:
chromothripsis, deletion, metastatic colorectal cancer, progression free survivalAbstract
Summary. Aim: In our previously reported study, we found a correlation between DNA massive fragmentation and increased progression free survival (PFS) in metastatic colorectal cancer (mCRC), but not overall survival. The aim of this study is to find overlapping deleted genome regions in selected mCRC patients with chromothripsis and detect possible cause of increased PFS, and find new genes or combinations, involved in colorectal cancer oncogenesis. Materials and Methods: 10 mCRC patients with chromothripsis receiving 5-fluorouracil, oxaliplatin, leucovorin (FOLFOX) first-line palliative chemotherapy between August, 2011 and October, 2012 were selected for this study. Microarray analysis was performed using the Infinium HumanOmniExpress-12 v1.0 formalin-fixed paraffin-embedded (FFPE) BeadChip kit (Illumina). BeadChip was scaned on HiScan (Illumina). Analysis was performed by GenomeStudio software (Illumina) and R version 3.1.2. Copy number variation and breakpoints on the chromosomes were analyzed using the DNA copy package. Results: Eight deleted tumor suppressor genes (ROBO2, CADM2, FAT4, PCDH10, PCDH18, CDH18, TSG1, CTNNA3) and four deleted oncogenes (CDH12, GPM6A, ADAM29, COL11A1) were identified in more than half of patients. In 70% patients’ deletion in COL11A1 was detected. Deletion of MIR1269, MIR4465, MIR1261 and MIR4490 in patients with longer time to progression was observed. Four patients (40%) with PFS over 14 months, presented with NRG3 deletion (oncogene, еpidermal growth factor receptor (EGFR) ligand) what could possibly decrease proliferation of cancer cells via decreasing EGFR activation. Conclusions: Multiple chromosomal deletions (MIR1269, NRG3, ADK) in mCRC patients with chromothripsis are associated with better response to first line palliative FOLFOX-type chemotherapy and increased PFS.
References
Stephens PJ, Greenman CD, Fu B, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 2011; 144: 27–40.
Magrangeas F, Avet-Loiseau H, Munshi NC, et al. Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients. Blood 2011; 118: 675–8.
Fontana MC, Marconi G, Feenstra JDM, et al. Chromothripsis in acute myeloid leukemia: biological features and impact on survival. Leukemia 2018; 32: 1609–20.
Skuja E, Kalniete D, Nakazawa-Miklasevica M, et al. Chromothripsis and progression free survival in metastatic colorectal cancer. Mol Clin Oncol 2017; 6: 182–6.
Rausch T, Jones DTW, Zapatka M, et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 2012; 148: 59–71.
Przybytkowski E, Lenkiewicz E, Barrett MT, et al. Chromosome-breakage genomic instability and chromothripsis in breast cancer. BMC Genomics 2014; 15: 579.
Shen L, Yang M, Lin Q, et al. COL11A1 is overexpressed in recurrent non-small cell lung cancer and promotes cell proliferation, migration, invasion and drug resistance. Oncol Rep 2016; 36: 877–85.
Yang XW, Shen GZ, Cao LQ, et al. MicroRNA-1269 promotes proliferation in human hepatocellular carcinoma via downregulation of FOXO1. BMC Cancer 2014; 14: 909.
López-Saavedra A, Ramírez-Otero M, Díaz-Chávez J, et al. MAD2γ, a novel MAD2 isoform, reduces mitotic arrest and is associated with resistance in testicular germ cell tumors. Cell Cycle 2016; 15: 2066–76.
Bu P, Wang L, Chen KY, et al. miR-1269 promotes metastasis and forms a positive feedback loop with TGF-β. Nat Commun 2015; 6: 6879.
Ashktorab H, Schäffer AA, Daremipouran M, et al. Distinct genetic alterations in colorectal cancer. PLoS One. 2010; 5: e8879.
Charfi C, Edouard E, Rassart E. Identification of GPM6A and GPM6B as potential new human lymphoid leukemia-associated oncogenes. Cell Oncol 2014; 37: 179–91.
Guan M, Xu C, Zhang F, Ye C. Aberrant methylation of EphA7 in human prostate cancer and its relation to clinicopathologic features. Int J Cancer 2009; 124: 88–94.
Giglioni S, Leoncini R, Aceto E, et al. Adenosine kinase gene expression in human colorectal cancer. Nucleosides Nucleotides Nucleic Acids 2008; 27: 750–4.
He W, Li X, Xu S, et al. Aberrant methylation and loss of CADM2 tumor suppressor expression is associated with human renal cell carcinoma tumor progression. Biochem Biophys Res Commun 2013; 435: 526–32.
Yang S, Yan HL, Tao QF, et al. Low CADM2 expression predicts high recurrence risk of hepatocellular carcinoma patients after hepatectomy. J Cancer Res Clin Oncol 2014; 140: 109–16.
Cai J, Feng D, Hu L, et al. FAT4 functions as a tumour suppressor in gastric cancer by modulating Wnt/β-catenin signalling. Br J Cancer 2015; 113: 1720–9.
Hou L, Chen M, Zhao X, et al. FAT4 functions as a tumor suppressor in triple-negative breast cancer. Tumour Biol 2016 Nov 28.
Yu J, Wu WK, Li X, et al. Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer. Gut 2015; 64: 636–45.
Lee HS, Lee HK, Kim HS, et al. Tumour suppressor gene expression correlates with gastric cancer prognosis. J Pathol 2003; 200: 39–46.
Sun M, Srikantan V, Ma L, et al. Characterization of frequently deleted 6q locus in prostate cancer. DNA Cell Biol 2006; 25: 597–607.
He B, Li T, Guan L, et al. CTNNA3 is a tumor suppressor in hepatocellular carcinomas and is inhibited by miR-425. Oncotarget 2016; 7: 8078–89.
Smith DI, Zhu Y, McAvoy S, et al. Common fragile sites, extremely large genes, neural development and cancer. Cancer Lett 2006; 232: 48–57.
Yamamoto K, Gandin V, Sasaki M, et al. Largen: a molecular regulator of mammalian cell size control. Mol Cell 2014; 53: 904–15.
Qiu C, Bu X, Jiang Z. Protocadherin-10 acts as a tumor suppressor gene, and is frequently downregulated by promoter methylation in pancreatic cancer cells. Oncol Rep 2016; 36: 383–9.
Zhong X, Shen H, Mao J, et al. Epigenetic silencing of protocadherin 10 in colorectal cancer. Oncol Lett 2017; 13: 2449–53.
Jao TM, Tsai MH, Lio HY, et al. Protocadherin 10 suppresses tumorigenesis and metastasis in colorectal cancer and its genetic loss predicts adverse prognosis. Int J Cancer 2014; 135: 2593–603.
Zhou D, Tang W, Su G, et al. PCDH18 is frequently inactivated by promoter methylation in colorectal cancer. Sci Rep 2017; 7: 2819.
Venkatachalam R, Verwiel ET, Kamping EJ, et al. Identification of candidate predisposing copy number variants in familial and early-onset colorectal cancer patients. Int J Cancer 2011; 129: 1635–42.
Chalmers IJ, Höfler H, Atkinson MJ. Mapping of a cadherin gene cluster to a region of chromosome 5 subject to frequent allelic loss in carcinoma. Genomics 1999; 57: 160–3.
Ma J, Zhao J, Lu J, et al. Cadherin-12 enhances proliferation in colorectal cancer cells and increases progression by promoting EMT. Tumour Biol 2016; 37: 9077–88.
Zhao J, Li P, Feng H, et al. Cadherin-12 contributes to tumorigenicity in colorectal cancer by promoting migration, invasion, adhersion and angiogenesis. J Transl Med 2013; 11: 288.
An CH, Je EM, Yoo NJ, et al. Frameshift mutations of cadherin genes DCHS2, CDH10 and CDH24 genes in gastric and colorectal cancers with high microsatellite instability. Pathol Oncol Res 2015; 21: 181–5.
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