Abstract
GLI1 is a transcription factor for hedgehog signaling that plays a crucial role in signaling pathways for controlling cell proliferation, alterations of which are known to contribute to tumorigenesis. Aim of this study was to explore whether GLI1 gene is mutated in gastric (GC) and colorectal cancers (CRC). In a public database, we found that GLI1 had a G7 mononucleotide repeat in the coding sequences that could be a mutation target in the cancers with microsatellite instability (MSI). In this study, we analyzed frameshift mutation of GLI1 in 79 GCs and 129 CRCs (high MSI (MSI-H) or microsatellite stable (MSS)) by single-strand conformation polymorphism analysis and DNA sequencing. We found 10 frameshift mutations in the repeat, nine for CRCs and one for GC. All of the mutations were detected in cancers with MSI-H and there was a statistical difference in the frameshift mutation frequencies between the cancers with MSI-H (10/113) and MSS (0/90). We also analyzed intratumoral heterogeneity (ITH) of the frameshift mutation in 16 CRCs and found that the mutations exhibited regional ITH in three of the CRCs (18.8%). Our data indicate GLI1 harbored not only frameshift mutation but also its mutational ITH, which together could be a feature of GC and CRC with MSI-H.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Lim L, Beachy PA (2004) The hedgehog response network: sensors, switches, and routers. Science 304:1755–1759
Ruiz i Altaba A (1999) Gli proteins encode context-dependent positive and negative functions: implications for development and disease. Development 126:3205–3216
Villavicencio EH, Walterhouse DO, Iannaccone PM (2000) The sonic hedgehog-patched-gli pathway in human development and disease. Am J Hum Genet 67:1047–1054
Jacob J, Briscoe J (2003) Gli proteins and the control of spinal-cord patterning. EMBO Rep 4:761–765
Sanchez P, Clement V, Ruiz i Altaba A (2005) Therapeutic targeting of the hedgehog-GLI pathway in prostate cancer. Cancer Res 65:2990–2992
Hui CC, Angers S (2011) Gli proteins in development and disease. Annu Rev Cell Dev Biol 27:513–537
Rubin JB, Rowitch DH (2002) Medulloblastoma: a problem of developmental biology. Cancer Cell 2:7–8
Kinzler KW, Bigner SH, Bigner DD, Trent JM, Law ML, O'Brien SJ, Wong AJ, Vogelstein B (1987) Identification of an amplified, highly expressed gene in a human glioma. Science 236:70–73
Oniscu A, James RM, Morris RG, Bader S, Malcomson RD, Harrison DJ (2004) Expression of sonic hedgehog pathway genes is altered in colonic neoplasia. J Pathol 203:909–917
Imai K, Yamamoto H (2008) Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics. Carcinogenesis 29:673–680
Calin GA, Gafà R, Tibiletti MG, Herlea V, Becheanu G, Cavazzini L, Barbanti-Brodano G, Nenci I, Negrini M, Lanza G (2000) Genetic progression in microsatellite instability high (MSI-H) colon cancers correlates with clinico-pathological parameters: a study of the TGRbetaRII, BAX, hMSH3, hMSH6, IGFIIR and BLM genes. Int J Cancer 89:230–235
Marusyk A, Almendro V, Polyak K (2012) Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 12:323–334
Murphy K, Zhang S, Geiger T, Hafez MJ, Bacher J, Berg KD, Eshleman JR (2006) Comparison of the microsatellite instability analysis system and the Bethesda panel for the determination of microsatellite instability in colorectal cancers. J Mol Diagn 8:305–311
Jo YS, Choi MR, Song SY, Kim MS, Yoo NJ, Lee SH (2016) Frameshift mutations of HSPA4 and MED13 in gastric and colorectal cancers. Pathol Oncol Res 22:769–772
Jo YS, Kim MS, Yoo NJ, Lee SH (2016) Absence of PRKD1 mutation, a salivary tumor-specific mutation, in solid tumors and Leukemias. Pathol Oncol Res 22:231–232
Choi EJ, Kim MS, Song SY, Yoo NJ, Lee SH (2017) Intratumoral heterogeneity of frameshift mutations in MECOM Gene is frequent in colorectal cancers with high microsatellite instability. Pathol Oncol Res 23:145–149
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674
Lee SW, Moskowitz MA, Sims JR (2007) Sonic hedgehog inversely regulates the expression of angiopoietin-1 and angiopoietin-2 in fibroblasts. Int J Mol Med 19:445–451
Adolphe C, Hetherington R, Ellis T, Wainwright B (2006) Patched1 functions as a gatekeeper by promoting cell cycle progression. Cancer Res 66:2081–2088
Athar M, Li C, Tang X, Chi S, Zhang X, Kim AL, Tyring SK, Kopelovich L, Hebert J, Epstein EH Jr, Bickers DR, Xie J (2004) Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis. Cancer Res 64:7545–7552
Choi YJ, Kim MS, An CH, Yoo NJ, Lee SH (2014) Regional bias of intratumoral genetic heterogeneity of nucleotide repeats in colon cancers with microsatellite instability. Pathol Oncol Res 20:965–971
Choi YJ, Rhee JK, Hur SY, Kim MS, Lee SH, Chung YJ, Kim TM, Lee SH (2017) Intraindividual genomic heterogeneity of high-grade serous carcinoma of the ovary and clinical utility of ascitic cancer cells for mutation profiling. J Pathol 241:57–66
Acknowledgements
This work was supported by a grant from National Research Foundation of Korea (2012R1A5A2047939).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of Interest
None to declare.
Rights and permissions
About this article
Cite this article
Lee, J.H., Song, S.Y., Kim, M.S. et al. Intratumoral Heterogeneity of Frameshift Mutations of GLI1 Encoding a Hedgehog Signaling Protein in Colorectal Cancers. Pathol. Oncol. Res. 24, 477–481 (2018). https://doi.org/10.1007/s12253-017-0272-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12253-017-0272-9