Mutations in the Hedgehog Pathway Genes SMO and PTCH1 in Human Gastric Tumors

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Jan 26

PMID 23349881

Citations 22

Authors

Xi-De Wang

Hector Inzunza

Han Chang

Zhenhao Qi

Beihong Hu

Daniel Malone

John Cogswell

Affiliations

Soon will be listed here.

Abstract

The causal role of the hedgehog pathway in cancer has been best documented in basal cell carcinoma of the skin. To assess potential DNA alterations of the hedgehog pathway in gastric cancer, we sequenced SMO and PTCH1 genes in a set of 39 gastric tumors. Tumors were classified by histology based on the Lauren classification and Sanger sequencing was performed to obtain full length coding sequences. Genomic instability was evident in these tumors as a number of silent or missense mutations were found. In addition to those that are potential germline polymorphisms, we found three SMO missense mutations, and one PTCH1 frameshift mutation that are novel and have not been documented in basal cell carcinoma. Mutations were found in both intestinal and diffuse type gastric tumors as well as in tumors that exhibit both intestinal and diffuse features. mRNA expression of hedgehog pathway genes was also examined and their levels do not indicate unequivocal higher pathway activity in tumors with mutations than those without. In summary, SMO and/or PTCH1 mutations are present at low frequency in different histologic subtypes of gastric tumors and these do not appear to be driver mutations.

Citing Articles

Towards Precision Oncology: The Role of Smoothened and Its Variants in Cancer.

Nicheperovich A, Townsend-Nicholson A J Pers Med. 2022; 12(10).

PMID: 36294790 PMC: 9605185. DOI: 10.3390/jpm12101648.

Personalized First-Line Treatment of Metastatic Pancreatic Neuroendocrine Carcinoma Facilitated by Liquid Biopsy and Computational Decision Support.

Szkukalek J, Doczi R, Dirner A, Boldizsar A, Varga A, Deri J Diagnostics (Basel). 2021; 11(10).

PMID: 34679548 PMC: 8534772. DOI: 10.3390/diagnostics11101850.

Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment.

Zhang J, Fan J, Zeng X, Nie M, Luan J, Wang Y Acta Pharm Sin B. 2021; 11(3):609-620.

PMID: 33777671 PMC: 7982428. DOI: 10.1016/j.apsb.2020.10.022.

The regulatory roles and mechanisms of the transcription factor FOXF2 in human diseases.

Wu Q, Li W, You C PeerJ. 2021; 9:e10845.

PMID: 33717680 PMC: 7934645. DOI: 10.7717/peerj.10845.

Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis.

Tabibzadeh A, Safarnezhad Tameshkel F, Moradi Y, Soltani S, Moradi-Lakeh M, Ashrafi G Sci Rep. 2020; 10(1):18713.

PMID: 33127962 PMC: 7599243. DOI: 10.1038/s41598-020-73770-1.

References

Yauch R, Dijkgraaf G, Alicke B, Januario T, Ahn C, Holcomb T . Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009; 326(5952):572-4. PMC: 5310713. DOI: 10.1126/science.1179386. View

Rudin C, Hann C, Laterra J, Yauch R, Callahan C, Fu L . Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009; 361(12):1173-8. PMC: 5317279. DOI: 10.1056/NEJMoa0902903. View

Berman D, Karhadkar S, Maitra A, Montes de Oca R, Gerstenblith M, Briggs K . Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003; 425(6960):846-51. DOI: 10.1038/nature01972. View

Vestergaard J, Pedersen M, Pedersen N, Ensinger C, Tumer Z, Tommerup N . Hedgehog signaling in small-cell lung cancer: frequent in vivo but a rare event in vitro. Lung Cancer. 2006; 52(3):281-90. DOI: 10.1016/j.lungcan.2005.12.014. View

LAUREN P . THE TWO HISTOLOGICAL MAIN TYPES OF GASTRIC CARCINOMA: DIFFUSE AND SO-CALLED INTESTINAL-TYPE CARCINOMA. AN ATTEMPT AT A HISTO-CLINICAL CLASSIFICATION. Acta Pathol Microbiol Scand. 1965; 64:31-49. DOI: 10.1111/apm.1965.64.1.31. View

Chang-Claude J, Dunning A, Schnitzbauer U, Galmbacher P, Tee L, Wjst M . The patched polymorphism Pro1315Leu (C3944T) may modulate the association between use of oral contraceptives and breast cancer risk. Int J Cancer. 2003; 103(6):779-83. DOI: 10.1002/ijc.10889. View

Xie J, Murone M, Luoh S, Ryan A, Gu Q, Zhang C . Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998; 391(6662):90-2. DOI: 10.1038/34201. View

Yan T, Angelini M, Alman B, Andrulis I, Wunder J . Patched-one or smoothened gene mutations are infrequent in chondrosarcoma. Clin Orthop Relat Res. 2008; 466(9):2184-9. PMC: 2492993. DOI: 10.1007/s11999-008-0332-2. View

La Thangue N, Kerr D . Predictive biomarkers: a paradigm shift towards personalized cancer medicine. Nat Rev Clin Oncol. 2011; 8(10):587-96. DOI: 10.1038/nrclinonc.2011.121. View

10.

Santos F, Kantarjian H, Quintas-Cardama A, Cortes J . Evolution of therapies for chronic myelogenous leukemia. Cancer J. 2011; 17(6):465-76. PMC: 3243359. DOI: 10.1097/PPO.0b013e31823dec8d. View

11.

Hafner C, Schmiemann V, Ruetten A, Coras B, Landthaler M, Reifenberger J . PTCH mutations are not mainly involved in the pathogenesis of sporadic trichoblastomas. Hum Pathol. 2007; 38(10):1496-500. DOI: 10.1016/j.humpath.2007.02.015. View

12.

Rubin L, de Sauvage F . Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov. 2006; 5(12):1026-33. DOI: 10.1038/nrd2086. View

13.

Ma X, Chen K, Huang S, Zhang X, Adegboyega P, Evers B . Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas. Carcinogenesis. 2005; 26(10):1698-705. DOI: 10.1093/carcin/bgi130. View

14.

Fukaya M, Isohata N, Ohta H, Aoyagi K, Ochiya T, Saeki N . Hedgehog signal activation in gastric pit cell and in diffuse-type gastric cancer. Gastroenterology. 2006; 131(1):14-29. DOI: 10.1053/j.gastro.2006.05.008. View

15.

Von Hoff D, LoRusso P, Rudin C, Reddy J, Yauch R, Tibes R . Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009; 361(12):1164-72. DOI: 10.1056/NEJMoa0905360. View

16.

Wang K, Kan J, Yuen S, Shi S, Chu K, Law S . Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet. 2011; 43(12):1219-23. DOI: 10.1038/ng.982. View

17.

Johnson R, Rothman A, Xie J, Goodrich L, Bare J, Bonifas J . Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996; 272(5268):1668-71. DOI: 10.1126/science.272.5268.1668. View

18.

Asplund A, Gustafsson A, Wikonkal N, Sela A, Leffell D, Kidd K . PTCH codon 1315 polymorphism and risk for nonmelanoma skin cancer. Br J Dermatol. 2005; 152(5):868-73. DOI: 10.1111/j.1365-2133.2005.06464.x. View

19.

Gailani M, Leffell D, Glynn M, Zaphiropoulos P, Pressman C, Unden A . The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. 1996; 14(1):78-81. DOI: 10.1038/ng0996-78. View

20.

Xie J, Johnson R, Zhang X, Bare J, Waldman F, Cogen P . Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res. 1997; 57(12):2369-72. View