The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by glial cell derived neutrotrophic factor (GDNF). Previous studies have found that a single nucleotide polymorphism (SNP), RETp (G691S), in the juxtamembrane domain enhances the signaling pathway and promotes tumor growth by GDNF in pancreatic and thyroid cancer in addition to melanoma. It is uncertain however whether this SNP is a germline variant or somatic mutation. A prior study reported that the RETp variant was a germline SNP in desmoplastic and non-desmoplastic melanomas. In the present study, we examined both melanoma tissue samples and matching peripheral blood DNA to determine if RETp was 1) a germline or somatic variant, 2) more frequent in certain melanoma subtypes, and 3) frequency in brain metastasis. We examined the peripheral blood of 197 melanoma patients whom had at least one matched tumor, and 42 patients with brain metastasis. RETp was present as a germline SNP in 33% of patients. There were no significant differences in RETp frequency among the different melanoma subtypes, and RETp was not correlated with brain metastasis.
Conflict(s) of Interest
References with DOI
1. Spagnolo F, Picasso V, Lambertini M, Ottaviano V, Dozin B, Queirolo P. Survival of patients with metastatic melanoma and brain metastases in the era of MAP-kinase inhibitors and immunologic checkpoint blockade antibodies: A systematic review. Cancer treatment reviews. 2016;45:38-45. https://doi.org/10.1016/j.ctrv.2016.03.0032. Amer MH, Al-Sarraf M, Baker LH, Vaitkevicius VK. Malignant melanoma and central nervous system metastases: incidence, diagnosis, treatment and survival. Cancer. 1978;42:660-8. https://doi.org/10.1002/1097-0142(197808)42:2<660::aid-cncr2820420237>3.0.co;2-e
3. Staudt M, Lasithiotakis K, Leiter U, Meier F, Eigentler T, Bamberg M, et al. Determinants of survival in patients with brain metastases from cutaneous melanoma. British journal of cancer. 2010;102:1213-8. https://doi.org/10.1038/sj.bjc.6605622
4. Dupin E, Le Douarin NM. Development of melanocyte precursors from the vertebrate neural crest. Oncogene. 2003;22:3016-23. https://doi.org/10.1038/sj.onc.1206460
5. Reed RJ, Leonard DD. Neurotropic melanoma. A variant of desmoplastic melanoma. The American journal of surgical pathology. 1979;3:301-11. https://doi.org/10.1097/00000478-197908000-00002
6. Plaza-Menacho I, Burzynski GM, de Groot JW, Eggen BJ, Hofstra RM. Current concepts in RET-related genetics, signaling and therapeutics. Trends in genetics : TIG. 2006;22:627-36. https://doi.org/10.1016/j.tig.2006.09.005
7. Sawai H, Okada Y, Kazanjian K, Kim J, Hasan S, Hines OJ, et al. The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling. Cancer research. 2005;65:11536-44. https://doi.org/10.1158/0008-5472.can-05-2843
8. Ibanez CF. Beyond the cell surface: new mechanisms of receptor function. Biochemical and biophysical research communications. 2010;396:24-7. https://doi.org/10.1016/j.bbrc.2010.01.136
9. Gui H, Tang WK, So MT, Proitsi P, Sham PC, Tam PK, et al. RET and NRG1 interplay in Hirschsprung disease. Human genetics. 2013;132:591-600. https://doi.org/10.1007/s00439-013-1272-9
10. Margraf RL, Crockett DK, Krautscheid PM, Seamons R, Calderon FR, Wittwer CT, et al. Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Human mutation. 2009;30:548-56. https://doi.org/10.1002/humu.20928
11. Elisei R, Cosci B, Romei C, Bottici V, Sculli M, Lari R, et al. RET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population. The Journal of clinical endocrinology and metabolism. 2004;89:3579-84. https://doi.org/10.1210/jc.2003-031898
12. Narita N, Tanemura A, Murali R, Scolyer RA, Huang S, Arigami T, et al. Functional RET G691S polymorphism in cutaneous malignant melanoma. Oncogene. 2009;28:3058-68. https://doi.org/10.1038/onc.2009.164
13. Bounacer A, Du Villard JA, Wicker R, Caillou B, Schlumberger M, Sarasin A, et al. Association of RET codon 691 polymorphism in radiation-induced human thyroid tumours with C-cell hyperplasia in peritumoural tissue. Br J Cancer. 2002;86:1929–1936 . https://doi.org/10.1038/sj.bjc.6600371
14. Barr J, Amato CM, Robinson SE, Kounalakis N, Robinson WA. The RET G691S polymorphism is a germline variant in desmoplastic malignant melanoma. Melanoma research. 2012;22:92-5. https://doi.org/10.1097/cmr.0b013e32834defd6
15. Hintzsche J, Kim J, Yadav V, Amato C, Robinson SE, Seelenfreund E, et al. IMPACT: a whole-exome sequencing analysis pipeline for integrating molecular profiles with actionable therapeutics in clinical samples. Journal of the American Medical Informatics Association : JAMIA. 2016. https://doi.org/10.1093/jamia/ocw022
16. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754-60. https://doi.org/10.1093/bioinformatics/btp324
17. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078-9. https://doi.org/10.1093/bioinformatics/btp352
18. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic acids research. 2010;38:e164. https://doi.org/10.1093/nar/gkq603
19. Cancer Genome Atlas N. Genomic Classification of Cutaneous Melanoma. Cell. 2015;161:1681-96.
20. Komminoth P. The RET proto-oncogene in medullary and papillary thyroid carcinoma. Molecular features, pathophysiology and clinical implications. Virchows Archiv : an international journal of pathology. 1997;431:1-9. https://doi.org/10.1007/s004280050062
Smith, Brent J. Jr; Hintzsche, Jennifer D.; Amato, Carol M.; Tan, Aik-Choon; Wells, Keith R.; Applegate, Allison J.; Gonzalez, Rita T.; Barr, Jodie R.; and Robinson, William A.
"Systematic Analysis of Whole Exome Sequencing Determines RET G691S Polymorphism as Germline Variant in Melanoma,"
Marshall Journal of Medicine:
2, Article 10.
Available at: https://mds.marshall.edu/mjm/vol3/iss2/10