| Gailani MR, et al.55 Gailani MR, Ståhle-Bäckdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. 1996 Set;14(1):78-81.
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1966 |
Experimental (amostra tumoral) |
PTCH1 |
The study showed that most mutations resulted in “truncated” proteins. Scattered throughout the gene, 5 premature “Stop Codon” were found, 3 frameshift mutations. Changes that do not cause truncated proteins - 4 missense mutations and 1 deletion. Mutations typical of sun exposure were found by the action of UVB: C-T substitution at the pyrimidine site, including double base-mutation CC-TT. A C-G transversion mutation in an allele was found in a patient with no history of sun exposure. The PTCH1 gene has tumor suppressor action, a membrane protein with an intracellular portion, but without a mechanism still known. |
| Aszterbaum M, et al.66 Aszterbaum M, Rothman A, Johnson RL, Fisher M, Xie J, Bonifas JM, et al. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J Invest Dermatol. 1998 Jun;110(6):885-8.
|
1998 |
Experimental (tumor sample and blood) |
PTCH1 |
The PTCH1 gene has somatic mutations in BCC. Encodes 12 transmembrane protein domains that are receptors of hedgehog ligands. They have an inhibiting function to signal such a pathway. In addition, they perform an inhibitory interaction to membrane SMO proteins (membrane G proteins). In BCC, there are three ways to its genesis: mutation in proto-oncogenes - SMO and SHH (expression increase) and/or mutation with inactivation of the PTCH1 tumor suppressor gene. Sporadic BCC requires a mutation in both alleles. The mutations found were: frameshift, premature stop codon, characteristic mutations of UVB action - C-T or CC-TT. Most mutations found had, as a consequence, truncated proteins, especially in the extracellular loop. |
| Zhang H, et al.77 Zhang H, Ping XL, Lee PK, Wu XL, Yao YJ, Zhang MJ, et al. Role of PTCH and p53 genes in early-onset basal cell carcinoma. Am J Pathol. 2001 Fev;158(2):381-5.
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2001 |
Experimental (Lesion sample in patients under 30 years of age) |
PTCH1 |
As mutações encontradas foram: mudança simples de nucleotídeos, inserção de AT e deleção de 15-bp. Nucleotídeo alterados característicos de UVB C-T ou CC-TT tiveram grande prevalência no sítio da pirimidina. Na amostra somática encontradas mutações - nonsense, missense, deleção e inserção - todas com terminação prematura da proteína. Mutação do PTCH1 altera duas grandes proteínas extracelulares - loops e 12 domínios transmembranas de ligação da via hedgehog. Indivíduos jovens com mesmas alterações que indivíduos idosos, apresentam alterações em suas capacidades de reparo de DNA - p53, além de mutações no PTCH1. |
| Maglic D, et al.88 Maglic D, Schlegelmilch K, Dost AF, Panero R, Dill MT, Calogero RA, et al. YAP-TEAD signaling promotes basal cell carcinoma development via a c-JUN/AP1 axis. EMBO J. 2018 Set;37(17):e98642.
|
2018
|
Experimental (tumor sample and blood) |
PTCH1 |
The main change caused by mutations in BCC development occurs in the hedgehog pathway, in its regulators - PTCH1 receptor, SMO (coupled G protein). Mutations instill the repressive function of PTCH1, releasing THE and promoting the growth factors of intranuclear GLI. BCCs that do not respond to MOS inhibitors escape such mutation at the drug binding site in THE OR with potentiation of GLI signaling. Hippo signaling is also related to the BCC. The hippo pathway outside the hedgehog acts through the YAP, but not the TAZ, to initiate the progression of the BCC, acting in JNK-JUN (phosphorylation) signaling; there is no impact on wnt or hedgehog. YAP works on wound healing, rapid recovery of basal cells and epidermis regeneration. There’s an increase in nuclear YAP in the BCC. YAP-TEAD-AP1 interaction is required for the initiation and maintenance of BCC. This pathway may be the cause of resistance to SMO inhibitors. |
| Smyth I, et al.99 Smyth I, Narang MA, Evans T, Heimann C, Nakamura Y, Chenevix-Trench G, et al. Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene in basal cell carcinoma and medulloblastoma on chromosome 1p32. Hum Mol Genet. 1999 Fev;8(2):291-7.
|
1999
|
Experimental (tumor sample and blood) |
PTCH2 |
Tumor suppressor gene homologous to PTCH1 located on chromosome 1. Presence of splice mutation at the donor site of the gene in BCC in exon 20. Not found in the other germ cells, only in the tumor sample. It has been shown that the inactivation of a PTCH2 allele is related to medulloblastoma and that a splice mutation is present in BCC since it is involved in tumor genesis. |
| Zaphiropoulos PG, et al.1010 Zaphiropoulos PG, Undén AB, Rahnama F, Hollingsworth RE, Toftgård R. PTCH2, a novel human patched gene, undergoing alternative splicing and up-regulated in basal cell carcinomas. Cancer Res. 1999 Fev;59(4):787-92.
|
1999 |
Experimental (tumor sample and blood) |
PTCH2 |
PTCH2 is 57% identical to PTCH1, with significant variation in transmembrane domains 6 and 7. It presents alternative Splice in exons 9 and 10 responsible for the extracellular loop and the transmembrane domains 2 and 3 of the PTCH1 protein structure. PTCH2, similar to PTCH1, acts as a tumor suppressor gene. PTCH2 has a distinct action from PTCH1 since its overexpression cannot compensate for the inactivation of PTCH1. |
| Rahnama F, et al.1111 Rahnama F, Toftgård R, Zaphiropoulos PG. Distinct roles of PTCH2 splice variants in Hedgehog signalling. Biochem J. 2004 Mar;378(Pt 2):325-34.
|
2004 |
Experimental (tumor sample and blood) |
PTCH2 |
PTCH2 presents itself as a target of SHH-N signaling, promoting regulation, but I could not actively inhibit the SMO-M2, in contrast to the PTCH1. PTCH2 is 57% identical to PTCH1, diverging in the transmembrane hydrophilic region between domains 6 and 7. The fact that PTCH1 mutated in BCC cannot be compensated by the overexpression of PTCH2 implies that PTCH2 is related to the PTCH1 pathway, but PTCH2 has a weak inhibiting function when compared to PTCH1. PTCH2 has multiple variants, with ptch2-∆22 being those with clinical importance and a variant that Splice exons 9 and 10 and maintains exons 8 and 11 - junction - PTCH2-∆9,10. PTCH2, in its 3 variants, produce proteins in the cytoplasm - vesicular intracellular. PTCH2 can change the location of moS dispersed in the cytoplasm to a pattern of overlap with PTCH1 or PTCH2. There is the combination of PTCH2 and PTCH1 - they are interacting in 20% of immunoprecipitate analysis. PTCH2 acts in the internalization of the SHH-N. The presence of GLI1 linked to the site in the position between bases 472-463 of the ATG initiation codon demonstrates the direct effect of the signaling SSH on the activation of PTCH2. The inclusion of exons 9 and 10 and the exclusion of exon 22 are necessary for dose-dependent inhibition. PTCH2-∆22 does not decrease its inhibition of MOS when linked to SHH - demonstrating that only PTCH1 presents a ligand-dependent transcriptional response. |
| Fujii K, et al.1212 Fujii K, Ohashi H, Suzuki M, Hatsuse H, Shiohama T, Uchikawa H, et al. Frameshift mutation in the PTCH2 gene can cause nevoid basal cell carcinoma syndrome. Fam Cancer. 2013 Dez;12(4):611-4.
|
2013 |
Experimental (Tumor Sample and Blood) |
PTCH2 |
Germline heterozygosity with a missense mutation in PTCH2 identified in Nevoid BCC Syndrome - there is a frameshift 2-bp deletion (c.1172_1173del CT in exon 9) in PTCH2 creating a premature stop codon - resulting in a truncated PTCH2 protein - p. S391X. No mutations were found in PTCH1, SUFU and SMO in peripheral blood. |
| Friedman E, et al.1313 Friedman E, Gejman PV, Martin GA, McCormick F. Nonsense mutations in the C-terminal SH2 region of the GTPase activating protein (GAP) gene in human tumours. Nat Genet. 1993 Nov;5(3):242-7.
|
1993 |
Experimental (Tumor sample) (Tumor sample) |
RASA1 |
Three different mutations in BCC were found in the C-terminal SH2 of ras-GAP (catalytic domain). Suggest that such mutation results in a dysfunctional domain that has no interaction with modified phosphotyrosine. There is the loss of lysine in the SH2 part, losing interaction with phosphotyrosine, and there is an interaction with amino-aromatic grouping or causing hydrophobicity. Lysine is replaced by glutamate in BCC - altering the phosphotyrosine binding site. ras-GAP acts on the growth factors (e.g., PDGF) - family of tyrosine kinases. The system used to detect DGGE mutations may be flawed and less sensitive. It has no relevant action in BCC - a 50% reduction in GAP activity does not sufficiently increase GTP (guanosine-triphosphate). |
| Xie J, et al.1414 Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, et al. Activating smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998 Jan;391(6662):90-2.
|
1998
|
Experimental |
SMO |
Activation of the SMO gene through somatic SMO missense mutation. This gene is a signaling component of the SHH-receptor complex and provides evidence that the mutation in SMO makes it an oncogene in BCC. Activation of the hedgehog pathway in BCC may result from failure of inhibition performed by PTCH or due to abnormal activation by a mutation in SMO. Found heterozygosity of missense mutation in base pair 1,685 - M1 changing Arg 562 (CGG) to Gln (CAG) - somatic origin, not present in the blood sample. It is hypothesized that the mutated SMO binds with PTCH and causes the inhibition of this cessation in other SMO receptors. Mutant SMO signaling occurs independently of ligands. There is effective signaling in the SHH cascade in the domain of zinc as a transcriptional factor of GLI. This gene is amplified in BCC, and its activity is increased. SMO-M2 is an intrinsic membrane protein; when overexpressed, it only acts on basal cells, with no action on other tissues. SMO is a proto-oncogene, being a target for BCC treatment. |
| Kunstfeld R1515 Kunstfeld R. Smoothened inhibitors in the treatment of advanced basal cell carcinomas. Curr Opin Oncol. 2014 Mar;26(2):184-95.
|
2014 |
Revision |
SMO |
Via hedgehog is identified as a key element for the development of various neoplasms.
Inhibition of SMO is the best way to interfere with the hedgehog pathway. The hedgehog pathway is fundamental in embryonic development and typically becomes silent/inactive in adult tissues. The pathway is initiated by connecting one of the hedgehog ligands - Desert, Indian or Sonic in the PTCH1 transmembrane receiver. In the inactive form, PTCH exerts inhibition in SMO receptors, and no internal signaling occurs. When hedgehog ligands bind in PTCH, a relaxation in inhibition occurs and signaling by SMO begins, regulating the expression and transcription of factors - GLI 1-3. SMO inhibitor drugs: Vismodegib, Sonidegib, BMS-833923 (XLI139), Taladegib. Drugs that do not target MOS: Itraconazole (prevents the accumulation of MOS in the primary eyelash), Vitamin D3 (direct binding to OSS). |
| Zhang H, et al.1616 Zhang H, Sun Z, Liu Z, Song C. Overcoming the emerging drug resistance of smoothened: an overview of small-molecule SMO antagonists with antiresistance activity. Future Med Chem. 2018 Dez;10(24):2855-2875.
|
2018 |
Revision |
SMO |
Hedgehog has importance in embryonic development, control of cell maturation, differentiation and proliferation. In adult tissues is silent, except in maintenance and repair when necessary. The components of Via Hedgehog are 3 HH binders (S, D and I), two 12-transmembrane receptors - PTCH1 and PTCH2, a frizzled receptor of the g-protein class - SMO and 3 factors of the GLI 1-3 transcription cascade. The transduction of HH signaling begins in the primary eyelash - an organelle similar to an antenna that protrudes out of cells. The inhibitory effect of inactive PTCH prevents the translocation of THE to the primary eyelash. The complete GLI2/3 is negatively regulated by the SUFU protein and left in the form of GLI2/3Repressor, and the track signal is off. When HH ligands attach to PTCH1, relax the repression on the SMO and induce the primary eyelash to traffic with MOS. Activated SMO promoters perform GLI2/3FL dissociation from SUFU (GLI2/3R), forming GLI2/3A - activated, inducing GLI2/3A transport to the inside of the nucleus and target transcription triggers of the gene. 80% of BCCs mutate in PTCH1, with no changes in MOS, so they are responsive to MOS inhibitors. Resistance occurs with the missense mutation of The SMO in the Locus D473H - aspartic acid loss. Several mutations at the drug binding site and at the sites with significant affinity reduction for GDC-0449 (vismodegib). There is resistance caused by chromosomal amplification of the GLI2 effector cascade or overexpression of the phosphoinositide-3-kinase signaling pathway. The binding of MOS antagonists induces a conformational alteration in both the transmembrane and extracellular domains, demonstrating how they manipulate the activity of the SMO protein. The D473 mutation causes the loss of hydrogen bonds, reducing affinity to GDC-0449 to SMO. |
| Souza AM, et al.1717 Souza AM, Lopes OS, Liberato AL, Oliveira PJR, Herrero SST, Nascimento ALD, et al. Association between SNPs and loss of methylation site on the CpG island of the promoter region of the smoothened gene, potential molecular markers for susceptibility to the development of basal cell carcinoma in the Brazilian population. Asian Pac J Cancer Prev. 2020 Jan;21(1):25-29.
|
2020 |
Case Study - Retrospective control (Patient samples with BCC and controls) |
SMO |
CpG-SNPs rs375350898 and rs75827493 showed significant association with BCC, and SNP rs75827493 showed a relationship with nodular BCC. Thus, such SNPs have been shown to be potential markers of susceptibility to BCC. The presence of SNPs in the CpG-promoting region of the SMO gene can modify methylation and cause susceptibility to BCC. BCC presents aberrant overregulation of the hedgehog pathway, typically with the loss of PTCH1 and activation of SMO-protein G receptor, resulting in the deregulation of GLI transcription and processes involving cell growth and proliferation factors.
SNPs represent the region of the code that is associated with many diseases. The study of SNPs in promoter and intron regions is important to understand the mechanisms of genetic regulation in carcinogenesis. |
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