Mutationer i genen för SMO som orsakar basalcellscancer och resistens mot SMO-hämmaren vismodegib
Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
Basal cell carcinoma (BCC) is the most common type of skin cancer in Sweden, with about 37 000 new diagnoses every year. The most commonly affected individuals are those with very light skin and bright eyes, as well as blonde or red hair. The primary external risk factor is the exposure to UV-light. BCC is developed in basal cells in the deepest layer of the epidermis and can further be divided into several subtypes. The cancer is slowly growing and rarely metastasizes, although it can be very destructive in local tissue if not treated. It has been identified that a defect hedgehog signalling pathway (Hh) plays an important role in the development of BCC. This pathway is normally active during embryonal development and in adults involved in, for instance, cell proliferation and tissue regeneration. Abnormal activation of Hh leads to intensive cell signalling, resulting in a too large number of transcription factors generating transcription of target genes and protein synthesis, causing tumorigenesis. In BCC, mutations in the receptor protein Smoothened (SMO) are associated with approximately 10% of the abnormal cell signalling. SMO has a characteristic similarity to the G-protein coupled receptors, and is a target for the relatively new (approved 2012 by the FDA) SMO inhibitor Vismodegib, which is a drug developed for treating advanced and metastasizing BCC. Although the drug has only been in use for a few years, unfortunately resistance against it has already been reported in a number of patients treated. Mutations in the gene for the protein SMO have been linked to the occurrence of this resistance. In this paper, the mutations in the gene for SMO associated with BCC were investigated, followed by an examination of the mutations causing Vismodegib resistance and their occurrence. A multiple sequence analysis was also made on proteins homologous to SMO to determine if these resistance mutations were novel to SMO. The results showed that 42 mutations were associated with BCC and 18 mutations associated with Vismodegib resistance. Out of these mutations (42 and 18 respectively) 14 were common, indicating that Vismodegib likely will not have effect in some cases of BCC, where the cause is SMO-mutations. The occurrence of pre-resistance mutations, in supposedly healthy individuals not exposed to Vismodegib, was found only of three mutations; W281C: with frequency of p=1/120 000, D373N: p=1/20 000, D473H: p=1/48 (of note, due to the small sample size it is likely that this estimation was too high). The multiple sequence analysis showed five resistance mutations (D473Y, D473H, G497W, S533N and W535R) in SMO not having equivalence in structurally similar proteins (245 analysed). This could potentially imply that these mutations are novel for SMO. Four out of these five resistance mutations also occur in the association with BCC, which could mean that these are driver mutations for the cancer. One (D473Y) out of these five was associated only with Vismodegib resistance, potentially being unique in this matter. The relatively high risk of having initial or requiring resistance mutations against Vismodegib raises questions regarding its future, as well as its effect in relation to its very high cost (44 892,08 SEK). Perhaps genetic analysis is a potential tool before starting treatment, to investigate if a patient already carries a resistance mutation. Also, focusing on development of substances against other components in Hh might be the way to go, although Vismodegib most likely has a substantial value in treatment of non-mutated patients in combination with surgical removal of a BCC tumour.
Place, publisher, year, edition, pages
2017. , 26 p.
basalcellscancer, SMO, vismodegib, resistens
Pharmaceutical Sciences Medical Genetics
IdentifiersURN: urn:nbn:se:lnu:diva-61672OAI: oai:DiVA.org:lnu-61672DiVA: diva2:1084264
Subject / course
Bachelor of Science Programme in Pharmacy, 180 credits
Friedman, Ran, Docent
Tågerud, Sven, Professor