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Exome Mutations In Sun-exposed Skin And Basal Cell Carcinoma
Sherry S. Collawn, M.D.,Ph.D., David Crossman, Ph.D., Timothy King, M.D.,Ph.D., Michael Crowley, Ph.D..
University of Alabama, Birmingham, Birmingham, AL, USA.

Exome Mutations in Sun-exposed Skin and Basal Cell Carcinoma
PURPOSE - Basal cell carcinoma (BCC) is the most common non-melanoma skin cancer and occurs more frequently on the nose 1,2. Several tumor suppressor genes and others have been implicated in the pathogenesis of BCC. Known involvement of the Hedgehog pathway, tumor suppressor TP53 and RAS family have been reported and now with advances in sequencing technology other associated mutations have been identified. Many BCCs carry ultraviolet (UV) somatic point mutations. In our study the entire exome was sequenced in non-UV exposed skin, UV exposed skin, and invasive basal cell carcinoma from one patient. We have identified mutations that are unique to non-UV exposed skin, UV-exposed skin, and invasive basal cell carcinoma.
METHODS -The entire genome was sequenced using Agilentís Clinical Research Exome kit and the Illumina NextSeq 500 sequencer. Broadís Genome Analysis ToolKit (GATK) was used to identify the variants. The skin of one patient was examined at 3 sites: UV-exposed, non UV-exposed skin, and invasive basal cell carcinoma for comparison. Examination was performed using a multigene panel including such genes as PTCH 1 and 2 and TP53.
RESULTS - Exome sequencing with informatics reveals 5 mutations unique to BCC, overlap of 1 mutation between BCC and UV-exposed skin, and 3 unique mutations in UV-exposed skin (Figure 1). The three unique mutations in UV-exposed skin are TP53 mutations. One TP53 mutation is in common between BCC and UV-exposed skin. Our previous proteomics on this patient displayed increases in DNA-dependent protein kinase catalytic subunit and basement membrane- specific heparin sulfate proteoglycan in his invasive basal cell carcinoma. This finding correlates with mutations seen in these 2 genes.
CONCLUSIONS - Involvement of TP53 occurs in many cancers. Using exome sequencing three TP53 mutations are associated with UV exposure. There is one TP53 mutation in common between UV-exposed skin and BCC. BCC has 5 specific gene mutations in HSPG2, PRKDC, and ITGB1. The proteins for HSPG2 and PRKDC were increased in this patientís BCC. These mutations and others can be confirmed with sanger sequencing. RNA sequencing can be performed to confirm that there is upregulation of these genes in BCC. In summary, exome sequencing will be useful in the molecular diagnosis of BCC and its subtypes.
Figure 1. Exome sequencing reveals 5 mutations unique to BCC.
1 Rogers, H. W., Weinstock, M. A., Feldman, S. R. & Coldiron, B. M. Incidence Estimate of Nonmelanoma Skin Cancer (Keratinocyte Carcinomas) in the U.S. Population, 2012. JAMA Dermatol 151, 1081-1086, doi:10.1001/jamadermatol.2015.1187 (2015).
2 Choi, J. H., Kim, Y. J., Kim, H., Nam, S. H. & Choi, Y. W. Distribution of Basal cell carcinoma and squamous cell carcinoma by facial esthetic unit. Arch Plast Surg 40, 387-391,
doi:10.5999/aps.2013.40.4.387 (2013).


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