Figure 1. Genomic analysis of vismodegib-resistant BCC.
(A) Schematic of the Hh pathway; see Introduction section in main text for details.
(B) Initial response and disease progression of a sporadic BCC from PT12 that metastasized to lung. A red arrow indicates the target lesion in computerized tomography (CT) scans of the chest before treatment (PreRx) and after 4 (showing a decrease in lesion size) and 37 (revealing disease progression) months of vismodegib treatment.
(C) Photographs of two locally advanced BCCs from Gorlin syndrome patient PT10 that initially responded to vismodegib but subsequently relapsed (black arrow) after the indicated length of treatment.
(D) Hematoxylin and Eosin (H&E) stained sections of a locally advanced sporadic BCC from PT09.1 before and after 11 months of vismodegib treatment. Note that the relapsed lesion maintains the histology of the untreated tumor. The scale bar represents 50 μm.
(E) GLI1 and MKI67 expression levels in vismodegib-resistant and normal skin biopsies. Pearson’s correlation coefficient (R) = 0.96. Normalized read counts are shown.
(F) Overview of genetic alterations in Hh pathway genes and TP53 identified in 12 relapsed BCC patients. Germline PTCH1 variants are reported for Gorlin BCCs, whereas only somatic mutations are shown for sporadic BCCs. Two regionally distinct biopsies were obtained upon regrowth of the same initial tumor for PT06, PT08 and PT09. Two separate BCCs developed resistance in PT10. LOH was determined by minor allele frequencies from SNP arrays. Green boxes highlight LOH events followed by copy number gain of the mutant allele. Allele-specific expression was determined by RNA-seq.