The sonic hedgehog (SHH) signaling pathway plays an essential role during human development, and its dysregulation causes developmental defects such as holoprosencephaly and a variety of human cancers, including basal-cell carcinomas.1 Although mutations in patched homologue 1 (PTCH1) and smoothened homologue (SMO) encoding the receptors PTCH1 and SMO, respectively, are known to predispose to inherited and sporadic basal-cell carcinomas, up-regulation of hedgehog ligands such as sonic hedgehog have been associated with lethal tumors such as pancreatic or lung cancer. Here, we describe a person with overexpression of SHH and widespread and aggressive basal-cell carcinomas.
A 41-year-old man presented with several advanced basal-cell carcinomas on his head, trunk, and all four extremities. He had microcephaly, hypotelorism, a flat nasal bridge (Fig. 1A), and T-shaped incisors (Fig. 1B); these characteristics were suggestive of mild holoprosencephaly. His skin was normal at birth, and the onset of tumors occurred at about 9 years of age (Fig. 1C).
Testing was negative for mutations in PTCH1 and SMO associated with Gorlin’s syndrome. A previous karyotype analysis showed a balanced translocation between chromosomes 7 and Y,2 and this was confirmed. To characterize the molecular characteristics of the translocation breakpoint, we sequenced DNA purified from whole blood with the use of paired-end sequencing (with the Illumina Genome Analyzer II or HiSeq), generating 77 million reads (more than twice the physical coverage of the haplotype). This analysis revealed products indicating a translocation between chromosomes 7 and Y. (The products contained three instances of either a 7–Y junction or a Y–7 junction.)
Using the hg19 human genome reference sequence, we determined that the translocation resulted in the juxtaposition of position 19466894 on the Y chromosome and position 155747671 (the SHH locus) on chromosome 7 (Fig. 1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The translocation fused the middle of the SHH promoter with Y-chromosome sequences, leaving intact 140 kb of regulatory sequences upstream of the SHH transcriptional start site.3 Juxtaposed Y-chromosome sequences derived from the “gene desert” between the azoospermia factor (AZF) regions AZFa and ZAFb, regions thought to contribute to sperm maturation.4 Analysis by means of poly-merase chain reaction confirmed the predicted junctions (Fig. 1D, and Fig. 2 in the Supplementary Appendix).
The translocation explains the mild holoprosencephaly; we suggest that aberrant control of SHH expression resulted in partial loss of SHH expression during development. It also explains the basal-cell carcinomas; we suggest that the mutant promoter drives SHH expression in the skin (Fig. 1E). Indeed, the patient’s tumors expressed higher levels of SHH protein (not shown) and in 5-azacytidine–treated, tumor-derived keratinocytes, significantly higher levels of SHH messenger RNA (Fig. 1F). SHH overexpression in this patient contrasts with the absence of SHH expression in common basal-cell carcinomas described in other patients with PTCH1 or SMO mutations.1 Given his large and aggressive tumor burden, the patient was enrolled in a phase 2 clinical trial (NCT00833417) that is described by Sekulic et al. in this issue of the Journal.5