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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
N Engl J Med. Author manuscript; available in PMC Nov 25, 2013.
Published in final edited form as:
PMCID: PMC3839666
NIHMSID: NIHMS509382
Translocation Affecting Sonic Hedgehog Genes in Basal-Cell Carcinoma
Natalia Gomez-Ospina, M.D., Ph.D., Anne Lynn S. Chang, M.D., Kun Qu, Ph.D., and Anthony E. Oro, M.D., Ph.D.
Stanford University School of Medicine, Stanford, CA
Anthony E. Oro: oro/at/stanford.edu
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).
Figure 1
Figure 1
Clinical, Molecular, and Histologic Findings in a 41-Year-Old Man with Overexpression of the Sonic Hedgehog (SHH) Gene
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
Supplementary Material
Acknowledgments
Supported by a grant (R01AR046786) from the National Institutes of Health.
Footnotes
Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
References
1. Rubin LL, de Sauvage FJ. Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov. 2006;5:1026–33. [PubMed]
2. Develing AJ, Conte FA, Epstein CJ. A Y-autosome translocation 46,X,t(Yq-7q+) associated with multiple congenital anomalies. J Pediatr. 1973;82:495–8. [PubMed]
3. Belloni E, Muenke M, Roessler E, et al. Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nat Genet. 1996;14:353–6. [PubMed]
4. Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature. 2003;423:825–37. [PubMed]
5. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171–9. [PubMed]