DNAJB6

Overview

DNAJB6 encodes a member of the HSP40/DNAJ family of molecular chaperones that assists HSP70 in protein folding and quality control. Germline mutations in DNAJB6 cause limb-girdle muscular dystrophy type D1 (LGMDD1). In medulloblastoma, DNAJB6 has been identified as the partner gene in a somatic structural rearrangement involving the SHH locus, producing a fusion transcript with markedly elevated SHH expression — providing a novel mechanism of SHH pathway activation beyond classical PTCH1, SUFU, or SMO alterations.

Alterations observed in the corpus

  • DNAJB6 is disrupted by a chromosome 7 amplicon in a medulloblastoma case from the ICGC WGS/WES cohort of 76 tumors; the first exon of DNAJB6 is juxtaposed to SHH, creating a DNAJB6-SHH fusion transcript with extremely high SHH expression compared to virtually absent expression in 301 other medulloblastomas, establishing a novel mechanism of SHH pathway activation PMID:22832583

Cancer types (linked)

  • MB (medulloblastoma): Structural rearrangement creating a DNAJB6-SHH fusion driving SHH pathway activation in the SHH subgroup; ICGC WGS/WES cohort (76 tumors) PMID:22832583

Co-occurrence and mutual exclusivity

  • The DNAJB6-SHH fusion is mutually exclusive with PTCH1 and SUFU alterations as alternative mechanisms of SHH pathway activation in medulloblastoma PMID:22832583

Therapeutic relevance

  • Tumors harboring the DNAJB6-SHH fusion drive SHH pathway signaling and may be sensitive to Smoothened (SMO) inhibitors (e.g., vismodegib) or other SHH pathway inhibitors, though upstream vs. downstream efficacy would depend on the mechanism of pathway activation PMID:22832583

Open questions

  • The frequency of DNAJB6 structural rearrangements in larger medulloblastoma cohorts is unknown; this was identified as a single case in 76 tumors, and its broader prevalence in SHH-subgroup medulloblastoma requires validation.

Sources

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