NBN

Overview

NBN (Nibrin) encodes a key component of the MRE11-RAD50-NBN (MRN) complex, which is central to the DNA double-strand break response and homologous recombination repair. Germline pathogenic variants in NBN are associated with Nijmegen breakage syndrome and elevated cancer predisposition, including lymphoma and breast cancer. In pan-cancer genomics, NBN appears as a germline cancer-predisposition gene at low prevalence across multiple tumor types.

Alterations observed in the corpus

  • Germline pathogenic variant identified as an additional cancer-predisposition finding (<1–1%) in advanced prostate cancer patients undergoing paired germline + somatic profiling via MSK-IMPACT PMID:28825054.
  • DNA-repair PPGM gene enriched in 500-patient MET500 metastatic cancer cohort vs. ExAC controls PMID:28783718.
  • Three LP/PVs in German pediatric cancer predisposition cohort: one homozygous (classical Nijmegen breakage syndrome + T-cell lymphoma) excluded from burden testing; two heterozygous c.657_661del p.(Lys219Asnfs*16) founder-mutation carriers developed hematologic neoplasms without NBS features (burden OR=9.4, p=.021 single-cohort); NBN carriers had 5.8-fold elevated secondary malignancy risk. PMID:29489754

Cancer types (linked)

  • Advanced prostate cancer (mCRPC, metastatic noncastrate, locoregional): rare germline pathogenic variant (<1%) identified in paired germline + somatic profiling PMID:28825054.
  • Pan-cancer metastatic disease: germline PPGM enriched relative to population controls PMID:28783718.

Co-occurrence and mutual exclusivity

  • Co-occurs with other germline DDR pathway alterations (BRCA1, BRCA2, ATM, CHEK2) in the context of the broader HR-deficiency landscape in prostate cancer PMID:28825054.

Therapeutic relevance

  • As an HR pathway gene, germline NBN pathogenic variants may be associated with PARP inhibitor sensitivity by analogy to BRCA1/BRCA2 alterations; not directly validated in this cohort PMID:28825054.

Open questions

  • Clinical actionability of NBN germline variants (vs. VUS) in the context of PARP inhibitor trials remains to be established.

Sources

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