TP73

Overview

TP73 encodes p73, a structural and functional homologue of TP53 with roles in apoptosis, cell-cycle regulation, and differentiation. Unlike TP53, TP73 is rarely mutated by point mutation in cancer; instead it is subject to genomic rearrangements that produce N-terminally truncated isoforms (ΔNp73) with dominant-negative activity over both p73 and p53. In small cell lung cancer (SCLC), recurrent intragenic rearrangements produce oncogenic p73Δex2 and p73Δex2/3 isoforms.

Alterations observed in the corpus

  • Recurrent intragenic genomic rearrangements (breakpoints in introns 1, 2, and 3) producing dominant-negative N-terminally truncated isoforms p73Δex2 and p73Δex2/3 in 7% of SCLC cases (8/110); total TP73 alteration rate (mutation or rearrangement) 13% PMID:26168399
  • One tumour had genomic exclusion of exon 10; p73Δex2/3 confirmed not to be a natural splice variant — found only in cases with genomic rearrangements PMID:26168399
  • Mutations in TP73 were largely mutually exclusive with CREBBP, EP300, RBL1, RBL2, and NOTCH-family genes, suggesting overlapping pro-tumorigenic functions PMID:26168399

Cancer types (linked)

  • SCLC: TP73 rearrangements occur in 13% of SCLC; mutations were NOT significantly associated with overall survival, total mutation number, or other clinical parameters PMID:26168399

Co-occurrence and mutual exclusivity

  • Mutually exclusive with CREBBP, EP300, RBL1, RBL2, and NOTCH-family gene inactivation in SCLC, implying convergent oncogenic function PMID:26168399

Therapeutic relevance

  • The N-terminally truncated p73 isoforms produced by rearrangements have dominant-negative activity over wild-type p73 and p53; prior reports suggest therapeutic approaches to restrict p73-dependent tumour growth in vivo may be promising in SCLC, including in Trp53-deficient settings PMID:26168399

Open questions

  • No significant association between TP73 alteration and overall survival or clinical parameters was found in the 110-tumour cohort; larger studies are needed to define prognostic value PMID:26168399

Sources

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