Association of subclonal TP53 deletions with multiple myeloma prognosis

The TP53 gene is a tumor suppressor that maps on chromosome 17 (17p13). In multiple myeloma (MM), 17p deletion (del17p) associates with poor prognosis of disease progression. TP53 deletions are rare at MM diagnosis, but they increase as disease advances and are associated with poor outcomes.

To understand the prognostic value of TP53 subclonal deletions, Vallari Shah from Martin Kaiser’s group at the Institute of Cancer Research, London, UK, and collaborators, studied the association between these deletions and the clinical outcomes of newly diagnosed (ND) MM patients. They used a technique known as MLPA (multiplex ligation-dependent probe amplification), to define a cut-off value of subclonal TP53 deletions that is clinically significant. MLPA can be easily set up in a diagnostic laboratory and, in contrast to iFISH (interphase fluorescent in situ hybridization), it easily allows detection of TP53 deletions in subclones of myeloma cells. The results of the study were published in Blood in October 2018.

Key Data:

• Number of NDMM patients analyzed with MLPA: 1,777
• Normalized cut-off TP53 MLPA value: < 0.8; the prognostic significance of this value was confirmed by:
  • Univariate Kaplan-Meier log-rank testing (P = 6.7 x 10^-15)
  • Cox regression (Wald-test, P = 4.1 x 10^-14)
  • C-statistics
• Number of tumors with subclonal TP53 deletions identified using MLPA < 0.8: 192/1,777 (10.8%)
• Relationship between MLPA value and tumor clonality:
  • MLPA < 0.8 = 10–20% del17p (subclonal)
  • MLPA < 0.6 = ≥ 50% del17p (subclonal)
  • MLPA < 0.5 = 95–100% del17p (fully clonal)
• Patients showed no differences in treatment allocation, key demographics, or induction response, independently of whether they had tumors with TP53 deletions (MLPA < 0.8) or not
• TP53 deletions associated with features of advanced disease: reduced platelet counts (150 x 10⁹/L, P = 5.1 x 10^-4) and poorer performance status (WHO ≥ 2, P = 0.0012)
• One hundred and ninety-two tumors with TP53 deletions were further divided into three groups, and each one of those independently associated with shorter overall survival (OS)
• Subclonal: MLPA ≥ 0.7 < 0.8; n = 67; hazard ratio (HR), 1.8; 95% confidence interval [CI], 1.2–2.8, P = 0.01
  • Intermediate clonal: MLPA ≥ 0.55 < 0.7; n = 64; HR, 2.9; 95% CI, 1.9–4.4, P = 5.6 x 10^-7
  • Clonal: MLPA < 0.55; n = 61; HR, 2.2; 95% CI, 1.4–3.2, P = 0.0002
• Clonal, but not subclonal, TP53 deletion was associated with:
  • Reduced platelet count < 150 x 10⁹/L (35% vs 9%, P = 0.00047)
  • High LDH level > 300 U/L (57% vs 32%, P = 0.012)
  • Higher rates of del(13q) (68% vs 40%, P = 0.002) and/or del(1p) (21% vs 4%, P = 0.006)
• Homozygous TP53 deletion rate was low (0.6%) and associated with a median OS of 22.4 months (HR, 3.7; 95% CI, 1.5–8.9, P = 0.004)
• Exome sequencing of 422 MLPA-studied tumors revealed 2.4% bi-allelic TP53 loss-of-function (mutation and deletion) and 11.1% mono-allelic loss. Bi-allelic and mono-allelic loss- of-function were associated with poor OS.

Conclusions

Subclonal TP53 deletions can be useful prognostic markers in MM and can be detected in a prognostic laboratory with the use of the MLPA assay.