General MM

Significant differences in gene mutations between patients of African American and Caucasian descent

With precision medicine a clear goal for future treatment strategies, identifying distinct genetic differences that can guide a more tailored treatment approach is critical. However, many of the studies to assess genetic links in Multiple Myeloma (MM) to date have been carried out on Caucasian (CA) populations of European descent, with limited numbers of African Americans (AA). Worldwide statistics for MM tell us that AAs are in fact at a much higher risk of developing MM, with higher morbidity rates, although the biological basis for this is little understood.

In a recent study published in PLOS Genetics by Zarko Manojlovic from the Keck School of Medicine, University of Southern California, whole exome RNA sequencing of 718 MM patients was analyzed and correlated with clinical data to assess key differences between Newly Diagnosed (ND) MM patients of AA and CA descent.

Key Highlights:
  • Data from MM patients (pts) from the Multiple Myeloma Research Foundation (MMRF) CoMMpass study Interim Analysis 9 were analyzed (n = 721)
  • Pts were self-reported as either AA or CA; STRUCTURE was also used for genetic analysis of ancestry, and on this basis 3 cases were excluded, leaving a final dataset of 718 pts: AA = 127 and CA = 591

The data points are given as CA vs AA:

  • Early age of onset (40±49 years) twofold higher for AA: 4.6% vs 11%; (p = 0.004; Fisher's)
  • Late age of onset (70±79 years) was higher for CA: 22% vs 14%; (p = 0.04; Fisher's) 
  • Based on race, age of onset and MM karyotype, no significant differences were observed in overall survival (OS)
  • No statistically significant difference in mean nonsynonymous mutation frequencies: 68 vs 63 (p = 0.574) and no difference in mutational signature
  • Somatic mutational analysis across the entire cohort confirmed common mutated MM driver genes: KRAS, NRAS, BRAF, TP53, DIS3, and FAM46C
  • Genes with Higher mutational frequency in AA: RYR1, RPL10, PTCHD3, BCL7A, SPEF2, MYH13, ABI3BP, BRWD3, GRM7, AUTS2, PARP4, PLD1, ANKRD26, DDX17 and STXBP4
  • FAM46C showed a higher frequency in AA: 8.3% vs 12.6%, though not significant (p = 0.09)
  • No differences in BRAF mutation frequency, but a difference was observed in BRAFV600E mutation, with higher frequency for CA: 4.34% vs 0.8% (p = 0.053; Fisher's)
  • Significantly higher frequency of IRF4 (p = 0.041) and TP53 (p = 0.035) mutations in CA
  • This analysis revealed a TP53 somatic mutation frequency of 6.3% vs 1.6% (p = 0.035)
  • An independent publically available MM somatic whole exome sequencing dataset (n = 205; mixed cohort of NDMM and relapsed MM) was used to verify this finding: TP53 coding mutations = 14/157; 8.9% vs 0/14; 0% (although the low numbers for AA are a limitation)
  • TP53 mutations were found to be strongly associated with European ancestry (>95%) (p = 0.01; Wilcoxon rank-sum test)
  • No statistically significant differences were identified in specific focal copy number events between AA and CA
  • A predominance of bi-allelic TP53 events among CA was found but was not statistically significant
  • No difference in overall survival (OS) in MM patients with tumors demonstrating mono-allelic events (loss of copy, or mutation only) and wild-type TP53

This is the first study to examine such a large cohort specifically for race-related genetic differences in MM and confirms several findings from previous studies, including an earlier age of onset for AA patients and a list of commonly mutated genes, with differences apparent between patients of different descent. In particular, FAM46C has been linked to other tumors in patients with African ancestry. The link with decreased survival in patients harboring the BRAFV600E mutation, and a higher frequency in CA, is also of note, as patients with this mutation can be treated specifically with BRAF inhibitors. Interestingly, three genes identified as having a higher mutational frequency in AA: BCL7A, BRWD3, and AUTS2, have also been linked with other hematological malignancies and are now new candidate genes for MM studies, possibly overlooked due to lower numbers of AA pts in previous studies. Finally, the differences between AA and CA in TP53 and IR4 mutation frequency were striking, with patients of European ancestry six times more likely to have mutations in TP53. Both genes have been linked with poorer survival, which does not tally with what is observed in MM – that AA patients have poorer survival, indicating that other factors may be at play. Ultimately, this beckons further studies to clarify specific genetic links and the underlying biological basis.

 
References
  1. Manojlovic Z. et al. Comprehensive molecular profiling of 718 Multiple Myelomas reveals significant differences in mutation frequencies between African and European descent cases. PLoS Genet. 2017 Nov 22;13(11):e1007087. DOI: 10.1371/journal.pgen.1007087.
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