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Title: Comprehensive molecular profiling of 718 Multiple Myelomas reveals significant differences in mutation frequencies between African and European descent cases}
Article:
Abstract:
Multiple Myeloma( MM) is a plasma cell malignancy with significantly greater incidence and mortality rates among African Americans( AA) compared to Caucasians( CA). The overall goal of this study is to elucidate differences in molecular alterations in MM as a function of self-reported race and genetic ancestry. Our study utilized somatic whole exome, RNA-sequencing, and correlated clinical data from 718 MM patients from the Multiple Myeloma Research Foundation CoMMpass study Interim Analysis 9. Somatic mutational analyses based upon self-reported race corrected for ancestry revealed significant differences in mutation frequency between groups. Of interest, BCL7A, BRWD3, and AUTS2 demonstrate significantly higher mutation frequencies among AA cases. These genes are all involved in translocations in B-cell malignancies. Moreover, we detected a significant difference in mutation frequency of TP53 and IRF4 with frequencies higher among CA cases. Our study provides rationale for interrogating diverse tumor cohorts to best understand tumor genomics across populations.
Introduction:
Multiple Myeloma( MM) is a malignancy of plasma cells provoked by immunoglobulin gene rearrangements, accounting for slightly more than 10% of all hematologic cancer diagnoses in the US[1–3]. Pathogenesis evolves from an asymptomatic premalignant stage of clonal plasma cell proliferation termed “monoclonal gammopathy of undetermined significance”( MGUS)[4, 5]. MGUS is present in more than 3% of the population above the age of 50 and progresses to MM, or related malignancy at a rate of 1% per year[2, 6]. High-levels of pathogenic heterogeneity in MM among distinct racial/ethnic distributions have been outlined by epidemiology[7]. For instance, African American( AA) patients matched for socioeconomics, age, and gender are three times more likely to be diagnosed with MM, and with death rates that double those observed among Caucasians( CA)[4, 8, 9]. In addition, reports have shown that AA have decreased frequency of IgM monoclonal gammopathy, and have an earlier age of onset compared to CA patients[4, 8, 10]. However, over the past decade there were effective improvements in treatments and disease management that contributed to an astonishing increase in overall survival for MM, but these improvements were observed predominantly in CA patients[10, 11]. Therefore, a deeper understanding of oncogenic processes driving MM pathogenesis in statistically powered multi-ethnic cohorts is still needed to addressing disparities in incidence and outcomes observed among AA or otherwise African descent patients. Several previous profiling studies have provided a view of the somatic landscape of MM[12, 13]. However, the representation of tumors from AA has been critically limited. To date, only one study has been reported comparing the frequencies of molecular alterations in MM between AA and CA cases[14]. This study revealed lower frequencies of IgH translocations by Fluorescence In Situ Hybridization among AA[14]. Although seminal, the small sample size of tumors from AA, lack of coding mutation data, and incomplete access to clinical data represented limitations of this study[14]. Recently, a comprehensive longitudinal study( CoMMpass) was initiated with the overall goal to prospectively observe the natural history of MM through comprehensively profiling 1, 000 MM cases at diagnosis, with multiple biological and clinical follow-up points throughout the course of clinical management. Genomic profiling includes whole exome sequencing of germline and MM tumors, low pass whole genome sequencing, and RNA sequencing of tumors. Data are publicly distributed as Interim Analyses throughout the course of the study. Interim Analysis 9( IA9) includes whole exome sequencing( WES) data from bone marrow tumor extracts with matching normal from 796 newly diagnosed MM cases. Patient ethnicity was one of the demographic parameters collected for each patient that included self-identification categories for African American, Caucasian, Asian, Hispanic, Middle Eastern, Other, Declined, and Unknown. This enabled us to perform genomic analyses to assess potential somatic differences from tumors based upon self-reported race. Alternatively, genetic ancestry is characterized by population genetic informative markers derived from allele frequencies of single nucleotide variances across biogeographical distributions[15] and is another way to characterize populations and individuals. The strength of genetic ancestry is that it offers information on ancestral genetic contributions based upon percent admixture within a given individual. While genetic ancestry provides molecular information with direct biological implications within the context of a disease[16, 17], we cannot disregard the importance of self-reporting that is influenced by socio-environmental behaviors that also play a critical role in disease risk. Most MM studies to date have been based upon self-reported race information. However, the availability of self-reported race and WES data from CoMMpass IA9 provided the unprecedented opportunity to search for novel and statistically significant somatic alterations relative to ancestrally-defined population differences in MM cases.
Discussion:
Not surprisingly, the vast majority of our current understanding of MM biology has been derived from data collected from largely European descent cohorts, even given significant disparities in disease incidence and outcomes seen among African American patients[10]. Through the analysis of CoMMpass data, we were able to analyze the largest multi-ethnic MM cohort at diagnosis to date, in an attempt to elucidate in-depth molecular differences in tumors derived from AA and CA cases to further understand the biological determinants of MM as a function of tumors derived from an ancestrally defined dataset. First, the nature of the CoMMpass dataset has allowed us to confirm previously reported results of published clinical and molecular studies of MM. Our study results were similar to previously reported data demonstrating earlier disease onset in MM among African Americans[10]. Furthermore, several MM genomics sequencing studies[12, 24, 25] have been reported in both newly diagnosed and relapse MM and we have validated commonly mutated genes in MM such as KRAS, NRAS, FAM46C, DIS3 and TP53. Differences in mutation frequencies in genes such as RYR1, RPL10, PTCHD3, BCL7A, SPEF2, MYH13, ABI3BP, BRWD3, GRM7, AUTS2, PARP4, PLD1, ANKRD26, DDX17 and STXBP4 that were more common in AA MM cases could possibly reflect differences of myelomagenesis by race and/or ancestry. FAM46C is among the most commonly mutated genes in MM based on several previously reported WES studies[12]. The reported FAM46C mutation frequency in MM ranges from 5%-11%[13, 26], and although the frequency was 8. 3% in Caucasian cases in our study, we observed an increased frequency of 12. 6% in African American cases in our study. Although the functional role of FAM46C in myelomagenesis is still yet to be determined, there seems to be a potential enrichment of its role in MM biology among tumors derived from patients of African ancestry. BRAF mutations have also been reported in MM, generally at frequencies of 2. 8%-5%[27–29]. Although overall BRAF mutation frequencies were not different between AA and CA, we did detect differences when stratifying specifically by BRAFV600E, with higher frequencies seen in CA( 4%) as compared to AA( 0. 8%), although this differenece did not exceed nominal significance due to limited power. Furthermore, we did not observe a difference in overall survival in primary MM cases harboring any BRAF mutation, nor specifically BRAFV600E mutation compared to BRAF wildtype cases( p = 0. 439, p = 0. 579; Long-rank, Gehan-Breslow-Wilcoxon). These results are of clinical consequence as BRAF mutations, particularly BRAFV600E, can be targeted with select BRAF inhibitors, which has shown effect in mutation positive MM cases[27, 29]. Three of the genes with significantly higher mutation frequency in AA are involved in other B-cell malignancies. BCL7A has been shown to be directly involved in a three-way gene translocation with Myc and IgH in high-grade B-cell non-Hodgkin lymphoma cell lines[30]. As a result of the gene translocation, the N-terminal region of the gene product is disrupted, which is thought to be related to the pathogenesis of a subset of high-grade B cell non-Hodgkin lymphoma[30]. The protein encoded by BRWD3 is a bromodomain and WD repeat containing protein that is thought to have chromatin-modifying function, and may play a role JAK/STAT pathway activity[31]. Importantly, this gene is involved in translocations in B-cell chronic lymphocytic leukemia[32]. Finally, AUTS2 is involved in translocations with PAX5 in B-cell precursor acute lymphoblastic leukemia and other cancers[33]. These findings are of considerable interest, and further validation and functional characterization of these genes in appropriate myeloma model systems could shed light on their potential role in myelomagenesis particularly in patients of African descent. Another significant observation of our study was the difference in TP53 mutation frequency among patients with higher European admixture in our dataset. Integrated mutation and copy number analysis demonstrated a trend towards higher TP53 bi-allelic inactivation in tumors derived from CA cases. This could have translational significance as bi-allelic TP53 inactivation is a universally validated predictor of poor outcome[34]. We further detected significant differences in IRF4 mutation frequency, which was also higher among CA MM cases. IRF4 is a credentialed MM oncogene, which is known to be an oncogenic fusion partner in MM, and is also among the known significantly mutated genes in MM[35, 36]. Moreover, IRF4 activity is associated with poor outcome, with potential therapeutic implications for immunomodulatory agents in MM[37, 38]. These data suggest that the significant enrichment of IRF4 mutations in CA cases could have strong clinical translational implications. Although the collection of longitudinal clinical data is ongoing for CoMMpass, one current limitation of this study is the limited long-term follow-up data from IA9. However, the CoMMpass study design will allow us to assess outcomes longitudinally, along with molecular profiles of both newly diagnosed and relapse disease in upwards of 1, 000 MM cases. Ultimately, our study represents among the most comprehensive( WES and RNAseq) genomics studies of a tumor type in patients of African descent, and sheds light on potential ancestry-related differences in biological mechanisms of myelomagenesis. Three genes that are known to be involved in B-cell malignancy translocations represent new candidate myeloma genes that may have been overlooked because of the lack of AA cases in most large genomic efforts. It is clear that there are molecular differences between MM tumors from AA and CA cases, and that it is absolutely critical to continue to delineate these observations to better improve clinical management of the disease. As the CoMMpass study matures, it will allow scientists to validate these findings as well as expand on studies such as recurrence, better elucidation of driving mutations, and clonal evolution during the course of treatment.
This study represents the largest comprehensive molecular analysis of ethnically defined newly diagnosed treatment naïve Multiple Myeloma ( MM ) . We revealed significant differences in mutation frequencies for important cancer genes between AA and CA MM . This study provides support for interrogating diverse tumor cohorts to best understand tumor genomics across populations .