Initial Whole-Genome Sequencing of Plasma Cell Neoplasms in First Responders and Recovery Workers Exposed to the World Trade Center Attack of September 11, 2001

Abstract

Purpose: The World Trade Center (WTC) attack of September 11, 2001 created an unprecedented environmental exposure to known and suspected carcinogens. High incidence of multiple myeloma and precursor conditions has been reported among first responders to the WTC disaster. To expand on our prior screening studies, and to characterize the genomic impact of the exposure to known and potential carcinogens in the WTC debris, we were motivated to perform whole-genome sequencing (WGS) of WTC first responders and recovery workers who developed a plasma cell disorder after the attack.

Experimental design: We performed WGS of nine CD138-positive bone marrow mononuclear samples from patients who were diagnosed with plasma cell disorders after the WTC disaster.

Results: No significant differences were observed in comparing the post-WTC driver and mutational signature landscapes with 110 previously published WGSs from 56 patients with multiple myeloma and the CoMMpass WGS cohort (n = 752). Leveraging constant activity of the single-base substitution mutational signatures 1 and 5 over time, we estimated that tumor-initiating chromosomal gains were windowed to both pre- and post-WTC exposure.

Conclusions: Although limitations in sample size preclude any definitive conclusions, our findings suggest that the observed increased incidence of plasma cell neoplasms in this population is due to complex and heterogeneous effects of the WTC exposure that may have initiated or contributed to progression of malignancy.

Figure 1.

Multiple myeloma genomic driver landscape in the World-Trade Center (WTC) cohort. The prevalence of each genomic driver is compared to that observed in 752 multiple myeloma patients enrolled in the CoMMpass trial with whole exome and low-coverage long-insert whole genome sequencing data available. HRD = hyperdiploid; MGUS = Monoclonal gammopathy of undetermined significance; SMM = smoldering multiple myeloma; MM = multiple myeloma; PCL = plasma cell leukemia. Only fully clonal copy number were reported for the WTC cohort.

Figure 2.

Mutational signature landscape in first responders and recovery workers exposed to the WTC disaster. A) Relative contribution of each mutational signature in the WTC cohort and in a validation set including 110 available WGS from 56 patients. B) Mutational signatures differences between clonal and subclonal CNVs in each case with more than 50 subclonal mutations. The confidence interval of each mutational signature estimate was generated by drawing 1000 mutational profiles from the multinomial distribution, each time repeating the signature fitting procedure (mmsig), and finally taking the 2.5^th and 97.5^th percentile for each signature.

Figure 3.

Timing multi-chromosomal gain events in first responders and recovery workers exposed to the WTC disaster with multiple myeloma and precursor conditions. A) Molecular time estimated for each clonal gain and copy-neutral loss of heterozygosity in the WTC cohort. Blue dots and lines represent the molecular time estimates and the 95% confidence intervals, respectively. Only large chromosomal gains (>1 Mb) with more than 50 clonal single nucleotide variants were considered. B) Absolute timing of each multi-gain event in relation to the WTC attack and the patient’s age at diagnosis for 6 evaluable patients. Dark blue and grey dots represent the first and second multi-gain events, respectively, with 95% confidence intervals. Blue dots represent MGUS diagnosis and red dots represent multiple myeloma diagnosis. The dotted line represents September 11, 2001.