Confirmation of the Reported Association of Clonal Chromosomal Mosaicism with an Increased Risk of Incident Hematologic Cancer

<div><p>Chromosomal abnormalities provide clinical utility in the diagnosis and treatment of hematologic malignancies, and may be predictive of malignant transformation in individuals without apparent clinical presentation of a hematologic cancer. In an effort to confirm previous reports of an association between clonal mosaicism and incident hematologic cancer, we applied the anomDetectBAF algorithm to call chromosomal anomalies in genotype data from previously conducted Genome Wide Association Studies (GWAS). The genotypes were initially collected from DNA derived from peripheral blood of 12,176 participants in the Group Health electronic Medical Records and Genomics study (eMERGE) and the Women’s Health Initiative (WHI). We detected clonal mosaicism in 169 individuals (1.4%) and large clonal mosaic events (>2 mb) in 117 (1.0%) individuals. Though only 9.5% of clonal mosaic carriers had an incident diagnosis of hematologic cancer (multiple myeloma, myelodysplastic syndrome, lymphoma, or leukemia), the carriers had a 5.5-fold increased risk (95% CI: 3.3–9.3; p-value = 7.5×10⁻¹¹) of developing these cancers subsequently. Carriers of large mosaic anomalies showed particularly pronounced risk of subsequent leukemia (HR = 19.2, 95% CI: 8.9–41.6; p-value = 7.3×10⁻¹⁴). Thus we independently confirm the association between detectable clonal mosaicism and hematologic cancer found previously in two recent publications.</p> </div

Summary of characteristics of studies included in the analysis.

1<p>Number of individuals included and analyzed in study;</p>2<p>Predominant ancestral group;</p>3<p>Age at baseline and/or sample collection;</p>4<p>Only phase 1 data included;</p>5<p>Only phase 2 data included.</p

Counts of detected mosaic anomalies by chromosomal location and event type.

<p>Counts of detected mosaic anomalies by chromosomal location and event type.</p

Characteristics of mosaic anomalies.

<p>A) BAF and LRR metrics for mosaic anomalies by estimated copy change from disomic state (red = loss, dark blue = gain, orange = copy neutral loss of heterozygosity. B) BAF and LRR metrics for mosaic anomalies by location (dark blue = interstitial, turquoise = p terminal, pink = q terminal or red = whole chromosome). C) BAF and LRR metrics for mosaic anomalies by type of chromosome (green circle = acrocentric, purple cross = metacentric). D) BAF and LRR metrics for mosaic (red) and non-mosaic (black) anomalies.</p

Comparison characteristics of hematologic cancer cases and individuals without a diagnosed hematologic cancer during study follow-up.

<p>Comparison characteristics of hematologic cancer cases and individuals without a diagnosed hematologic cancer during study follow-up.</p

Kaplan Meier plots of the proportion of individuals remaining without diagnosed A) Hematologic cancer stratified by presence (blue) or absence (red) of a mosaic anomaly or B) Leukemia stratified by presence (blue) or absence (red) of a large mosaic anomaly (>2 mb).

<p>Kaplan Meier plots of the proportion of individuals remaining without diagnosed A) Hematologic cancer stratified by presence (blue) or absence (red) of a mosaic anomaly or B) Leukemia stratified by presence (blue) or absence (red) of a large mosaic anomaly (>2 mb).</p

Mosaic anomalies plotted across chromosome in megabases (mb) by estimated copy change from disomic state (red = loss, dark blue = gain, orange = copy neutral loss of heterozygosity).

<p>The red box around the ideogram represents the region of interest for the plot located below. Chromosome 21 is omitted due to the absence of detected mosaic anomalies on the chromosome. (Note: plots are not drawn to scale).</p

Concordance between power in logistic regression and slope of power curve given by equation 6.

<p>Proportion of scenarios in which observed change in power agreed with predicted slope of chi-square power. The observed change in power is calculated as the sign of the difference of the median likelihood ratio statistic at γca  = 0 and at γca  = 1. 160 parameter values were considered, a subset of the parameter space described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063481#pone-0063481-t001" target="_blank">table 1</a>. 500 realizations at γca  = 0 and at γca  = 1 of each combination were undertaken to find the median likelihood ratio statistics.</p

Empirical power and asymptotic power.

<p>Comparison of empirical power (E) to asymptotic (A) for various <i>γ_ca</i> and <i>R</i> = 1 (solid line), <i>R</i> = 2 (dashed), <i>R</i> = 4 (dotted) at two loci that nominally replicate in the gold standard subset. Power is shown as 20^th percentile of X² statistics over 1000 bootstrapped replicates for empirical graphs or as 20^th percentile of the chi squared distribution for asymptotic graphs, with non-centrality determined from genotypic disease model given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063481#pone-0063481-t002" target="_blank">table 2</a>.</p

Participants by institution and genotyping center in combined gold/silver standard association study.

<p>Abbreviations: MF, Marshfield Clinic Personalized Medicine Research Project; VU, Vanderbilt University BioVU; GH, Group Health/University of Washington Adult Changes in Thought and Alzheimer's Disease Patient Registry; MAYO, Mayo Clinic biobank; CIDR, Center for Inherited Disease Research.</p