Shared genomic segment analysis in a large high-risk chronic lymphocytic leukemia pedigree implicates CXCR4 in inherited risk.

AIM: Chronic lymphocytic leukemia (CLL) has been shown to cluster in families. First-degree relatives of individuals with CLL have an ~8 fold increased risk of developing the malignancy. Strong heritability suggests pedigree studies will have good power to localize pathogenic genes. However, CLL is relatively rare and heterogeneous, complicating ascertainment and analyses. Our goal was to identify CLL risk loci using unique resources available in Utah and methods to address intra-familial heterogeneity. METHODS: We identified a six-generation high-risk CLL pedigree using the Utah Population Database. This pedigree contains 24 CLL cases connected by a common ancestor. We ascertained and genotyped eight CLL cases using a high-density SNP array, and then performed shared genomic segment (SGS) analysis - a method designed for extended high-risk pedigrees that accounts for heterogeneity. RESULTS: We identified a genome-wide significant region (P = 1.9 × 10-7, LOD-equivalent 5.6) at 2q22.1. The 0.9 Mb region was inherited through 26 meioses and shared by seven of the eight genotyped cases. It sits within a ~6.25 Mb locus identified in a previous linkage study of 206 small CLL families. Our narrow region intersects two genes, including CXCR4 which is highly expressed in CLL cells and implicated in maintenance and progression. CONCLUSION: SGS analysis of an extended high-risk CLL pedigree identified the most significant evidence to-date for a 0.9 Mb CLL disease locus at 2q22.1, harboring CXCR4. This discovery contributes to a growing literature implicating CXCR4 in inherited risk to CLL. Investigation of the segregating haplotype in the pedigree will be valuable for elucidating risk variant(s).

Mobile element insertions and associated structural variants in longitudinal breast cancer samples.

While mobile elements are largely inactive in healthy somatic tissues, increased activity has been found in cancer tissues, with significant variation among different cancer types. In addition to insertion events, mobile elements have also been found to mediate many structural variation events in the genome. Here, to better understand the timing and impact of mobile element insertions and associated structural variants in cancer, we examined their activity in longitudinal samples of four metastatic breast cancer patients. We identified 11 mobile element insertions or associated structural variants and found that the majority of these occurred early in tumor progression. Most of the variants impact intergenic regions; however, we identified a translocation interrupting MAP2K4 involving Alu elements and a deletion in YTHDF2 involving mobile elements that likely inactivate reported tumor suppressor genes. The high variant allele fraction of the translocation, the loss of the other copy of MAP2K4, the recurrent loss-of-function mutations found in this gene in other cancers, and the important function of MAP2K4 indicate that this translocation is potentially a driver mutation. Overall, using a unique longitudinal dataset, we find that most variants are likely passenger mutations in the four patients we examined, but some variants impact tumor progression.

Large-Scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers.

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations useable for CHIP detection by performing a data mining analysis of 48 somatic mutation studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with hematologic malignancies. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole exome sequencing data from 4,538 persons belonging to three non-cancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in children. Our findings may help to improve CHIP detection and pre-cancer surveillance for both children and adults.

The Simons Genome Diversity Project: A Global Analysis of Mobile Element Diversity.

Ongoing retrotransposition of Alu, LINE-1, and SINE-VNTR-Alu elements generates diversity and variation among human populations. Previous analyses investigating the population genetics of mobile element insertions (MEIs) have been limited by population ascertainment bias or by relatively small numbers of populations and low sequencing coverage. Here, we use 296 individuals representing 142 global populations from the Simons Genome Diversity Project (SGDP) to discover and characterize MEI diversity from deeply sequenced whole-genome data. We report 5,742 MEIs not originally reported by the 1000 Genomes Project and show that high sampling diversity leads to a 4- to 7-fold increase in MEI discovery rates over the original 1000 Genomes Project data. As a result of negative selection, nonreference polymorphic MEIs are underrepresented within genes, and MEIs within genes are often found in the transcriptional orientation opposite that of the gene. Globally, 80% of Alu subfamilies predate the expansion of modern humans from Africa. Polymorphic MEIs show heterozygosity gradients that decrease from Africa to Eurasia to the Americas, and the number of MEIs found uniquely in a single individual are also distributed in this general pattern. The maximum fraction of MEI diversity partitioned among the seven major SGDP population groups (FST) is 7.4%, similar to, but slightly lower than, previous estimates and likely attributable to the diverse sampling strategy of the SGDP. Finally, we utilize these MEIs to extrapolate the primary Native American shared ancestry component to back to Asia and provide new evidence from genome-wide identical-by-descent genetic markers that add additional support for a southeastern Siberian origin for most Native Americans.

The evolving genetic risk for sporadic ALS.

OBJECTIVE: To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)-associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity. METHODS: Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls. RESULTS: Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls. CONCLUSIONS: Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates.