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Pair of Studies Link Telomere, Cohesin-related Variants to Myeloma

NEW YORK (GenomeWeb News) – A pair of studies appearing in Nature Genetics yesterday reported on a number of variants linked to myeloma, including a variant located near a gene involved in telomere function and ones linked to the cohesin complex.

While researchers have previously linked a handful of genes to the disease, these two new studies highlight more genes that may be involved in the blood cancer as well as suggest functions that may go awry during the development of the disease.

In one of the new papers, researchers from the UK and Germany described their meta-analysis of nearly 4,700 cases and almost 11,000 controls, through which they identified four risk loci for myeloma.

Previously, the researchers led by Richard Houlston from the UK's Institute of Cancer Research and Hartmut Goldschmidt at the University of Heidelberg had conducted a genome-wide association study examining myeloma cases and controls in a British and German population that uncovered three risk loci. In this new study, they folded in additional German cases and controls and found nine SNPs that appeared to be associated with myeloma.

To validate those findings, the researchers turned to replication sets drawing from both the UK and German populations, totaling some 4,700 cases and 3,700 controls. Of the nine SNPs, four were validated — including risk loci at 3q26.2, 6p21.33, 17p11.2, and 22q13.1.

While some of those loci are within regions that have previously been linked to cancers like Hodgkin's lymphoma or in areas associated with a regulator of B-cell and T-cell function, one loci, rs10936599 at 3q26.2, is within a 250-kilobase linkage disequilbrium distance of the gene TERC, a telomere RNA component gene. In addition, the study authors noted, carrier status for the rs10936599 G risk allele is associated with long telomeres, making this loci "an attractive candidate for multiple myeloma susceptibility."

"We know cancer often seems to ignore the usual controls over aging and cell death, and it will be fascinating to explore whether in blood cancers that is a result of a direct genetic link," Houlston said in a statement. "Eventually, understanding the complex genetics of blood cancers should allow us to assess a person's risk or identify new avenues for treatment."

Meanwhile, the University of Tokyo's Seishi Ogawa and his colleagues turned to exome sequencing to study recurrent mutations in myeloid neoplasms, finding that multiple parts of the cohesin complex were mutated in the disease, as they also reported in Nature Genetics.

Previous work from the group examined whole-exome sequences from 29 tumor-normal pairs from people with myeloma. In that study, while the researchers linked mutations affecting the spliceosome to the disease, they also uncovered a number of other mutations, including one that they subsequently traced to a component of the cohesin complex. Cohesin is involved in a number of cellular processes, including the cohesion of sister chromatids, DNA repair, and the regulation of transcription.

To follow up in this new study on that cohesin connection, the investigators examined nearly 600 myeloid neoplasms for mutations in cohesin or cohesin-related genes through next-gen sequencing. They additionally searched for copy-number changes in those loci in 453 samples. Any known or putative polymorphisms appearing in dbSNP, the 1000 Genomes Project database, or predicted from a number of computational imputations, were excluded from their analysis.

Through this, they identified some 60 mutations in nine genes, which they validated through Sanger sequencing. After validation and evaluation of random mutational events, four genes involved in the cohesin complex — STAG2, RAD21, SMC1A, and SMC3 —appeared to house significant mutations.

Myeloid leukemia cell lines with mutated cohesin, Ogawa and his colleagues found, had reduced levels of chromatin-bound cohesin components. Further, forcing the expression of a wild-type RAD21 gene in a cell line with a mutated cohesin or decreased expression of cohesin components led to the suppression of growth.

"These findings suggest a role for comprised cohesin functions in myeloid leukemogenesis," the researchers wrote. "Given the integral functions of cohesin for cell viability, genetic defects in cohesin might be potential targets in myeloid neoplasms," they added.