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GWAS Yields Locus Linked to Multiple Myeloma Survival

NEW YORK (GenomeWeb) – An international team led by investigators in the UK, US, and Germany reported online today in Nature Communications that it has identified a germline locus with apparent ties to survival in individuals who develop multiple myeloma.

Through a genome-wide association study involving nearly 3,300 individuals with multiple myeloma from four cohorts, including 1,200 individuals who died from the disease, the researchers narrowed in on an overall survival-associated locus on chromosome 6. A handful of SNPs at other sites in the genome showed more tenuous ties to survival times.

"Our findings support the hypothesis that germline variation influences outcome following treatment of [multiple myeloma]," corresponding and co-senior author Richard Houston, a molecular pathology, genetics, and epidemiology researcher at the Institute of Cancer Research, and colleagues wrote.

While encouraged by the results, they noted that "trials larger than ours are required to identify additional loci associated with [overall survival]."

The researchers began by assessing variant patterns at millions of SNPs — which were genotyped with Illumina Human OmniExpess-12 arrays or imputed using information from the 1000 Genomes Project and UK10K database — in 3,256 multiple myeloma patients.

Their analysis led to a chromosome 6 region containing eight suspicious SNPs. The strongest association involved a SNP called rs12748648, which coincided with overall survival in a manner independent of patients' age, sex, and tumor staging.

Because treatment differed somewhat between cohorts, the team also looked at outcomes for those with or without the SNP within each of the studies considered. In each cohort, multiple myeloma patients received autologous cell transplant, though transplants were tandem at some sites and sometimes given with induction and/or consolidation therapy.

Despite such differences, the researchers saw associations between rs12748648 and overall survival for individuals in all four cohorts.

In individuals from the UK-My9 study who had two copies of guanine at this site, for example, they saw a median overall survival time of 26.7 months. In contrast, the presence of two adenine bases was associated with 60 months median survival in that cohort.

The team saw similar patterns in patients from the other studies as well: in a German study, individuals with the GG genotype showed an average overall survival time of nearly 43 months compared to 92 months for those with the AA genotype.

Survival in a US study came in at 80 months, on average, for those homozygous for guanine at rs12748648, but stretched to 137 months in adenine homozygous individuals.

Houston and colleagues noted that the same chromosome 6 locus was previously implicated in coronary heart disease and late-onset Alzheimer disease risk, though the variants associated with those conditions are not in linkage disequlibrium with the survival-associated SNP identified in the current study.

Instead, rs12748648 showed linkage disequilibrium with variants in non-coding sequences between the MTHFD1L and AKAP12 genes. While the researchers did not detect rs12748648-related expression shifts for those or other genes in the region, the riskier version of the allele did appear to coincide with diminished MTHFD1L and AKAP12 methylation.