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Synchronous Colorectal Cancers Contain Distinct Mutations, Coincide With Inherited Immune Mutations

NEW YORK (GenomeWeb) – Mutational patterns frequently differ from one tumor to the next in individuals who develop more than one primary colorectal cancer (CRC) at once, according to a study published online today in Nature Communications.

Researchers from the UK and Italy used exome sequencing to profile mutational patterns in 20 tumors from 10 individuals with so-called synchronous CRCs, which form in different sites at roughly the same time. They also considered germline genotype patterns in the synchronous CRC patients to search for potential CRC risk factors.

Their results suggest that synchronous CRC tumors from the same individuals typically contain distinct sets of driver and other mutations, though the individuals afflicted with these multiple primary tumors tend to be genetically prone to inherited alterations affecting immune-related genes.

"Currently, colorectal cancer patients with synchronous tumors receive the same type of treatments as other cancer patients, but we now know that each of their multiple cancers are likely to respond to therapy and develop resistance in a different way. Therefore, their treatment should be tailored accordingly," senior author Francesca Ciccarelli, a cancer studies researcher at King's College London, said in a statement.

The researchers focused on two tumors apiece from 10 individuals who had at least two primary CRC tumors resected within six months or less — representing the synchronous CRCs that occur in roughly two to five percent of CRC cases. The patients considered in the analysis included individuals affected by cancer-predisposing syndromes such as Lynch syndrome, though other cases appeared to be sporadic.

Using Agilent SureSelect kits, they captured protein-coding sequences from the genomes of 19 formalin-fixed paraffin-embedded tumor samples and one fresh frozen sample before sequencing these tumor exomes with Illumina HiSeq 2000 or 2500 instruments. Independent exome libraries were sequenced for eight of the tumor samples, with 81 percent of mutations from separate libraries matching, on average.

When the team compared the tumor exomes from each individual to one another, to exome sequences from matched normal tissue samples, and to data from CRCs profiled for the Cancer Genome Atlas project, it found mutational heterogeneity and clonal representation differences in tumor pairs from the same individuals.

While similar copy number amplifications turned up in tumors from three of the synchronous CRC patients, for example, each had distinct breakpoints suggesting they arose independently, even in tumors from the same individuals.

On the germline side, meanwhile, the researchers noted that individuals with synchronous CRCs seemed to have somewhat higher rates of inherited, rare, damaging mutations affecting genes implicated in conditions such as early-onset inflammatory bowel disease or migraine relative to 406 individuals from TCGA with just one primary tumor or apparently healthy individuals from the 1,000 Genomes Project.

They also saw an over-representation of alterations affecting immune-related genes in cytokine receptor interaction or toll-like receptor signaling pathways, along with shifts in immune T cell populations in the colonic mucosa, assessed by T cell staining, and changes in expression of some immune response-related genes in the synchronous CRC samples from TCGA.

"We still do not know whether the damaging mutations in immune system genes of these patients have a direct effect on the composition of the gut immune cells," Ciccarelli said. "To unravel this aspect, we will do further studies to profile the gene expression pattern of these cells and, in case we find differences with healthy people, this can be used as a biomarker to predict the development of synchronous tumors."