NEW YORK (GenomeWeb) – In Nature Genetics, an international team led by investigators in Canada and the UK describes the distinct cancer development trajectory detected in tumors from children with an inherited cancer susceptibility syndrome called biallelic mismatch repair deficiency (bMMRD).
The bMMRD condition stems from inherited mutations affecting one of four genes in the mismatch repair pathway, researchers explained. And their genome sequencing, exome sequencing, and array-based analyses of tumor and/or blood samples from dozens of children with bMMRD suggest that this condition can lead to extreme hypermutation — what they dubbed "ultra-hypermutation" — when paired with somatic driver mutations affecting the proofreading skills of DNA polymerase enzymes.
By analyzing the mutation signature in these tumors and tracking mutations in biopsy samples collected by a subset of patients over time, the team determined that cancers with impaired mismatch repair and polymerase proofreading develop through an explosion of substitution mutations. Those glitches arise rapidly, and the results suggest they tend to peak at around 20,000 coding mutations per tumor, perhaps pointing to a mutation load ceiling for cancer cell survival.
"The ultra-hypermutated phenotype occurs rapidly and is limited to substitutions, making it distinct from other tumors which carry a variety of mutation types that typically accumulate in a slow and stepwise manner to provide sufficient clonal advantage," members of the Biallelic Mismatch Repair Deficiency Consortium wrote, noting that the bMMRD/polymerase-mutant cancers "suggest a new and unique mechanism for cancer initiation."
Using samples collected by the consortium and housed at a Hospital for Sick Children tumor bank, the researchers did genome sequencing, exome sequencing, and array-based copy number analysis on 17 tumor samples from a dozen individuals with bMMRD. They also considered exome or genome sequences from 18 bMRRD patients' non-neoplastic tissue samples.
The team's analysis uncovered overwhelming mutation rates in the 10 malignant brain tumors included in the study.
Whereas most pediatric cancers exhibit 0.61 mutations per million bases, on average, the bMMRD brain tumors contained an average of 249 mutations for every million bases, or roughly 7,911 protein-coding mutations apiece.
Point mutations were peppered across the brain tumor genomes. But other alterations typically found in pediatric brain tumors — particularly copy number changes and microsatellite instability — were largely absent from the malignant brain tumors in bMMRD patients.
The non-neoplastic bMMRD samples had variant profiles that resembled those in unaffected controls, pointing to protection by intact polymerase proofreading systems in these cells. But that was not the case in the brain tumors, where researchers consistently saw somatic mutations affecting either the polymerase epsilon gene POLE or the polymerase delta gene POLD1.
With the help of clinical samples collected sequentially from bMMRD/POLE brain cancer samples, the study's authors determined that such tumors develop through rampant and rapid mutation, with hundreds of new mutations arising each cell cycle.
"Once the proofreading ability of the DNA polymerases are lost in a mismatch repair-deficient cell," they wrote, "There is no defense against a rapid and catastrophic accumulation of point mutations."
"Ultra-hypermutated cells mutate continuously, potentially generating multiple independent subclones, until confronting a threshold," the team continued. "The high mutation load and threshold may be this cancer's Achilles' heel, exploitable for therapeutic intervention."