NEW YORK – New research suggests secondary somatic mutations in the NF1 gene may be more widespread than previously appreciated in individuals with germline NF1 variants linked to a multisystem cancer predisposition syndrome called neurofibromatosis type 1, appearing in both tumors and normal, cancer-free tissues from the same individual.
"Individuals with neurofibromatosis are born with one faulty copy of NF1 in every cell of their body and one intact copy," Sam Behjati, a pediatrician scientist and group leader affiliated with the Wellcome Sanger Institute, Cambridge University Hospitals NHS Foundation Trust, and the University of Cambridge, said in an email. "The single intact copy of NF1 suffices for cells to function normally and orderly."
"So, the traditional view has been a second mutation in NF1 turns a cell into a cancer cell," he added. "We now found that this is not the case."
In a paper published in Nature Genetics on Tuesday, Behjati and colleagues from the UK and elsewhere began by analyzing whole-genome or exome sequences representing more than 800 postmortem biopsy samples from three children with high-grade midline glioma, including 479 tissue biopsy samples from one child with neurofibromatosis type 1.
After bringing in another 71 tissue genome sequences and 180 microdissected tissue samples, the team was able to characterize substitutions, small insertions and deletions, rearrangements, and copy number changes within and across the samples, highlighting somatic driver mutations in samples with or without cancer.
Among them were apparent somatic NF1 driver mutations in glioma-affected tissues and in macro- and microscopically cancer-free tissues from outside the central nervous system in the neurofibromatosis type 1 patients that were not found in 610 samples from children without the cancer predisposition syndrome, the authors explained, suggesting that somatic NF1 mutations are not limited to tissues where progression to cancer occurs.
The new results "demonstrate that normal tissues in neurofibromatosis type 1 commonly harbor second hits in NF1," they reported, "the extent and pattern of which may underpin the syndrome's cancer phenotype."
That notion was backed up by the investigators' targeted duplex sequencing analyses on 60 samples from another 21 children with neurofibromatosis type 1, 39 children without the cancer predisposition syndrome, and nine adult cases of neurofibromatosis type 1. In those analyses, they found that truncating NF1 mutations not only appeared in cancer-free tissues but also seemed to be under positive selection in those normal tissues.
"[W]hile it is still true that every neurofibromatosis-related cancer has lost both copies of NF1, our findings show that most cells function perfectly normally without the second copy of NF1 and do not turn cancerous," Behjati said.
"Our work therefore fundamentally changes the question we need to ask about NF1 mutations in neurofibromatosis-related cancers," he explained. "The key question is not how the somatic NF1 mutation turns a normal cell into a cancer but why, in the vast majority of cases, cells can tolerate loss of NF1 without transforming into cancer."
To build on their current findings, the researchers are continuing to unravel the molecular features that distinguish cancer and normal cells containing mutations that affect both copies of NF1 in the hopes of understanding the molecular and cellular contexts that prompt second-hit, somatic NF1 mutations to progress to cancer in specific tissues and circumstances.
"We believe that distilling that difference may hold the key to understanding why a cell does or does not transform into a cancer cell," Behjati explained, noting that the investigators are also starting to look for similar scenarios in other cancer predisposition syndromes.
Because secondary NF1 mutations can be measured and quantified, the study's authors are optimistic that there may be opportunities to better understand, detect, and potentially prevent progression from cancer predisposition to cancer in individuals with neurofibromatosis type 1 in the future.
"[I]t might be that by understanding how cells can tolerate two NF1 mutations without becoming cancer cells, we could devise treatments that stabilize cells without intact NF1 and thus prevent cancer formation," Behjati suggested, though he emphasized that the idea "is very much hypothetical."