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Secondary Malignancies Reveal Radiation-Associated Mutation Signatures

NEW YORK (GenomeWeb) – An international team led by investigators at the Wellcome Trust Sanger Institute has characterized somatic mutation signatures found in secondary tumors formed after ionizing radiation treatment.

As they reported in Nature Communications yesterday, the researchers did whole-genome sequencing on tumor and matched normal samples from a dozen individuals with radiation-associated second malignancies. By analyzing the sequences alongside those from hundreds of tumors that had not been exposed to radiation, they found that the radiation-associated tumors were far more prone to balanced inversions or to deletions that were peppered relatively evenly across the genome.

"The main aim of our analyses was to search for tumor-type independent, overarching signatures of ionizing radiation," corresponding author Peter Campbell, a researcher affiliated with the Sanger Institute and the University of Cambridge, and his co-authors wrote. "[W]e identified two such signatures in radiation-associated second malignancies, an excess of balanced inversions and of deletions."

Ionizing radiation — including radiation used for diagnostic medical imaging or cancer treatment — is a known to damage DNA and increase cancer risk, the team noted, though mutation signatures associated with ionizing radiation have not been fully explored in human tissues.

For their new analysis, the researchers focused on 12 individuals who had been treated years earlier for osteosarcoma, spindle cell sarcoma, angiosarcoma, or breast cancer with therapeutic ionizing radiation. The authors cautioned that "in the absence of biomarkers, a diagnosis of a tumor being radiation-induced cannot be definitively made," though these second malignancies can provide clues to radiation-associated tumors.

Using DNA extracted from fresh frozen radiation-associated tumors and matched normal samples for each individual, the team generated 40-fold coverage of the tumor genomes, on average, and 30-fold average coverage of the normal samples.

Though the driver mutations detected in the tumors tended to coincide with individuals' original tumor type, the group noted that small insertions and deletions —deletions, in particular — outnumbered substitutions in the radiation-associated second tumors. And clonal analyses on three tumors supported the notion that deletions may be early radiation-related events.

When they compared the radiation-associated tumor genomes with sequences from 33 breast tumors with pathogenic germline mutations in BRCA1 or BRCA2, 251 other breast tumors, and 35 osteosarcomas that had not been treated with radiation, the researchers also saw an over-representation of balanced inversions — which are typically rare — stretching over hundreds to thousands of bases in the radiation-associated second malignancies.

The team noted that deletions and balanced inversions also appeared to be enhanced in tumor samples from six individuals with metastatic prostate cancer who were treated with radiation, but not in metastatic prostate cancer patients who had not received radiation. One patient had an excess of deletions in a radiation-treated primary tumor that were absent in a metastatic tumor that had formed prior to that treatment.

"Both signatures were present across four different tumor types and could be validated in a cohort of radiation-exposed prostate cancer lesions," Campbell and his co-authors wrote, "despite differences in the biological context of radiation-exposed prostate tumors and radiation-associated second malignancies."

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