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Low-Frequency TP53 Gene Mutations Found in Women With, Without Cancer

NEW YORK – TP53 gene mutations that are typically associated with cancer are also found in samples from healthy individuals, a new study has found.

Researchers are increasingly examining whether liquid biopsy-based approaches to detect cells or DNA shed from tumors can be harnessed as cancer tests. But when researchers from the University of Washington and their colleagues investigated whether duplex sequencing of the TP53 gene could detect ovarian cancer from uterine lavages, they found it could also detect low-frequency TP53 mutations among cancer-free women.

As they reported today in Cell Reports, the researchers uncovered a connection between aging and the development of TP53 mutations that resemble those found in tumors — a finding they said could have ramifications for liquid biopsy-based cancer screening tests.

"The implications of our findings are important as a cautionary message for mutation-based cancer biomarkers," UW's Rosa Ana Risques and her colleagues wrote in their paper. "At the same time as we have shown that highly sensitive [next-generation sequencing] methods are essential for maximal mutation detection, we have also illustrated a substantial specificity challenge related to biology, not technology, the extent of which has been underappreciated."

Risques and her colleagues combined trans-cervical lavage of the uterine cavity with duplex sequencing, an approach they argued would boost collection efficiency and their ability to detect mutations.  Under blinded conditions, they analyzed samples from 10 women with ovarian cancer and 11 controls, and correctly identified ovarian cancer in eight of the 10 cases.

But they noticed low-frequency background TP53 mutations within lavages from all the women, even those who did not have cancer, a finding they confirmed by droplet digital PCR.

This, they noted, indicates that these cancer-associated mutations are not cancer-specific, as they can be found in normal tissue.

The TP53 mutations they found in samples from cancer-free women were not spread randomly across the gene. Instead, they reported that about a quarter of them occurred in a CpG dinucleotide context, even though those dinucleotides make up less that 5 percent of the TP53 coding region, and that mutations were enriched for in the exons that encode the protein's DNA-binding domain. This, they said, indicates the mutations are under positive selection.

Further, these background TP53 mutations strongly resembled ones logged in cancer databases, the researchers reported. Mutations from both groups, they added, were largely missense mutations and enriched in G to A and C to T transitions.

The researchers expanded their cohort to include tissue samples from a neonate who died of a congenital vascular malformation and 101-year-old woman who died of natural causes. TP53 mutations were more frequent in three different tissues tested in the centenarian than in the neonate, they found. They also reported that the types of mutations present also appeared to shift with age, as tissues from the newborn were more likely to harbor C and G mutations, while the centenarian was more likely to have A and T mutations.

Finding cancer-linked mutations in normal tissue isn't unexpected, the researchers noted, but they added that it has implications for using these mutations to screen for disease. In particular, they said that efforts to develop universal liquid biopsy cancer screening tests should move with caution. They suggested that as background mutations accumulate with age that perhaps age-adjusted thresholds could be applied to that screening process to account for their accumulation.

"Our results illustrate that subclonal cancer evolutionary processes are a ubiquitous part of normal human aging, and great care must be taken to distinguish tumor-derived from age- associated mutations in high-sensitivity clinical cancer diagnostics," Risques and her colleagues wrote in their paper.