Pathogenic TP53 Gene Mutations Linked With Aggressive Prostate Cancer

By Lorraine L. Janeczko

December 28, 2021

NEW YORK (Reuters Health) - Men with inherited pathogenic variants in the TP53 gene are at elevated risk for aggressive prostate cancer, a new study suggests.

"Men who are known to carry these gene mutations should be considered for prostate cancer screening," Dr. Colin C. Pritchard of the University of Washington, in Seattle, told Reuters Health by email. "However, men with known TP53 inherited mutations are not currently routinely screened for prostate cancer and are at risk of dying of this potentially preventable disease."

As reported in European Urology, Dr. Pritchard and his colleagues investigated the incidence of prostate cancer in the inherited condition Li-Fraumeni syndrome (LFS), which can arise due to TP53 mutations.

They analyzed data on men for whom genetic testing confirmed heterozygous TP53 pathogenic variant or obligate carrier status within a family. For all the men with LFS, they collected dates of genetic testing, prostate cancer diagnosis, or latest follow-up or death.

The researchers created a cohort of 6,850 men from four large series of prostate-cancer patients who had undergone tumor or tumor/germline sequencing. Among the 163 men with LFS from 132 families, they identified 31 who had prostate cancer. Of the 117 men with LFS who did not have prostate cancer at the time of genetic testing, six were diagnosed with the disease over a median of three years, indicating a 25-fold increased risk of prostate cancer (P<0.0001).

The researchers identified the pathogenic TP53 variant in 38 of the 6,850 (0.6%) men with prostate cancer, representing a risk 9.1-fold higher than that of the population controls (P<0.0001).

Among the men with pathogenic TP53 variant prostate cancer, the median age at diagnosis was 56 years, 44% had Gleason scores of 8 or higher, and 29% had advanced disease at diagnosis.

"Our hope is that new prostate cancer screening guidelines will be developed for men with inherited TP53 mutations (Li-Fraumeni syndrome). In addition, our findings may result in more men getting genetic testing for inherited TP53 mutations," Dr. Pritchard said. "Our findings may also impact prostate cancer treatment because inherited TP53 mutations are associated with toxicity to radiation therapy."

"A strength of our study is that we looked at the question from a number of different angles, and in the setting of a large multi-institutional collaboration, while a weakness is that the populations we studied were subject to bias," Dr. Pritchard noted. "For example, in our prostate cancer patient cohort, many men had genetic testing for cause, so there was going to be bias in the mutation prevalence estimate related to family cancer history."

"Nonetheless," he added, "the magnitude of the effect we observed, with an over 20-fold increased risk of prostate cancer in TP53 mutation carriers, and finding inherited TP53 mutations almost 10 times higher in men with prostate cancer compared to the general population, make us confident in the overall results."

Dr. Otis W. Brawley, a professor of oncology at the Johns Hopkins University School of Medicine and the associate director of community outreach and engagement at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, called this "a well-done study with a who's who of cancer molecular biology."

"The number of families worldwide with Li-Fraumeni syndrome is estimated to be about 1,000. The number with attenuated LFS is unknown and hard to identify," Dr. Brawley, who was not involved in the study, told Reuters Health by email. "The usefulness of (the new findings) to the clinician right now is very limited."

"I do not see immediate effect on patient care," he added. "Possibly, it will help develop better genomic predictors of aggressive vs. less-aggressive prostate cancer."

SOURCE: European Urology, online December 1, 2021.