Sequencing TP53 Mutations in Myeloid Neoplasms

Routine testing for the presence of TP53 mutations in myeloid neoplasms by sequencing will become an important part of routine care as TP53-targeting agents become available, according to a poster presented at the Association for Molecular Pathology (AMP) 2020 Annual Meeting and Expo.¹

“We found that 82% of cases with [TP53 mutations] may be suitable for targeted therapies with these novel [p53-targeted] agents, emphasizing the importance of incorporating sequencing analysis into standard of care for patients with myeloid neoplasms,” the study authors, led by Andres E. Mindiola Romero, MD, wrote in their poster.

Alterations in the TP53 gene are found in about half of all cancers, including hematologic malignancies, and are predictive of poorer survival outcomes. These aberrations most often include missense alterations of p53 due to altered protein structure or folding, or due to decreased thermostability. TP53 gene mutations have historically not been considered to be therapeutically targetable, presenting an unmet need for new therapeutic strategies. As there are now an increasing number of small molecule agents in development that can reactivate missense-altered p53 by stabilizing and/or refolding the p53 core domain, determining which patients may benefit from these novel targeted agents will require detection of TP53 variants.

This poster presented results from the characterization of TP53 mutations in a cohort of patients with myeloid neoplasms at a single institution, Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire.

The study authors evaluated all Illumina TruSight Myeloid Sequencing Panel data from 752 studies performed on blood and bone marrow biopsies from 692 patients obtained between 2017 and 2020.

The next-generation sequencing panel covered 54 genes with frequent oncogenic hotspots in myeloid malignancies. Sequencing was performed on the MiSeq platform. Base-calling and sequence alignment were performed using MiSeq Reporter Software and analyzed on the PierianDx CGW platform.

TP53 gene alterations were evaluated in relation to type, numbers/frequency, neoplasm subtype, and co-mutational profile. Patient diagnoses included confirmed myeloid neoplasms of all types, clonal hematopoiesis of indeterminate potential (CHIP), a few non-myeloid malignancies, and marrow with no evidence of disease.

Of 367 cases with at least one gene variant, 62 had an alteration in TP53. A total of 75 TP53 variants were found, these included missense mutations within the p53 DNA-binding domain (n = 58, 77%), nonsense mutations (n = 2, 3%), frameshift/truncating mutations (n = 8, 11%), and splice-site variants (n = 7, 9%).

In 28 cases, TP53 was the only variant. There were 22 cases with a paired deletion or structural alteration involving chromosome-17p13 as detected by karyotype/fluorescence in situ hybridization (FISH), including 19 of 50 cases with one TP53 alteration and 3 of 12 cases with at least 2 TP53 variants.

A second TP53 variant was the most frequent co-alteration in 12 cases, and co-variants were seen in 16 other genes, with ASXL1, DNMT3A, SF3B1, STAG2, and TET2 being the most frequent (n = 5 each).

Diagnoses of those with TP53 gene variants included de novo acute myeloid leukemia (AML; n = 4), secondary AML (n = 18), therapy-related myeloid neoplasms (n = 6), myelodysplastic syndrome (MDS; n = 18), MDS/myeloproliferative neoplasms (MPNs; n = 5), CHIP (n = 3), and a few non-myeloid neoplasms (n = 8). Of the cases with detectable variants, 58% with TP53-mutant disease were deceased at the time of data collection versus 20% of those with wild-type TP53.

One novel therapy targeted at reactivating mutant p53 that is currently in clinical trials for TP53 mutations in MDS, AML, and other hematologic malignancies is eprenetapopt (APR-246), which reactivates the function of p53. Eprenetapopt has received Breakthrough Therapy, Orphan Drug, and Fast Track designations from the FDA for the treatment of patients with MDS.²

_References

_{1. Mindiola Romero AE, Green DC, Houde BE, Deharvengt SJ, Tsongalis GJ, Loo EY. Characterization of TP53 Mutations in Myeloid Neoplasms for Targeted Therapy. Presented at: virtual Association for Molecular Pathology (AMP) 2020 Annual Meeting and Expo; November 16-20, 2020. Abstract H27.}

_{2. Aprea Therapeutics. Accessed November 16, 2020. https://www.aprea.com/our-pipeline/.}