bims-lifras 2024-05-05 papers

Issue of 2024–05–05
three papers selected by
Joanna Zawacka, Karolinska Institutet

Cold Spring Harb Perspect Med. 2024 May 01. pii: a041584. [Epub ahead of print]

New Paradigms in the Clinical Management of Li-Fraumeni Syndrome.

Camilla Giovino, Vallijah Subasri, Frank Telfer, David Malkin.

Approximately 8.5%-16.2% of childhood cancers are associated with a pathogenic/likely pathogenic germline variant-a prevalence that is likely to rise with improvements in phenotype recognition, sequencing, and variant validation. One highly informative, classical hereditary cancer predisposition syndrome is Li-Fraumeni syndrome (LFS), associated with germline variants in the TP53 tumor suppressor gene, and a >90% cumulative lifetime cancer risk. In seeking to improve outcomes for young LFS patients, we must improve the specificity and sensitivity of existing cancer surveillance programs and explore how to complement early detection strategies with pharmacology-based risk-reduction interventions. Here, we describe novel precision screening technologies and clinical strategies for cancer risk reduction. In particular, we summarize the biomarkers for early diagnosis and risk stratification of LFS patients from birth, noninvasive and machine learning-based cancer screening, and drugs that have shown the potential to be repurposed for cancer prevention.

DOI: https://doi.org/10.1101/cshperspect.a041584

J Natl Cancer Inst. 2024 May 03. pii: djae102. [Epub ahead of print]

Identification of TP53 germline variants in pediatric patients undergoing tumor testing: strategy and prevalence.

Minjie Luo, Derek Wong, Kristin Zelley, Jinhua Wu, Jeffery Schubert, Elizabeth H Denenberg, Elizabeth A Fanning, Jiani Chen, Daniel Gallo, Netta Golenberg, Maha Patel, Laura K Conlin, Kara N Maxwell, Gerald B Wertheim, Lea F Surrey, Yiming Zhong, Garrett M Brodeur, Suzanne P MacFarland, Marilyn M Li.

BACKGROUND: TP53 alterations are common in certain pediatric cancers, making identification of putative germline variants through tumor genomic profiling crucial for patient management.
METHODS: We analyzed TP53 alterations in 3123 tumors from 2788 pediatric patients sequenced using tumor-only or tumor-normal paired panels. Germline confirmatory testing was performed when indicated. Somatic and germline variants were classified following published guidelines.
RESULTS: In 248 tumors from 222 patients, 284 Tier 1/2 TP53 sequence and small copy number variants were detected. Following germline classification, 73.9% of 142 unique variants were pathogenic/likely pathogenic (P/LP). Confirmatory testing on 118 patients revealed germline TP53 variants in 28 patients (23 P/LP and 5 uncertain significance), suggesting a minimum Li-Fraumeni syndrome (LFS) incidence of 0.8% (23/2788) in this cohort, 10.4% (23/222) in patients with TP53 variant-carrying tumors, and 19.5% (23/118) with available normal samples. About 25% (7/28) of patients with germline TP53 variants did not meet LFS diagnostic/testing criteria while 20.9% (28/134) with confirmed or inferred somatic origins did. TP53 biallelic inactivation occurred in 75% of germline carrier tumors and was also prevalent in other groups, causing an elevated tumor-observed variant allelic fraction (VAF). However, somatic evidence including low VAF correctly identified only 27.8% (25/90) of patients with confirmed somatic TP53 variants.
CONCLUSION: The high incidence and variable phenotype of LFS in this cohort highlights the importance of assessing germline status of TP53 variants identified in all pediatric tumors. Without clear somatic evidence, distinguishing somatic from germline origins is challenging. Classifying germline and somatic variants should follow appropriate guidelines.

DOI: https://doi.org/10.1093/jnci/djae102

Cancer Genet. 2024 Apr 23. pii: S2210-7762(24)00014-0. [Epub ahead of print]284-285 43-47

Clinical management of TP53 mosaic variants found on germline genetic testing.

Abigail Ward, Dana Farengo-Clark, Danielle B McKenna, Anton Safonov, Madeline Good, Anh Le, Lisa Kessler, Payal D Shah, Angela R Bradbury, Susan M Domchek, Katherine L Nathanson, Jacquelyn Powers, Kara N Maxwell.

BACKGROUND: Germline heterozygous TP53 pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). TP53 PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management.
PATIENTS AND METHODS: Retrospective analysis of probands who presented to an academic cancer genetics program with a TP53 PV result on germline genetic testing.
RESULTS: Twenty-one of 125 unrelated probands (17 %) were found to harbor a TP53 PV with VAF<30 % or a designation of "mosaic". A diagnosis of PZM was made in nine (43 %) due to a clinical phenotype consistent with LFS with (n = 8) or without (n = 1) positive ancillary tissue testing. Twelve patients (57 %) were diagnosed with presumed CH (pCH) due to a diagnosis of a myeloproliferative neoplasm, negative ancillary tissue testing, clinical phenotype not meeting LFS criteria, no cancer, and/or no first cancer age<50. Of the 19 patients with biological offspring, nine had either partial or complete offspring testing, all negative.
CONCLUSIONS: Determining the etiology of low VAF TP53 PVs requires ancillary tissue testing and incorporation of clinical phenotype. Discerning PZM versus CH is important to provide optimal care and follow-up.

Keywords: Abnormal clonal expansion; Clonal hematopoiesis; Li Fraumeni Syndrome; Pozt-zygotic mosaicism; TP53

DOI: https://doi.org/10.1016/j.cancergen.2024.04.002