Report of a bi-allelic truncating germline mutation in TP53

Brown, Natasha J; Bhatia, Kanika; Teague, Julie A.; White, Susan; Lo, Patrick; Challis, Jackie; Beshay, Victoria; Sullivan, Michael J.; Malkin, David; Hansford, Jordan R.

doi:10.1007/s10689-018-0087-1

Cited by 6 publications

(4 citation statements)

References 10 publications

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“…23 The fifth report is of homozygous truncating pathogenic variants in a child age 2 years with CPC and rhabdomyosarcoma. 24 In stark contrast, in this study, the proband’s father is homozygous for c.799C > T and presents phenotypically normal at 39 years with no personal history of cancer. By age 50 years, men with LFS have a 68% risk of developing cancer, with an average age of onset at 40 years.…”

Section: Discussioncontrasting

confidence: 55%

Rare TP53 variant associated with Li-Fraumeni syndrome exhibits variable penetrance in a Saudi family

et al. 2018

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Li-Fraumeni syndrome (LFS) is an inherited, autosomal-dominant condition that predisposes individuals to a wide-spectrum of tumors at an early age. Approximately 70% of families with classic LFS have pathogenic variants in the tumor suppressor gene TP53 that disrupt protein function or stability. While more than 70% of pathogenic variants in TP53 are missense variants, the vast majority occur very infrequently, and thus their clinical significance is uncertain or conflicting. Here, we report an extremely rare TP53 missense variant, c.799C > T (p.Arg267Trp), identified in a 2-year-old Saudi proband diagnosed with choroid plexus carcinoma (CPC) and six of his first- and second-degree relatives. CPC is frequently found in families with LFS, and this is the first detailed report of a family with this variant. Intriguingly, the proband’s father is homozygous for TP53 c.799C > T and phenotypically normal at 39 years of age. While loss of TP53 heterozygosity is often observed in tumors from individuals with LFS, homozygous germline TP53 pathogenic variants are rare. Based on our analysis of this single family, we hypothesize that TP53 c.799C > T has low or variable penetrance for LFS, with predisposition to the development of CPC. The observations from this family have furthered our understanding of the phenotypic variability that may be caused by one variant of TP53, even in the same family, and suggest that other factors (genetic and/or environmental) may play a role in mechanism of disease manifestation in LFS.

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Section: Discussioncontrasting

confidence: 55%

Rare TP53 variant associated with Li-Fraumeni syndrome exhibits variable penetrance in a Saudi family

et al. 2018

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“…Twelve patients harbored heterozygous loss of function (LOF) mutations, 6 had heterozygous dominant negative mutations in the DNA binding domain (DBD-DN), one had a heterozygous partial function (PF) mutation and one had a heterozygous gain of function mutation in the DBD domain (DBD-GOF) (Fig.1B). Notably, one patient (4333) presented with a homozygous TP53 frameshift mutation (T18Hfs*26) related to consanguinity12 , and a second (5526B) presented with two distinct TP53 variants at the same base position in addition to a wildtype allele (G105S/G105R/WT), possibly…”

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confidence: 99%

Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis

et al. 2023

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Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 pathogenic variants. Here, we perform whole-genome sequence (WGS) analysis of tumors from 22 patients with TP53 germline pathogenic variants. We observe somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identify near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurs earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, reveal that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising years prior to tumor diagnosis.

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“…One patient diagnosed with an anaplastic embryonal rhabdomyosarcoma (ERMS) at age 5 years, harbored a compound heterozygous genotype with two pathogenic TP53 variants in trans : the hotspot R248Q variant (MAF = 0.29) and a pathogenic splicing variant in intron 5 (MAF = 0.22). Another notable patient, harbored an extremely rare, homozygous truncating TP53 variant and developed two aggressive synchronous primary malignancies ( 59 ).…”

Section: Resultsmentioning

confidence: 99%

Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Subasri

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Kanwar

et al. 2023

Cancer Research Communications

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Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of individuals who fit the clinical definition of LFS harbour a pathogenic germline variant in the TP53 tumour suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers, approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumour detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of LFS patients (n=396) with variant (n=374) or wildtype TP53 (n=22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harboured a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the non-coding genome and methylome to identify inherited epimutations in genes including ASXL1, ETV6 and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in LFS patients with an AUROC of 0.725 [0.633-0.810].

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Report of a bi-allelic truncating germline mutation in TP53

Cited by 6 publications

References 10 publications

Rare TP53 variant associated with Li-Fraumeni syndrome exhibits variable penetrance in a Saudi family

Rare TP53 variant associated with Li-Fraumeni syndrome exhibits variable penetrance in a Saudi family

Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis

Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

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