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

Light, Nicholas; Layeghifard, Mehdi; Attery, Ayush; Subasri, Vallijah; Zatzman, Matthew; Anderson, Nathaniel D.; Hatkar, Rupal; Blay, Sasha; Chen, David; Novokmet, Ana; Fuligni, Fabio; Tran, James; Borja, Richard de; Agarwal, Himanshi; Waldman, Larissa; Abegglen, Lisa M.; Albertson, Daniel J.; Finlay, Jonathan L.; Hansford, Jordan R.; Behjati, Sam; Villani, Anita; Gerstung, Moritz; Alexandrov, Ludmil B.; Somers, Gino R.; Schiffman, Joshua D.; Rotter, Varda; Malkin, David

doi:10.1038/s41467-022-35727-y

Cited by 16 publications

(13 citation statements)

References 36 publications

(42 reference statements)

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“…Our data suggest that TP53 related breast tumor formation in the germline state requires biallelic loss of TP53 as a first step in tumor formation. This is consistent with data from pediatric tumors in LFS patients 10 which showed that TP53 biallelic loss occurs early in tumor formation. Our comprehensive analysis of oncogenic mutations, copy number changes and mutational signatures further shows that biallelic TP53 loss does not lead to accumulation of single nucleotide variants nor is marked by specific single base pair substitution signatures, likely explaining the absence of other oncogenic mutations in LFS-BC.…”

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

“…This distribution of hormone receptor subtypes along with younger age of onset of BC in LFS patients compared to sporadic BC suggests unique mechanisms of breast tumor formation driven by TP53 PGVs. Indeed, a recent study of pediatric LFS tumors showed that TP53 PGVs are associated with earlier biallelic loss of TP53 compared to sporadic TP53 mutant tumors 10 .…”

Section: Introductionmentioning

confidence: 99%

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Distinct genomic and immunologic tumor evolution in germlineTP53-driven breast cancers

Boruah,

Hoyos,

Moses

et al. 2024

Preprint

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Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of TP53 with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibited a high burden of short amplified aneuploid segments (SAAS). Pro-apoptotic p53 target genes BAX and TP53I3 failed to be up-regulated in LFS-BC as was seen in sporadic BC compared to normal breast tissue. LFS-BC had lower CD8+ T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from in situ to invasive BC was marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Distinct genomic and immunologic tumor evolution in germlineTP53-driven breast cancers

Boruah,

Hoyos,

Moses

et al. 2024

Preprint

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“…TP53 mut are noted to be present long before the eventual development of t-MN—sometimes even before the original exposure to DNA-damaging therapies. Recent evidence suggests a deterministic order of genetic and genomic changes following TP53 mutation/loss [ 36 , 37 ]. A comprehensive characterization of the genomic changes, and its correlation with the resultant morphological changes, may help identify patients at the risk of imminent leukemic transformation and devise effective preventive strategies.…”

Section: Discussionmentioning

confidence: 99%

TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms

et al. 2023

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Revised diagnostic criteria for myeloid neoplasms (MN) issued by the International Consensus Classification (ICC) and the World Health Organization (WHO) recommended major change pertaining to TP53-mutated (TP53mut) MN. However, these assertions have not been specifically examined in therapy-related myeloid neoplasm (t-MN), a subset enriched with TP53mut. We analyzed 488 t-MN patients for TP53mut. At least one TP53mut with variant allele frequency (VAF) ≥ 2% with or without loss of TP53 locus was noted in 182 (37.3%) patients and 88.2% of TP53mut t-MN had a VAF ≥10%. TP53mut t-MN with VAF ≥ 10% had a distinct clinical and biological profile compared to both TP53mut VAF < 10% and wild-type TP53 (TP53wt) cases. Notably, TP53mut VAF ≥ 10% had a significantly shorter survival compared to TP53wt (8.3 vs. 21.6 months; P < 0.001), while the survival of TP53mut VAF < 10% was comparable to TP53wt. Within TP53mut VAF ≥ 10% cohort, the inferior outcomes persisted irrespective of the single- or multi-hit status, co-mutation pattern, or treatments received. Finally, survival of TP53mut patients was poor across all the blast categories and MDS patients with >10% blasts had inferior survival compared to <5%. In summary, TP53mut VAF ≥10% signified a clinically and molecularly homogenous cohort regardless of the allelic status.

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“…Previous studies have shown that TERT promoter and TP53 mutations are among the earliest mutational events in glioblastomas and other cancer (51–53). Our analysis suggested that glioblastoma lesions with high metabolic activity commonly exhibit key driver mutations, particularly in genes such as TERT, NF1, TP53, FLG, SYNE1, and HMCN1, whereas hypometabolic lesions do not.…”

Section: Discussionmentioning

confidence: 99%

Insight into spatial intratumoral genomic evolution in glioblastoma

Anand,

Petersen,

Andersen

et al. 2023

Preprint

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Glioblastoma undergoes a complex and dynamic evolution involving genetic and epigenetic changes. Understanding the mechanisms underlying this evolution is vital for the development of efficient therapeutic strategies. Although treatment resistance is associated with intratumoral heterogeneity in glioblastoma, it remains uncertain whether hypometabolic and hypermetabolic lesions observed through positron emission tomography (PET) imaging are influenced by spatial intratumoral genomic evolution. In this study, we precisely isolated autologous hypometabolic and hypermetabolic lesions from glioblastoma using advanced neurosurgical and brain tumor imaging technologies, followed by comprehensive whole-genome exome and transcriptome analyses. Our findings revealed that hypermetabolic lesions evolved from hypometabolic lesions, harbored shrewd focal amplifications and deletions, and exhibited a higher frequency of critical genomic alterations linked to increased aggressiveness, upregulated APOBEC3 and hypoxic genes, and downregulated putative tumor suppressors. This study highlights spatial genomic evolution with diagnostic implications and unveils the obstacles and possibilities that should be considered in the development of novel therapeutic strategies.Statement of significance:Glioblastoma is a multifaceted disease that is difficult to treat, and insights into the metabolic gradient observed in imaging and the underlying role of genomic evolution are lacking. This study is the first to investigate the molecular basis of hypermetabolic tumor lesions in glioblastoma using precise three-dimensional biopsy isolation, whole genome/exome, and mRNA sequencing. These findings have diagnostic significance, provide insights into therapeutic resistance, and shed light on the obstacles encountered by precision therapeutics for glioblastoma.

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

Cited by 16 publications

References 36 publications

Distinct genomic and immunologic tumor evolution in germlineTP53-driven breast cancers

Distinct genomic and immunologic tumor evolution in germlineTP53-driven breast cancers

TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms

Insight into spatial intratumoral genomic evolution in glioblastoma

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