<i>TP53</i> Mutation Spectrum in Breast Cancer Is Subtype Specific and Has Distinct Prognostic Relevance

Silwal-Pandit, Laxmi; Vollan, Hans Kristian Moen; Chin, Suet-Feung; Rueda, Oscar M.; McKinney, Steven; Osako, Tomo; Quigley, David A.; Kristensen, Vessela N.; Aparicio, Samuel; Børresen-Dale, Anne Lise; Caldas, Carlos; Langerød, Anita

doi:10.1158/1078-0432.ccr-13-2943

Cited by 255 publications

(280 citation statements)

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“…For METABRIC, we downloaded the normalized gene expression profiles generated using the Illumina HT 12 IDATS platform and the clinical information from the European genome-phenome archive (EGAS00000000083). The mutation calls for TP53 generated by Sanger sequencing of coding exons used were from the work by Silwal-Pandit et al (10). A3B del polymorphism genotypes were identified using Nexus Copy Number 7.0 software (BioDiscovery Inc.) to process Affymetrix-generated CEL files (EGAD00010000164).…”

Section: Methodsmentioning

confidence: 99%

“…Analyses of cell line and tumor datasets have shown that A3B gene expression is up-regulated in malignant vs. normal tissues and epithelial cell lines and have shown correlations between A3B expression and the presence of certain somatic mutations, particularly in TP53 (7,10) and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) (11). Although the factors that cause up-regulation of A3B in cancer cell lines and tumors remain unknown, these observations form the basis for a model where A3B expression contributes to the accumulation of somatic alterations during the process of carcinogenesis and subsequent evolution, and it has been suggested that inhibition of this activity could represent a strategy for cancer prevention or an adjuvant to other therapies (7,12).…”

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confidence: 99%

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APOBEC3Bexpression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation

Cescon

Haibe‐Kains

Mak

2015

Proc. Natl. Acad. Sci. U.S.A.

122

121

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Genomic sequencing studies of breast and other cancers have identified patterns of mutations that have been attributed to the endogenous mutator activity of APOBEC3B (A3B), a member of the AID/APOBEC family of cytidine deaminases. A3B gene expression is increased in many cancers, but its upstream drivers remain undefined. Furthermore, there exists a common germ-line deletion polymorphism (A3B del ), which has been associated with a paradoxical increase in breast cancer risk. To examine causes and consequences of A3B expression and its constitutive absence in breast cancer, we analyzed two large clinically annotated genomic datasets [The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC)]. We confirmed that A3B expression is associated with aggressive clinicopathologic characteristics and adverse outcomes and show that A3B expression is highly correlated with proliferative features (mitosis and cell cycle-related gene expression) in breast and 15 of 16 other solid tumor types. However, breast cancers arising in homozygous A3B del individuals with A3B absent did not differ in these features, indicating that A3B expression is a reflection rather than a direct cause of increased proliferation. Using gene set enrichment analysis (GSEA), we detected a pattern of immune activation in A3B del breast cancers, which seems to be related to hypermutation arising in A3B del carriers. Together, these results provide an explanation for A3B overexpression and its prognostic effect, giving context to additional study of this mutator as a cancer biomarker or putative drug target. In addition, although immune features of A3B del require additional study, these findings nominate the A3B del polymorphism as a potential predictor for cancer immunotherapy.cancer | mutagenesis | cellular proliferation T he recent application of next generation sequencing technologies to characterize the landscape of somatic alterations in solid tumors has yielded major insights into the genes and pathways operant in various cancers. In addition, these studies have enabled the identification of distinct patterns of DNA base alterations that reflect underlying mutational processes (1-6). One of the major discoveries of this effort was the high prevalence of C > T transitions occurring in a preferred sequence motif (TCW, thymine/cytosine/adenine or thymine). This pattern is consistent with the deaminase activity of the AID/APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family of enzymes, and thus, its identification invoked an endogenous mutator as a significant contributor to the somatic mutational burden across several cancer types (2-9). Based on the sequence motifs, expression levels, and subcellular localization of APOBEC family members, APOBEC3B (A3B) has been implicated as the likely mutator (6-8).Analyses of cell line and tumor datasets have shown that A3B gene expression is up-regulated in malignant vs. normal tissues and epithelial cell lines and have shown correl...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

APOBEC3Bexpression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation

Cescon

Haibe‐Kains

Mak

2015

Proc. Natl. Acad. Sci. U.S.A.

122

121

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“…Furthermore, a wealth of in vitro data as well as data from animal models indicate that the oncogenic activities of TP53 variants are heterogeneous and can vary according to the tissue type and the genetic background of the cells (33)(34)(35)(36). In breast carcinoma, the spectrum of TP53 variants is subtype specific, each one with a different prognostic relevance (37). Classifying TP53 status as either "wild-type" or "mutant" is therefore an oversimplification, as TP53-null tumors due to loss of p53 expression have a different phenotype compared to tumors overexpressing an oncogenic TP53 variant.…”

Section: Heterogeneity Of Tp53 Variantsmentioning

confidence: 99%

Recommended Guidelines for Validation, Quality Control, and Reporting of TP53 Variants in Clinical Practice

et al. 2017

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Accurate assessment of TP53 gene status in sporadic tumors and in the germline of individuals at high risk of cancer due to Li-Fraumeni Syndrome (LFS) has important clinical implications for diagnosis, surveillance, and therapy. Genomic data from more than 20,000 cancer genomes provide a wealth of information on cancer gene alterations and have confirmed TP53 as the most commonly mutated gene in human cancer. Analysis of a database of 70,000 TP53 variants reveals that the two newly discovered exons of the gene, exons 9b and 9g, generated by alternative splicing, are the targets of inactivating mutation events in breast, liver, and head and neck tumors. Furthermore, germline rearrangements in intron 1 of TP53 are associated with LFS and are frequently observed in sporadic osteosarcoma. In this context of constantly growing genomic data, we discuss how screening strategies must be improved when assessing TP53 status in clinical samples. Finally, we discuss how TP53 alterations should be described by using accurate nomenclature to avoid confusion in scientific and clinical reports.

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“…2B; Table 1) [9]. Conversely, the frequency of TP53 mutations (29%) is higher in luminal B cancers and is associated with worse outcome [20].There is also higher frequency of ATM loss and CCND1, CDK4, CDK6, and MDM2 amplifications in luminal B cancers [9]. ER-positive cancers have relatively few recurrent CNAs compared with TNBCs (Table 1) [9,10,21,22].…”

Section: The Genomic Landscape Of Breast Cancersmentioning

confidence: 99%

“…These cancers have the highest frequency of TP53 disabling mutations (up to 80%) [9,20]. Mutations and/or deletions in RB1 (retinoblastoma 1; 20%) and mutations in PIK3CA (9%), MLL3 (5%), and GATA3 (2%), as well as amplification of the CCNE1 gene (9%), occur at relatively low frequencies (Fig.…”

Section: Triple-negative Breast Cancersmentioning

confidence: 99%

Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer

et al. 2016

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Advances in DNA and RNA sequencing revealed substantially greater genomic complexity in breast cancer than simple models of a few driver mutations would suggest. Only very few, recurrent mutations or copy-number variations in cancer-causing genes have been identified. The two most common alterations in breast cancer are TP53 (affecting the majority of triple-negative breast cancers) and PIK3CA (affecting almost half of estrogen receptor-positive cancers) mutations, followed by a long tail of individually rare mutations affecting <1%–20% of cases. Each cancer harbors from a few dozen to a few hundred potentially high-functional impact somatic variants, along with a much larger number of potentially high-functional impact germline variants. It is likely that it is the combined effect of all genomic variations that drives the clinical behavior of a given cancer. Furthermore, entirely new classes of oncogenic events are being discovered in the noncoding areas of the genome and in noncoding RNA species driven by errors in RNA editing. In light of this complexity, it is not unexpected that, with the exception of HER2 amplification, no robust molecular predictors of benefit from targeted therapies have been identified. In this review, we summarize the current genomic portrait of breast cancer, focusing on genetic aberrations that are actively being targeted with investigational drugs.

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TP53 Mutation Spectrum in Breast Cancer Is Subtype Specific and Has Distinct Prognostic Relevance

Abstract: This study reveals that TP53 mutations have different clinical relevance in molecular subtypes of breast cancer, and suggests diverse roles for TP53 in the biology underlying breast cancer development.

Cited by 255 publications

References 39 publications

APOBEC3Bexpression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation

APOBEC3Bexpression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation

Recommended Guidelines for Validation, Quality Control, and Reporting of TP53 Variants in Clinical Practice

Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer

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