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XAF1 as a modifier of p53 function and cancer susceptibility.

ABSTRACT: Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma (P = 0.003) and subsequent malignancies (P = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic TP53 variants, whereas XAF1-E134* is markedly attenuated in this activity. We propose that cosegregation of XAF1-E134* and TP53-R337H mutations leads to a more aggressive cancer phenotype than TP53-R337H alone, with implications for genetic counseling and clinical management of hypomorphic TP53 mutant carriers.

SUBMITTER: Pinto EM

PROVIDER: S-EPMC7314530 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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XAF1 as a modifier of p53 function and cancer susceptibility.

Pinto Emilia M EM Figueiredo Bonald C BC Chen Wenan W Galvao Henrique C R HCR Formiga Maria Nirvana MN Fragoso Maria Candida B V MCBV Ashton-Prolla Patricia P Ribeiro Enilze M S F EMSF Felix Gabriela G Costa Tatiana E B TEB Savage Sharon A SA Yeager Meredith M Palmero Edenir I EI Volc Sahlua S Salvador Hector H Fuster-Soler Jose Luis JL Lavarino Cinzia C Chantada Guillermo G Vaur Dominique D Odone-Filho Vicente V Brugières Laurence L Else Tobias T Stoffel Elena M EM Maxwell Kara N KN Achatz Maria Isabel MI Kowalski Luis L de Andrade Kelvin C KC Pappo Alberto A Letouze Eric E Latronico Ana Claudia AC Mendonca Berenice B BB Almeida Madson Q MQ Brondani Vania B VB Bittar Camila M CM Soares Emerson W S EWS Mathias Carolina C Ramos Cintia R N CRN Machado Moara M Zhou Weiyin W Jones Kristine K Vogt Aurelie A Klincha Payal P PP Santiago Karina M KM Komechen Heloisa H Paraizo Mariana M MM Parise Ivy Z S IZS Hamilton Kayla V KV Wang Jinling J Rampersaud Evadnie E Clay Michael R MR Murphy Andrew J AJ Lalli Enzo E Nichols Kim E KE Ribeiro Raul C RC Rodriguez-Galindo Carlos C Korbonits Marta M Zhang Jinghui J Thomas Mark G MG Connelly Jon P JP Pruett-Miller Shondra S Diekmann Yoan Y Neale Geoffrey G Wu Gang G Zambetti Gerard P GP

Science advances 20200624 26

Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma (P = 0.0 ...[more]

PMID: 32637605

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Project description:BackgroundMethylated DNA in fluids may be a suitable biomarker for cancer patients. XAF1 has been shown to be frequently down-regulated in human gastric cancer (GC). Here, we investigated if XAF1 methylation in GC could be a useful biomarker.MethodsReal-time RT-PCR was used to detect XAF1 mRNA expression; immunohistochemistry and western blot were used to examine XAF1 protein expression in GC tissues (n = 202) and their corresponding para-cancerous histological normal tissues (PCHNTs). Real-time methylation specific-PCR was used to investigate XAF1 promoter methylation in the same panel of GC tissues, their PCHNTs and sera.ResultsWe confirmed frequent XAF1 down-regulation in both mRNA and protein levels in GC tissues as compared to normal controls and PCHNTs. XAF1 hypermethylation was evidenced in 83.2% (168/202) of GC tissues and 27.2% (55/202) of PCHNTs, while no methylation was detected in the 88 normal controls. The methylation level in GC tissues was significantly higher than that in PCHNTs (p<0.05). The hypermethylation of XAF1 significantly correlated with the down-regulation of XAF1 in GC tissues in both mRNA and protein levels (p<0.001 each). Moreover, we detected high frequency of XAF1 methylation (69.8%, 141 out of 202) in the sera DNAs from the same patients, while the sera DNAs from 88 non-tumor controls were negative for XAF1 methylation. The XAF1 methylation in both GC tissues and in the sera could be a good biomarker for diagnosis of GC (AUC = 0.85 for tissue and AUC = 0.91 for sera) and significantly correlated with poorer prognosis (p<0.001). In addition, after-surgery negative-to-positive transition of XAF1 methylation in sera strongly associated with tumor recurrence.Conclusions1) Dysfunction of XAF1 is frequent and is regulated through XAF1 promoter hypermethylation; 2) Detection of circulating methylated XAF1 DNAs in the serum may be a useful biomarker in diagnosis, evaluating patient's outcome (prognosis and recurrence) for GC patients.

Project description:Family history remains one of the strongest risk factors for breast cancer. It is well established that women with a first-degree relative affected by breast cancer are twice as likely to develop the disease themselves. Twins studies indicate that this is most likely due to shared genetics rather than shared epidemiological/lifestyle risk factors. Linkage and targeted sequencing studies have shown that rare high- and moderate-penetrance germline variants in genes involved in the DNA damage response (DDR) including BRCA1, BRCA2, PALB2, ATM, and TP53 are responsible for a proportion of breast cancer cases. However, breast cancer is a heterogeneous disease, and there is now strong evidence that different risk alleles can predispose to different subtypes of breast cancer. Here, we review the associations between the different genes and subtype-specificity of breast cancer based on the most comprehensive genetic studies published. Genome-wide association studies (GWAS) have also been used to identify an additional hereditary component of breast cancer, and have identified hundreds of common, low-penetrance susceptibility alleles. The combination of these low penetrance risk variants, summed as a polygenic risk score (PRS), can identify individuals across the spectrum of disease risk. However, there remains a substantial bottleneck between the discovery of GWAS-risk variants and their contribution to tumorigenesis mainly because the majority of these variants map to the non-protein coding genome. A range of functional genomic approaches are needed to identify the causal risk variants and target susceptibility genes and establish their underlying role in disease biology. We discuss how the application of these multidisciplinary approaches to understand genetic risk for breast cancer can be used to identify individuals in the population that may benefit from clinical interventions including screening for early detection and prevention, and treatment strategies to reduce breast cancer-related mortalities.

Dataset Information

XAF1 as a modifier of p53 function and cancer susceptibility.

Publications

XAF1 as a modifier of p53 function and cancer susceptibility.

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