TP53 somatic mutations in Asian breast cancer are associated with subtype-specific effects

Ragu, Mohana Eswari; Lim, Joanna; Ng, Pei-Sze; Yip, Cheng‐Har; Rajadurai, Pathmanathan; Teo, Soo‐Hwang; Pan, Jia-Wern

doi:10.1186/s13058-023-01635-2

Cited by 5 publications

(3 citation statements)

References 42 publications

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“…SNVs of interest also were assessed independently in two cohorts: 859 women with breast cancer from the Malaysian Breast Cancer Study (MyBrCa) [74,75] and 393 AFA women with TNBC from the Breast Cancer in African Americans: Understanding Somatic Mutations and Etiology (B-CAUSE) study (Supplemental Tables S19 and S20) [76]. Validation SNVs for the MyBrCa study were excluded from analyses if they mapped to the X chromosome or if they had a MAF less than 1% in Malaysian individuals.…”

Section: Methodsmentioning

confidence: 99%

Association ofESR1germline variants withTP53somatic variants in breast tumors in a genome-wide study

Tjader,

Beer,

Ramroop

et al. 2023

Preprint

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BackgroundIn breast tumors, somatic mutation frequencies inTP53andPIK3CAvary by tumor subtype and ancestry. HER2 positive and triple negative breast cancers (TNBC) have a higher frequency ofTP53somatic mutations than other subtypes.PIK3CAmutations are more frequently observed in hormone receptor positive tumors. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somaticTP53orPIK3CAmutation status in breast tumors.MethodsA genome-wide association study was conducted using breast cancer mutation status ofTP53andPIK3CAand functional mutation categories includingTP53gain of function (GOF) and loss of function mutations andPIK3CAactivating/hotspot mutations. The discovery analysis consisted of 2850 European ancestry women from three datasets. Germline variants showing evidence of association with somatic mutations were selected for validation analyses based on predicted function, allele frequency, and proximity to known cancer genes or risk loci. Candidate variants were assessed for association with mutation status in a multi-ancestry validation study, a Malaysian study, and a study of African American/Black women with TNBC.ResultsThe discovery Germline x Mutation (GxM) association study found five variants associated with one or moreTP53phenotypes withPvalues <1×10-6, 33 variants associated with one or moreTP53phenotypes withPvalues <1×10-5, and 44 variants associated with one or morePIK3CAphenotypes withPvalues <1×10-5. In the multi-ancestry and Malaysian validation studies, germlineESR1locus variant, rs9383938, was associated with the presence ofTP53mutations overall (Pvalues 6.8×10-5and 9.8×10-8, respectively) andTP53GOF mutations (Pvalue 8.4×10-6). Multiple variants showed suggestive evidence of association withPIK3CAmutation status in the validation studies, but none were significant after correction for multiple comparisons.ConclusionsWe found evidence that germline variants were associated withTP53andPIK3CAmutation status in breast cancers. Variants near the estrogen receptor alpha gene,ESR1,were significantly associated with overallTP53mutations and GOF mutations. Larger multi-ancestry studies are needed to confirm these findings and determine if these variants contribute to ancestry-specific differences in mutation frequency.

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Section: Methodsmentioning

confidence: 99%

Association ofESR1germline variants withTP53somatic variants in breast tumors in a genome-wide study

Tjader,

Beer,

Ramroop

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

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“…Mutations in the PIK3CA gene, present in about 32% of Luminal B cases, can activate the PI3K/AKT/mTOR signaling pathway, contributing to breast cancer development and progression. Additionally, TP53 gene mutations are relatively common in this subtype, occurring in approximately 31% of cases, which is a higher frequency than in Luminal A breast cancer [70]. These mutations are considered possible predictors of resistance to endocrine therapy.…”

Section: Genetic Biomarkersmentioning

confidence: 99%

Exploring Biomarkers in Breast Cancer: Hallmarks of Diagnosis, Treatment, and Follow-Up in Clinical Practice

Lopez-Gonzalez,

Sanchez Cendra,

Sanchez Cendra

et al. 2024

Medicina

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Breast cancer is a prevalent malignancy in the present day, particularly affecting women as one of the most common forms of cancer. A significant portion of patients initially present with localized disease, for which curative treatments are pursued. Conversely, another substantial segment is diagnosed with metastatic disease, which has a worse prognosis. Recent years have witnessed a profound transformation in the prognosis for this latter group, primarily due to the discovery of various biomarkers and the emergence of targeted therapies. These biomarkers, encompassing serological, histological, and genetic indicators, have demonstrated their value across multiple aspects of breast cancer management. They play crucial roles in initial diagnosis, aiding in the detection of relapses during follow-up, guiding the application of targeted treatments, and offering valuable insights for prognostic stratification, especially for highly aggressive tumor types. Molecular markers have now become the keystone of metastatic breast cancer diagnosis, given the diverse array of chemotherapy options and treatment modalities available. These markers signify a transformative shift in the arsenal of therapeutic options against breast cancer. Their diagnostic precision enables the categorization of tumors with elevated risks of recurrence, increased aggressiveness, and heightened mortality. Furthermore, the existence of therapies tailored to target specific molecular anomalies triggers a cascade of changes in tumor behavior. Therefore, the primary objective of this article is to offer a comprehensive review of the clinical, diagnostic, prognostic, and therapeutic utility of the principal biomarkers currently in use, as well as of their clinical impact on metastatic breast cancer. In doing so, our goal is to contribute to a more profound comprehension of this complex disease and, ultimately, to enhance patient outcomes through more precise and effective treatment strategies.

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“…Generally, the prevalence of BRCA1 mutation is more common than BRCA2 mutation except for Asian women where equal prevalence has been reported [ 7 ]. However, in addition to BRCA1 and BRCA2 , it has been reported that the mutation of the Apolipoprotein B mRNA-editing enzyme, the catalytic polypeptide-like (APOBEC3B) and tumor suppressor gene ( TP53 ) are associated with breast cancer and observed more commonly among Asian women than European women [ 8 , 9 ]. A recent study in Thailand identified the significance of PALB2 and ATM genetic mutations among breast cancer patients as well as BRCA1 and BRCA2 [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Risk-Stratified Breast Cancer Screening in Malaysia: Challenges and Opportunities

Htay,

Su,

Donnelly

2024

Asian Pac J Cancer Prev

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Breast cancer in MalaysiaBreast cancer is the commonest cancer in the Malaysian population and approximately one out of five cancer patients have breast cancer (19% of all cancer) [1]. Age-standardised incidence rates of breast cancer among Malaysian women have been increasing and were 34.1 in 2016 [1]. Late-stage diagnosis has been increasing also -the most recent report estimated that 47.9% of women were diagnosed at Stage III and IV even though cancer screening, prevention, and control programmes have been implemented in Malaysia [1][2][3]. Furthermore, the onset of breast cancer among Malaysian women is early and approximately half of patients are diagnosed before the age of 50 years [4].

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TP53 somatic mutations in Asian breast cancer are associated with subtype-specific effects

Cited by 5 publications

References 42 publications

Association ofESR1germline variants withTP53somatic variants in breast tumors in a genome-wide study

Association ofESR1germline variants withTP53somatic variants in breast tumors in a genome-wide study

Exploring Biomarkers in Breast Cancer: Hallmarks of Diagnosis, Treatment, and Follow-Up in Clinical Practice

Risk-Stratified Breast Cancer Screening in Malaysia: Challenges and Opportunities

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