Somatic Mutations of TP53 and Prognostic Factors for Primary Operable Breast Cancer: Correspondence.
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ABSTRACT:
SUBMITTER: Sookaromdee P
PROVIDER: S-EPMC9807318 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
Publications
Somatic Mutations of <i>TP53</i> and Prognostic Factors for Primary Operable Breast Cancer: Correspondence.
Sookaromdee Pathum P Wiwanitkit Viroj V
Journal of breast cancer 20221201 6
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Project description:Few studies have reported on the clinical utility of targeted next-generation sequencing (NGS) for breast cancer in Korea. We retrospectively reviewed the targeted NGS data of 219 patients with breast cancer who underwent surgical resection between August 2018 and April 2021. Here, we described the mutational profiles of breast cancer and examined their prognostic implications. The most frequently mutated gene was PIK3CA (n = 97/219, 44.3%), followed by TP53 (n = 79/219, 36.1%), AKT1 (n = 23/219, 10.5%), and GATA3 (n = 20/219, 9.1%). TP53 mutations were associated with aggressive histologic features. We followed up for 31 (range, 1-39) months and observed 11 (5.0%) recurrences: nine were TP53 mutant and two were TP53 wild-type. Multivariable analysis revealed that TP53 mutation was an independent prognostic factor for recurrence (p = 0.012). Although no drug is currently available for TP53 mutations, it is valuable to know the mutational status of TP53 for the precise management of breast cancer.
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Project description:Tumor protein 53 (TP53) is a tumor suppressor gene that encodes tumor protein p53. Tumor protein p53 regulates the expression of target genes in response to cellular stress. Additionally, p53 participates in the regulation of cell cycle checkpoints, DNA repair and apoptosis. Mutations in the TP53 gene are associated with numerous types of human cancer, including breast cancer, sarcomas, brain tumors and adrenal cortical carcinomas. In breast cancer, TP53 mutations are a negative prognostic factor. Tumors with TP53 mutations are more likely to be aggressive (triple-negative or human epidermal growth factor receptor 2-positive breast cancer), and resistant to chemotherapy and radiotherapy. In addition to a well-known TP53 mutation, a number of single nucleotide polymorphisms have been systematically identified and evaluated in human populations. In the present article, the role of TP53 mutations and polymorphisms in clinical practice and breast cancer treatment has been described. Additionally, the existing data on TP53 polymorphisms in breast cancer as prognostic and predictive factors have been summarized. A literature search of these topics was performed through PubMed and abstracts of the main cancer congresses in recent years.
| S-EPMC6006469 | biostudies-literature
Project description:BackgroundRecent genomics studies of breast cancer in Asian cohorts have found a higher prevalence of TP53 mutations in Asian breast cancer patients relative to Caucasian patients. However, the effect of TP53 mutations on Asian breast tumours has not been comprehensively studied.MethodsHere, we report an analysis of 492 breast cancer samples from the Malaysian Breast Cancer cohort where we examined the impact of TP53 somatic mutations in relation to PAM50 subtypes by comparing whole exome and transcriptome data from tumours with mutant and wild-type TP53.ResultsWe found that the magnitude of impact of TP53 somatic mutations appears to vary between different subtypes. TP53 somatic mutations were associated with higher HR deficiency scores as well as greater upregulation of gene expression pathways in luminal A and luminal B tumours compared to the basal-like and Her2-enriched subtypes. The only pathways that were consistently dysregulated when comparing tumours with mutant and wild-type TP53 across different subtypes were the mTORC1 signalling and glycolysis pathways.ConclusionThese results suggest that therapies that target TP53 or other downstream pathways may be more effective against luminal A and B tumours in the Asian population.
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Project description:BackgroundTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. In the elderly (≥70 years old) primary operable (T1-3N0-1M0) TNBC, individualized treatment modalities for this population are pivotal and important, but limited studies are explored.MethodsThe clinicopathological features of elderly primary operable TNBC patients were retrospectively selected from the Surveillance, Epidemiology, and End Results (SEER) database between January 2010 and December 2015. Kaplan-Meier curves were used to show the survival patterns in the different subgroups. Multivariate Cox analysis was used to identify independent risk factors in the 3-, 5-, and 7- year overall survival (OS) and cancer-specific survival (CSS) in this subpopulation. The predictive model was further developed and validated for clinical use.ResultBetween 2010 and 2015 years, a total of 4,761 elderly primary operable TNBC patients were enrolled for the study, with a mean age of 76 years and a median follow-up of 56 months. The multivariate Cox analysis showed that age (increased per year: hazard ratio (HR) = 1.05), race (Asian/Pacific Islander and American Indian/Alaska Native, HR = 0.73), differentiation grade (grade II: HR = 2.01; grade III/IV: HR = 2.67), larger tumor size (T1c: HR = 1.83; T2: HR = 2.78; T3: HR = 4.93), positive N stage (N1mi: HR = 1.60; N1: HR = 1.54), receiving radiation therapy (HR = 0.66), and receiving adjuvant chemotherapy (HR = 0.61) were the independent prognostic factors for OS, and a similar prognostic pattern was also determined in CSS. Besides, two nomograms for predicting the 3-, 5-, and 7-year OS and CSS in this population were developed with a favorable concordance index of 0.716 and 0.746, respectively.ConclusionThe results highlight that both radiation and adjuvant chemotherapy are significantly associated with favorable long-term OS and CSS probability in elderly primary operable TNBC patients. Based on the determined independent prognostic factors, the novel nomograms could assist the oncologists to make individualized clinical decisions for the subpopulation at different risks.
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Project description:Despite controversy on the correlation between p53 accumulation and TP53 mutational status, immunohistochemical (IHC) detection of overexpressed protein has long been used as a surrogate method for mutation analysis. The aim of our study was to characterise the IHC expression features of TP53 somatic mutations and define their occurrence in human cancers. A large-scale database analysis was conducted in the IARC TP53 Database (R17); 7878 mutations with IHC features were retrieved representing 60 distinct tumour sites. The majority of the alterations were immunopositive (p <0.001). Sex was known for 4897 mutations showing a female dominance (57.2%) and females carrying negative mutations were significantly younger. TP53 mutations were divided into three IHC groups according to mutation frequency and IHC positivity. Each group had female dominance. Among the IHC groups, significant correlations were observed with age at diagnosis in breast, bladder, liver, haematopoietic system and head & neck cancers. An increased likelihood of false negative IHC associated with rare nonsense mutations was observed in certain tumour sites. Our study demonstrates that p53 immunopositivity largely correlates with TP53 mutational status but expression is absent in certain mutation types.Besides, describing the complex IHC expression of TP53 somatic mutations, our results reveal some caveats for the diagnostic practice.
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Project description:Here we report targeted sequencing of 83 genes using DNA from primary breast cancer samples from 625 postmenopausal (UBC-TAM series) and 328 premenopausal (MA12 trial) hormone receptor-positive (HR+) patients to determine interactions between somatic mutation and prognosis. Independent validation of prognostic interactions was achieved using data from the METABRIC study. Previously established associations between MAP3K1 and PIK3CA mutations with luminal A status/favorable prognosis and TP53 mutations with Luminal B/non-luminal tumors/poor prognosis were observed, validating the methodological approach. In UBC-TAM, NF1 frame-shift nonsense (FS/NS) mutations were also a poor outcome driver that was validated in METABRIC. For MA12, poor outcome associated with PIK3R1 mutation was also reproducible. DDR1 mutations were strongly associated with poor prognosis in UBC-TAM despite stringent false discovery correction (q = 0.0003). In conclusion, uncommon recurrent somatic mutations should be further explored to create a more complete explanation of the highly variable outcomes that typifies ER+ breast cancer.
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Project description:BackgroundWhereas the genomic landscape of endocrine-resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non-responsiveness to endocrine treatment in luminal early breast cancer.MethodsIn this study, 622 estrogen receptor-expressing breast cancer cases treated with short-term preoperative endocrine therapy (pET) from the WSG-ADAPT trial (NCT01779206) were analyzed for genetic alterations associated with impaired endocrine proliferative response (EPR) to 3-week pET with tamoxifen or aromatase inhibitors. EPR was categorized as optimal (post-pET Ki67 <10%) versus slightly, moderately, and severely impaired (post-pET Ki67 10%-19%, 20%-34%, and ≥35%, respectively). Recently described gene mutations frequently found in previously treated advanced breast cancer were analyzed (ARID1A, BRAF, ERBB2, ESR1, GATA3, HRAS, KRAS, NRAS, PIK3CA, and TP53) by next-generation sequencing. Amplifications of CCND1, FGFR1, ERBB2, and PAK1 were determined by digital PCR or fluorescence in situ hybridization.ResultsERBB2 amplification (p = 0.0015) and mutations of TP53 (p < 0.0001) were significantly associated with impaired EPR. Impaired EPR in TP53-mutated breast cancer cases was independent from the Oncotype DX Recurrence Score group and was seen both with tamoxifen- and aromatase inhibitor-based pET (p = 0.0005 each).ConclusionWe conclude that impaired EPR to pET is suitable to identify cases with primary endocrine resistance in early luminal breast cancer and that TP53-mutated luminal cancers might not be sufficiently treated by endocrine therapy alone.
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Project description:Breast cancer, one of the most frequently occurring cancers worldwide, is the leading cause of cancer-related death among women. AKT1, PIK3CA, PTEN and TP53 mutations were common observed in breast cancer representing potential clinical biomarkers for cancer classification and treatment. A comprehensive knowledge of AKT1, PIK3CA, PTEN and TP53 mutations in breast cancer was still insufficient in Chinese population. In this study, the complete coding regions and exon-intron boundaries of AKT1, PIK3CA, PTEN and TP53 genes were sequenced in paired breast tumor and normal tissues from 313 Chinese breast cancer patients using microfluidic PCR-based target enrichment and next-generation sequencing technology. Total 120 somatic mutations were identified in 190 of the 313 patients (60.7%), with the mutation frequency of AKT1 as 3.2%, PIK3CA as 36.4%, PTEN as 4.8%, and TP53 as 33.9%. Among these mutations, 1 in PIK3CA (p.I69N), 3 in PTEN (p.K62X, c.635-12_636delTTAACCATGCAGAT and p.N340IfsTer4) and 5 in TP53 (p.Q136AfsTer5, p.K139_P142del, p.Y234dup, p.V274LfsTer31 and p.N310TfsTer35) were novel. Notably, PIK3CA somatic mutations were significantly associated with ER-positive or PR-positive tumors. TP53 somatic mutations were significantly associated with ER-negative, PR-negative, HER2-positive, BRCA1 mutation, Ki67 high expression and basal-like tumors. Our findings provided a comprehensive mutation profiling of AKT1, PIK3CA, PTEN and TP53 genes in Chinese breast cancer patients, which have potential implications in clinical management.
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