Characterizations of Cancer Gene Mutations in Chinese Metastatic Breast Cancer Patients

Tao, Zhonghua; Li, Ting; Feng, Zhe; Liu, Chang; Shao, Yilin; Zhu, Mingyu; Gong, Chengcheng; Wang, Biyun; Cao, Ji; Wang, Leipin; Du, Ye; Lizaso, Analyn; Li, Bing; Zhang, Jian; Hu, Xichun

doi:10.3389/fonc.2020.01023

Cited by 26 publications

(20 citation statements)

References 42 publications

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“… 26 Another recent study on cfDNA molecular profiling in Chinese patients with MBC reported a TP53 mutation rate of 64.1% compared with 52% in Caucasian patients. 27 , 28 These discrepancies could reflect differences between patient ethnicities, such as in the median age of breast cancer patients with TP53 mutations in our study of 48 years compared with 55.2 years in Caucasians. 29 …”

Section: Discussionmentioning

confidence: 65%

Prognostic Value of the TP53 Mutation Location in Metastatic Breast Cancer as Detected by Next-Generation Sequencing

Bai¹,

Yu²,

Jia³

et al. 2021

CMAR

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Purpose The status of TP53 mutations was measured in cell-free DNA from patients with metastatic breast cancer (MBC) to investigate disease characteristics and the prognostic role of different locations of the TP53 mutation site. Patients and Methods Blood samples were taken from a total of 187 patients diagnosed with MBC who were treated at the Department of Breast Oncology, Peking University Cancer Hospital between January 2013 and March 2020. Next-generation sequencing was used to investigate the TP53 mutation spectra of circulating free DNA in these blood samples. Results Among the 187 MBC patients, TP53 -mutated patients had a significantly shorter median disease-free survival (DFS) and overall survival (OS) compared with TP53 wild-type patients (P=0.001 and P=0.006, respectively). Additionally, in hormone receptor positive/HER2 negative (HR+/HER2-) and triple negative (TNBC) cohorts, TP53 -mutated patients had a significantly shorter median DFS than TP53 wild-type patients (P=0.038 and P=0.023, respectively). The 79 patients with TP53 mutations carried 87 somatic TP53 mutations, of which most (77.0%) mapped to the DNA-binding domain (DBD) of the protein encoded by TP53 exons 5–8. In patients with TP53 mutations, those occurring in the non-DBD had a significantly shorter median DFS and OS than TP53 wild type (P<0.001 and P=0.001, respectively). Additionally, patients with non-missense mutations in the DBD had a significantly shorter median DFS and OS than TP53 wild-type patients (P=0.001 and P<0.001, respectively). TP53 -mutated patients had a significantly shorter DFS than TP53 wild-type patients in the adjuvant endocrine therapy sensitive group (P=0.008), but differences in the endocrine therapy resistant group were not significant. Conclusion TP53 -mutated MBC patients had a significantly worse outcome than TP53 wild-type patients especially those in HR+/HER2– and TNBC cohorts. Of TP53 -mutated patients, those with non-missense mutations in the DBD had worse breast cancer-related survival. TP53 mutations were also associated with endocrine resistance.

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Section: Discussionmentioning

confidence: 65%

Prognostic Value of the TP53 Mutation Location in Metastatic Breast Cancer as Detected by Next-Generation Sequencing

Bai¹,

Yu²,

Jia³

et al. 2021

CMAR

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“…In addition, there is evidence that genomic changes are obtained in the process of cancer metastasis and progression and the genomic pattern of early cancers cannot represent lethal cancers ( 32 – 36 ). Recently, there have been subsequent reports on the genomic landscape of mBC ( 16 – 18 ). However, the molecular mechanism for LM remains an area that has not yet been fully developed ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

“…Another example is that the interaction between chemokine receptors on tumor cell membranes and chemokines in the microenvironment, such as CCL2 ( 10 , 11 ) and CXCR4-CXCL12/SDF-1 ( 12 – 14 ), plays important roles in LM. Moreover, with the rapid development of sequencing technology in the recent years, a large number of early BC gene maps have been reported, along with several reports on the overall mutation characteristics of mBC ( 15 – 18 ). However, the genetic landscape related to LM alone has not yet been characterized.…”

Section: Introductionmentioning

confidence: 99%

Prognosis and Genomic Landscape of Liver Metastasis in Patients With Breast Cancer

et al. 2021

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ObjectiveThe prognosis of breast cancer liver metastasis (BCLM) is poor, and its molecular mechanism is unclear. We aimed to determine the factors that affect the prognosis of patients with BCLM and investigate the genomic landscape of liver metastasis (LM).MethodsWe described the prognosis of patients with BCLM and focused on prognosis prediction for these patients based on clinicopathological factors. Nomogram models were constructed for progression-free survival (PFS) and overall survival (OS) by using a cohort of 231 patients with BCLM who underwent treatment at Shandong Cancer Hospital and Institute (SCHI). We explored the molecular mechanism of LM and constructed driver genes, mutation signatures by using a targeted sequencing dataset of 217 samples of LM and 479 unpaired samples of primary breast cancer (pBC) from Memorial Sloan Kettering Cancer Center (MSKCC).ResultsThe median follow-up time for 231 patients with BCLM in the SCHI cohort was 46 months. The cumulative incidence of LM at 1, 2, and 5 years was 17.5%, 45.0%, and 86.8%, respectively. The median PFS and OS were 7 months (95% CI, 6–8) and 22 months (95% CI, 19–25), respectively. The independent factors that increased the progression risk of patients with LM were Karnofsky performance status (KPS) ≤ 80, TNBC subtype, grade III, increasing trend of CA153, and disease-free interval (DFS) ≤ 1 year. Simultaneously, the independent factors that increased the mortality risk of patients with LM were Ki-67 ≥ 30%, grade III, increasing trend of CA153, pain with initial LM, diabetes, and DFI ≤ 1 year. In the MSKCC dataset, the LM driver genes were ESR1, AKT1, ERBB2, and FGFR4, and LM matched three prominent mutation signatures: APOBEC cytidine deaminase, ultraviolet exposure, and defective DNA mismatch repair.ConclusionThis study systematically describes the survival prognosis and characteristics of LM from the clinicopathological factors to the genetic level. These results not only enable clinicians to assess the risk of disease progression in patients with BCLM to optimize treatment options, but also help us better understand the underlying mechanisms of tumor metastasis and evolution and provide new therapeutic targets with potential benefits for drug-resistant patients.

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“…PTEN is a multifunctional tumor suppressor gene, which is mutated in large number of cancers at different frequency. PTEN alterations are more frequent in glioblastoma (30%-60%) [22,23], breast cancer(11%-15%) [24,25], prostate cancer (17%-21%) [26,27]. PTEN mutation is thought to be an early step in the development and progression of EC patients [28,29].…”

Section: Discussionmentioning

confidence: 99%

The Critical Role of PTEN Mutation in Cellular Process and Drug Selection of Endometrial Cancer

Liu¹,

Zhou²,

Niu³

et al. 2020

Preprint

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Background: Phosphatase and tensin homolog (PTEN) is a frequently mutated genes found in endometrial cancer (EC), making it a potential biomarker for individualized treatment opinions. In this study, a method was designed to evaluate the role of the PTEN mutation in the prognosis and drug selection of EC. We identified the potential alterations in pathways and genes related to the mechanism. Methods: cBioPortal database was used to analyze the PTEN mutation status for EC patients. Kaplan-Meier was used to analyze the prognosis of PTEN mutation in EC patients. GDSC dataset was used to identified the drugs that sensitive to cell lines with PTEN mutation. DEGs between PTEN mutation and wide type group were identified using the edgeR package. GO and KEGG analysis were carried out using the DAVID database. GSEA v3.0 were used to dig out the differences in gene mRNA levels of biological function annotation and pathways between PTEN mutation and wide type patients. PPI network of DEGs was performed using STRING and then visualized using Cytoscope software (3.7.2).Results: Our results showed that PTEN mutation was carried in 68% of EC patients. The mRNA expression level of PTEN was lower in patients with PTEN mutation than that with wide type. Prognosis analysis showed that there were favorable overall survival and progression free survival in EC patients with PTEN mutation. Moreover, it is more sensitive to AKT inhibitor (Afuresertib and AZD5363), and Mcl-1 inhibitor (MIM1) on EC cell lines with PTEN mutation than that with wide type. A total of 216 genes were identified as DEGs. GO analysis showed that DEGs significantly enriched in chemical synaptic transmission, extracellular region, etc.. KEGG analysis suggested that DEGs significantly enriched in categories associated with metabolic progression. GSEA analysis identified signaling pathways including fatty acid metabolism, fructose and mannose metabolism, etc.. PPI network analysis identified top 10 genes and top three clusters.Conclusions: Multiple genes and pathways may play an important role in EC patients with PTEN mutation. These results provide a potential target and therapeutic strategies for patients with PTEN mutation.

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Characterizations of Cancer Gene Mutations in Chinese Metastatic Breast Cancer Patients

Cited by 26 publications

References 42 publications

Prognostic Value of the TP53 Mutation Location in Metastatic Breast Cancer as Detected by Next-Generation Sequencing

Prognostic Value of the TP53 Mutation Location in Metastatic Breast Cancer as Detected by Next-Generation Sequencing

Prognosis and Genomic Landscape of Liver Metastasis in Patients With Breast Cancer

The Critical Role of PTEN Mutation in Cellular Process and Drug Selection of Endometrial Cancer

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