Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer

Santarpia, Libero; Bottai, Giulia; Kelly, Catherine M.; Győrffy, Balázs; Székely, Borbála; Pusztai, Lajos

doi:10.1634/theoncologist.2015-0369

Cited by 44 publications

(45 citation statements)

References 128 publications

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“…Based on these results, we determined that most breast cancers differed from all others (27). Significant correlations between TP53 mutational status and certain clinicopathological characteristics of the primary tumor were in concordance with literature data (29). BRCA1/2 are tumor suppressor genes that are involved in DNA repair pathways associated with hereditary breast and ovarian cancer syndrome (30).…”

Section: Discussionsupporting

confidence: 81%

Circulating tumor cells and breast cancer‑specific mutations in primary breast cancer

et al. 2020

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Circulating tumor cells (CTCs) play a pivotal role in tumor dissemination and progression, and are considered to be a critical part of the metastatic cascade. The aim of the present research article was to examine breast cancer-specific mutations in primary breast cancer (PBC) using targeted resequencing. A total of 78 patients with PBC were enrolled into this translational study. Reverse transcription-quantitative PCR assay for the expression of epithelial markers (CK19) or epithelial-to-mesenchymal transition (EMT)-related genes (TWIST1, SNAIL1, SLUG and ZEB1) was applied for identification of CTCs prior to surgery. Total DNA was isolated from fresh frozen primary tumors. Sequencing was performed by Agilent SureSelect target enrichment and Illumina paired-end sequencing on the MiSeq platform. The most commonly affected genes were TP53 (mutated in 21 tumors; 26.9%), followed by PIK3CA (mutated in 16 tumors; 20.5%) and BRCA1/2 (mutated in 7 tumors, BRCA1 n=2 and BRCA2 n=5; 9.0%). In our cohort, a significantly higher proportion of patients with epithelial CTCs harbored mutations in the BRCA1/2 genes in the tumor tissue. There were no mutations in specific genes associated with CTCs with the EMT phenotype. To the best of our knowledge, this study is the first to report a correlation between the presence of epithelial CTCs in the peripheral blood and mutations of the BRCA1/2 genes in primary tumor tissue.

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Section: Discussionsupporting

confidence: 81%

Circulating tumor cells and breast cancer‑specific mutations in primary breast cancer

et al. 2020

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“…It seems, however, that only stable EBV positive tumors, that is, those without mutations, confer the anticipated favorable outcome as compared to EBV negative tumors. This on/off mutation effect on patient outcome has been described before and it seems that it is not gene specific but rather reflects different oncogenic processes and tumor‐host interactions operating in each class of tumors. Genomic instability in NPC seems clinically important because it affects drug‐targetable genes and pathways.…”

Section: Discussionmentioning

confidence: 52%

Prevalent somatic BRCA1 mutations shape clinically relevant genomic patterns of nasopharyngeal carcinoma in Southeast Europe

Fountzilas

Psyrri

Giannoulatou

et al. 2017

Intl Journal of Cancer

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Genomic patterns of nasopharyngeal carcinomas (NPCs) have as yet been studied in Southeast Asian (SEA) patients. Here, we investigated genomic patterns of locally advanced NPC Southeast European (SEE) patients treated with chemoradiotherapy. We examined 126 tumors (89% EBV positive) from Greek and Romanian NPC patients with massively parallel sequencing. Paired tumor-cell-rich (TC) and infiltrating-lymphocyte-rich (TILs) samples were available in 19 and paired tumor-germline samples in 68 cases. Top mutated genes were BRCA1 (54% of all tumors); BRCA2 (29%); TP53 (22%); KRAS (18%). Based on the presence and number of mutations and mutated genes, NPC were classified as stable (no mutations, n 5 27); unstable (>7 genes with multiple mutations, all BRCA1 positive, n 5 21); and of intermediate stability (1-7 singly mutated genes, n 5 78). BRCA1 p.Q563* was present in 59 tumors (48%), more frequently from Romanian patients (p < 0.001). No pathogenic germline mutations were identified. NPC exhibited APOBEC3A/B and nucleotide-excision-repair-related mutational signatures. As compared to TC, TILs demonstrated few shared and a higher number of low frequency private mutations (p < 0.001). In multivariate analysis models for progressionfree survival, EBV positivity was a favorable prognosticator in stable tumors; BRCA1 mutations were unfavorable only in tumors of intermediate stability. In conclusion, other than described for SEA NPC, somatic BRCA1 mutations were common in SEE NPC; these were shared between TC and TILs, and appeared to affect patient outcome according to tumor genomic stability status. Along with the identified mutational signatures, these novel data may be helpful for designing new treatments for locally advanced NPC.

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“…Another point concerns mutated cells displaying an apparently normal phenotype despite typical oncogenic genome alterations. [87][88][89][90][91][92] Actual unambiguous precancer lesions may appear after a long latent period or may possibly never appear. Then, transition from indolent precancer to cancer, a likely infinitesimal probability event involving a trophoblastic-like reprogramming, would yet again be lasting a long time ( Figure 5).…”

Section: Modulation Of Tumor Propagation By Gap Junction Intercellulamentioning

confidence: 99%

<p>Plausibility of trophoblastic-like regulation of cancer tissue</p>

Piechowski¹

2019

CMAR

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Background: Thus far, a well-established logical pattern of malignancy does not exist. The current approach to cancer properties is primarily descriptive with usually, for each of them, extensive analyses of the underlying associated biomolecular mechanisms. However, this remains a catalog and it would be valuable to determine the organizational chart that could account for their implementation, hierarchical links and input into tumor regulation. Hypothesis: Striking phenotypic similarities exist between trophoblast (invasive and expanding early placenta) and cancer regarding cell functions, logistics of development, means of protection and capacity to hold sway over the host organism. The concept of cancer cell trophoblastic-like transdifferentiation appears to be a rational proposal in an attempt to explain this analogy and provide a consistent insight into how cancer cells are functioning. Should this concept be validated, it could pave the way to promising research and therapeutic perspectives given that the trophoblastic properties are vital for the tumor while they are permanently epigenetically turned off in normal cells. Specifically targeting expression of the trophoblastic master genes could thereby be envisaged to jeopardize the tumor and its metastases without, in principle, inducing adverse side effects in the healthy tissues. Conclusion: A wide set of functional features of cancer tissue regulation, including some apparently paradoxical facts, was reviewed. Cancer cell misuse of physiological trophoblastic functions can clearly account for them, which identifies trophoblastic-like transdifferentiation as a likely key component of malignancy and makes it a potential relevant anticancer target.

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Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer

Cited by 44 publications

References 128 publications

Circulating tumor cells and breast cancer‑specific mutations in primary breast cancer

Circulating tumor cells and breast cancer‑specific mutations in primary breast cancer

Prevalent somatic BRCA1 mutations shape clinically relevant genomic patterns of nasopharyngeal carcinoma in Southeast Europe

<p>Plausibility of trophoblastic-like regulation of cancer tissue</p>

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