The status of Her2 amplification and Kras mutations in mucinous ovarian carcinoma

Chang, Kuang-Leei; Lee, Ming‐Yung; Chao, Wan‐Ru; Han, Chih-Ping

doi:10.1186/s40246-016-0096-9

Cited by 30 publications

(20 citation statements)

References 9 publications

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“…Concurrent aberrant ERBB2 and KRAS signaling has been observed in a marked number of cases (~11%), suggesting that acquired ERBB2 amplification is secondary to the emergence of KRAS activating mutation (10). Although oncogenic KRAS driver mutations and ERBB2 amplification are not mutually exclusive (15), KRAS mutations may be mutually exclusive with c-MYC amplification (9).…”

Section: Potential Candidate Gene Alterations In Mucinous Ovarian Cancermentioning

confidence: 99%

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

et al. 2018

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Abstract. Cases of mucinous ovarian cancer are predominantly resistant to chemotherapies. The present review summarizes current knowledge of the therapeutic potential of targeting the Wingless (WNT) pathway, with particular emphasis on preclinical and clinical studies, for improving the chemoresistance and treatment of mucinous ovarian cancer. A review was conducted of English language literature published between January 2000 and October 2017 that concerned potential signaling pathways associated with the chemoresistance of mucinous ovarian cancer. The literature indicated that aberrant activation of growth factor and WNT signaling pathways is specifically observed in mucinous ovarian cancer. An evolutionarily conserved signaling cascade system including epidermal growth factor/RAS/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase, phosphoinositide 3-kinase/Akt and WNT signaling regulates a variety of cellular functions; their crosstalk mutually enhances signaling activity and induces chemoresistance. Novel antagonists, modulators and inhibitors have been developed for targeting the components of the WNT signaling pathway, namely Frizzled, low-density lipoprotein receptor-related protein 5/6, Dishevelled, casein kinase 1, AXIN, glycogen synthase kinase 3β and β-catenin. Targeted inhibition of WNT signaling represents a rational and promising novel approach to overcome chemoresistance, and several WNT inhibitors are being evaluated in preclinical studies. In conclusion, the WNT receptors and their downstream components may serve as novel therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer.

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Section: Potential Candidate Gene Alterations In Mucinous Ovarian Cancermentioning

confidence: 99%

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

et al. 2018

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“…mEOC is not associated with BRCA1/2 mutations, whereas approximately 25% of HGSOCs carry either germline or somatic mutations of these genes [12,14]. KRAS mutations are observed in 40-50% of patients, and ERBB2 (human epidermal growth factor receptor 2, HER2) gene amplification has been observed in 20-30% of invasive mEOCs [15,16]. Furthermore, mEOC has been associated with a homozygous loss of the cyclin-dependent kinase inhibitor 2A (CDKN2A) locus, and mutations in genes that activate the mitogen activated protein kinase (MAPK) pathways (such as BRAF, AKT1 and PI3K) [13].…”

Section: Introductionmentioning

confidence: 99%

Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

Affatato

Carrassa

Chilà

et al. 2020

Cancers

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Mucinous epithelial ovarian cancer (mEOC) is a rare subset of epithelial ovarian cancer. When diagnosed at a late stage, its prognosis is very poor, as it is quite chemo-resistant. To find new therapeutic options for mEOC, we performed high-throughput screening using a siRNA library directed against human protein kinases in a mEOC cell line, and polo-like kinase1 (PLK1) was identified as the kinase whose downregulation interfered with cell proliferation. Both PLK1 siRNA and two specific PLK1 inhibitors (onvansertib and volasertib) were able to inhibit cell growth, induce apoptosis and block cells in the G2/M phase of the cell cycle. We evaluated, in vitro, the combinations of PLK1 inhibitors and different chemotherapeutic drugs currently used in the treatment of mEOC, and we observed a synergistic effect of PLK1 inhibitors and antimitotic drugs. When translated into an in vivo xenograft model, the combination of onvansertib and paclitaxel resulted in stronger tumor regressions and in a longer mice survival than the single treatments. These effects were associated with a higher induction of mitotic block and induction of apoptosis, similarly to what was observed in vitro. These data suggest that the combination onvansertib/paclitaxel could represent a new active therapeutic option in mEOC.

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“…[17,18] After merging the previously reported raw data of HER2 ampli cations, HER2 mutations and KRAS mutations with the new information of BRAF, we identi ed that their corresponding frequencies are 35% for HER2 ampli cations, 35% for HER2 mutations, 60% for KRAS mutations and 80% for BRAF mutations in all 20 MOC Taiwanese patients (Table 1). [9,10] Our ndings also indicated that there was no signi cant difference in the frequency between BRAF mutations and KRAS mutations when they were compared. However, the frequency of BRAF mutations was signi cant higher than that of HER2 ampli cations and HER2 mutations, respectively.…”

Section: Discussionmentioning

confidence: 58%

“…However, except for one case missing residual DNA and lacking of enough extra tumor component, the characteristics of all remaining study materials of all 20 cases of MOC were described in our previous report, including tissue retrieval and DNA preparation. [2,[8][9][10] Additionally, 7 normal ovarian tissues are used as negative controls. The research was conducted according to International Conference on Harmonization guidelines and complied with all applicable regulations for protection of human subjects of research, including review and approval by the Institutional Review Board, Chung-Shan Medical University Hospital Taichung, Taiwan.…”

Section: Methodsmentioning

confidence: 99%

High frequency of BRAF mutations in mucinous ovarian carcinoma of Taiwanese patients

Wan-Ru¹,

Chao²,

Li³

et al. 2020

Preprint

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Background In view of the encouraging clinical evidence of BRAF inhibitors that can treat some melanoma patients successfully, we aimed to investigate the status of BRAF mutations of primary mucinous ovarian carcinomas (MOC) in Taiwanese women, and apply the emerging paradigm classification of BRAF mutation groups. Methods DNA was extracted from micro-dissected tissue samples using the QIAamp® DNA FFPE Kit. The mutations of activation segment (exon 15), CR3 (conserved regions 3), kinase domain of the BRAF gene were analyzed using the highly sensitive BRAF mutant enriched kit (FemtoPath®) with subsequent Sanger sequencing method. Additionally, we extended our prior data of HER2 aberrations and KRAS mutation into this study in order to compare with the status of BRAF mutation. Results Out of the 20 cases tested, 16 (80%) harbored BRAF missense mutations. Their mutation profile and case number (n) were categorized as (1) class I: V600E (n = 1), V600M (n = 1); (2) class II: A598V (n = 1), T599I (n = 10); (3) class III: none (n = 0); and (4) unclassified variants: S602F (n = 2), dual T599I plus S602F (n = 1). The BRAF missense mutation (S602F) is novel. In addition, the prevalence of BRAF gene mutation is significantly higher than HER2 gene mutation (80% vs. 35%; p = 0.022,) and HER2 gene amplification (80% vs. 35%; p = 0.022), respectively. However, the mutation rates of BRAF and KRAS were not significantly different (80% vs. 60%; p = 0.289). Discussion Our results showed that BRAF mutation is not uncommon in primary MOC of Taiwanese. When taken together with previous published data, we found that the activating BRAF mutation, HER2 amplification, HER2 mutation and KRAS mutation were not mutually exclusive, but simultaneously independent. However, they may even have a synergistic effect in tumorigenesis. Conclusions The BRAF variant with T599I stands the majority. These findings suggested that there was a lower potential response to the existing V600 BRAF inhibitors, but may be responsive to dual BRAF plus MEK inhibitors or single MEK inhibitor in MOC. Further studies are warranted to investigate the clinical benefits of newly targeted therapy in recurrent or advanced stage MOC patients carrying each class of BRAF mutation.

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The status of Her2 amplification and Kras mutations in mucinous ovarian carcinoma

Cited by 30 publications

References 9 publications

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

High frequency of BRAF mutations in mucinous ovarian carcinoma of Taiwanese patients

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