Mutational spectrum in clinically aggressive low-grade serous carcinoma/serous borderline tumors of the ovary—Clinical significance of BRCA2 gene variants in genomically stable tumors

Zhang, Xiaoming; Devins, Kyle M.; Ko, Emily; Reyes, Maria R.; Simpkins, Fiona; Drapkin, Ronny; Schwartz, Lauren E.; Yoon, Ju‐Yoon

doi:10.1016/j.ygyno.2021.03.019

Cited by 10 publications

(11 citation statements)

References 35 publications

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“…Analysing a case series comprising predominantly effusions, we found mutations involving the MAPK pathway in tumours from 8 of 22 patients (36%). Previous studies in which mutations in KRAS, BRAF and NRAS were all studied found a mutation in one of these genes in 37%-63% of analysed tumours, 10,[12][13][14][16][17][18] -our findings are consequently at the lower end of this range. This may owe to the fact that this study focused on metastatic disease rather than on the primary tumours, thereby possibly analysing more aggressive tumour clones, having survived at extra-ovarian sites.…”

Section: Discussionsupporting

confidence: 51%

“…ERBB2 mutation, found in one case, was not found in two previous series 10,13 but was recently found in two cases of LGSC in a series of clinically aggressive SBT and LGSC cases. 18 Mutations in the tyrosine kinase receptors MET and FLT3 and the kinase STK11…”

Section: Discussionmentioning

confidence: 99%

“…In several studies, molecular analysis has shown that the mitogen-activated protein kinase (MAPK) pathway is frequently altered in LGSC, with KRAS, NRAS and BRAF mutations most often detected, while TP53 mutations, a hallmark of HGSC, are rare or absent. [6][7][8][9][10][11][12][13][14][15][16][17][18] MAPKs are signalling proteins consisting of the extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun amino-terminal kinases 1-3 (JNK1-3), p38 (α, β, γ, and δ), and ERK5 families. They regulate critical cellular processes, including cellular development, differentiation, proliferation, and apoptosis.…”

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confidence: 99%

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Molecular characteristics of low‐grade serous carcinoma in effusions

et al. 2023

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Objective The molecular characteristics of low‐grade serous carcinoma (LGSC) in serous effusions have not been studied previously. The present study analysed the molecular profile of LGSC at this anatomical site. Methods Specimens consisted of a series of 17 serous effusions (15 peritoneal, 2 pleural) from 16 patients, of which 15 were LGSC and 2 serous borderline tumour (SBT) who later progressed to LGSC. For comparative purposes, 9 surgical specimens from 6 patients with LGSC were analysed. Fresh‐frozen cell pellets and surgical specimens underwent targeted next‐generation sequencing covering 50 unique genes. Results Mutations were found in tumours from 14 of the 22 patients, of whom 4 had 2 different mutations and 10 had a single mutation. Overall, the most common mutations were in KRAS (n = 3) and BRAF (n = 3), followed by NRAS (n = 2), CDK2NA (n = 2), TP53 (n = 2), ATM (n = 2). Mutations in MET, STK11, ERBB2 and FLT3 were found in one case each. Patient‐matched specimens had the same molecular profile. Both effusions with TP53 mutation had concomitant ATM mutation, and both stained immunohistochemically with a wild‐type pattern. The absence of mutations was associated with a trend for shorter overall survival in univariate analysis (p = 0.072). Conclusions The molecular alterations in LGSCs in serous effusions are consistent with those found in solid tumours, with frequent alterations in the mitogen‐activated protein kinase pathway. Mutations in LGSC may be a marker of better outcomes.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Molecular characteristics of low‐grade serous carcinoma in effusions

et al. 2023

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“…9 Most low-grade tumors typically harbor KRAS mutation in 30-50% of cases or BRAF mutation in 15-40% of cases. 21,27,29,[74][75][76] Somatic mutation of KRAS in codons 12 and 13 and BRAF mutation in codon 599 are most common. 77 Activating NRAS (Q61R) mutation has been detected in 4% of LGSOC tumors, indicating that NRAS plays a limited role in this subtype.…”

Section: Low-grade Serous Carcinoma (Lgsoc)mentioning

confidence: 99%

Aberrant MAPK Signaling Offers Therapeutic Potential for Treatment of Ovarian Carcinoma

Colic¹,

Patel²,

Kent³

2022

OTT

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Ovarian cancer remains the most lethal gynecological malignancy worldwide due to lack of effective screening, vague early symptoms, poor description of biomarkers, and absence of effective treatment regimes. Epithelial ovarian carcinoma (EOC) is categorized into five distinct disease subtypes which collectively account for ~90% of ovarian carcinomas. Most women present at advanced stages contributing to a poor overall 5-year survival rate. Standard treatment for EOC is cytoreductive surgery and platinumbased chemotherapy; however, most patients suffer from recurrence and platinum-resistant disease, which highlights an urgent need for targeted therapy. The high frequency of molecular alterations affecting gain-of-function signaling through the RAS mitogenactivated protein kinase (MAPK) pathway in EOC has prompted pre-clinical and clinical efforts toward research into the effectiveness of MAPK pathway inhibition as a second-line treatment. The RAS/MAPK pathway is a highly conserved signal transduction cascade, often disrupted in cancer, that regulates tumorigenic phenotypes including cellular proliferation, survival, migration, apoptosis, and differentiation. Herein, the role of the MAPK pathway in EOC with emphasis on targetability of the pathway is described. Pre-clinical and clinical efforts to target MAPK signaling in EOC have identified several MAPK pathway inhibitors that offer efficacious potential for monotherapy and in combination with other compounds. Thus, inhibition of the RAS/MAPK pathway is emerging as a tractable strategy for treatment of ovarian cancer that may permit development of personalized therapy and improved prognosis for women challenged by this disease.

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“…Other prognostic factors include family predisposition related mainly to mutations in the BRCA 1 and 2 genes, and Lynch syndrome, as well as infertility, childlessness, endometriosis, obesity, menopausal age and the use of talcum powder in cosmetics [7]. A mutation in the BRCA 1 gene increases the in vivo risk of ovarian cancer by 40-60%, and in BRCA 2 by 11-27% [8,9]. The factors reducing the risk of this cancer are mainly oral contraceptives and having many children.…”

Section: Introductionmentioning

confidence: 99%