Genomic alterations in gynecological malignancies: histotype-associated driver mutations, molecular subtyping schemes, and tumorigenic mechanisms

Mori, Seiichi; Gotoh, Osamu; Kiyotani, Kazuma; Low, Siew‐Kee

doi:10.1038/s10038-021-00940-y

Cited by 7 publications

(10 citation statements)

References 200 publications

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“…On the other hand, the endometrial endometrioid carcinoma was mainly characterized by somatic mutations in the PTEN gene (71%) which is the most common genomic aberration in this concrete subtype, occurring between 63% and 82% of endometrioid affected cases [ 14 , 46 ]. The PIK3CA gene was situated as the second more altered gene (60%), which is in accordance with described molecular genetics data in endometrial carcinomas [ 47 ]. An unexpected finding concerned the SNV of the NOTCH1 gene occurring in 48% of the endometrial endometrioid cases.…”

Section: Discussionsupporting

confidence: 88%

Comprehensive Approach to Genomic and Immune Profiling: Insights of a Real-World Experience in Gynecological Tumors

et al. 2022

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Gynecological cancer accounts for an elevated incidence worldwide requiring responsiveness regarding its care. The comprehensive genomic approach agrees with the classification of certain tumor types. We evaluated 49 patients with gynecological tumors undergoing high-throughput sequencing to explore whether identifying alterations in cancer-associated genes could characterize concrete histological subtypes. We performed immune examination and analyzed subsequent clinical impact. We found 220 genomic aberrations mostly distributed as single nucleotide variants (SNV, 77%). Only 3% were classified as variants of strong clinical significance in BRCA1 and BRCA2 of ovarian high-grade serous (HGSC) and uterine endometrioid carcinoma. TP53 and BRCA1 occurred in 72% and 28% of HGSC. Cervical squamous cell carcinoma was entirely HPV-associated and mutations occurred in PIK3CA (60%), as well as in uterine serous carcinoma (80%). Alterations were seen in PTEN (71%) and PIK3CA (60%) of uterine endometrioid carcinoma. Elevated programmed death-ligand 1 (PD-L1) was associated with high TILs. Either PD-L1 augmented in deficient mis-matched repair (MMR) proteins or POLE mutated cases when compared to a proficient MMR state. An 18% received genotype-guided therapy and a 4% immunotherapy. The description of tumor subtypes is plausible through high-throughput sequencing by recognizing clinically relevant alterations. Additional concomitant assessment of immune biomarkers identifies candidates for immunotherapy.

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Section: Discussionsupporting

confidence: 88%

Comprehensive Approach to Genomic and Immune Profiling: Insights of a Real-World Experience in Gynecological Tumors

et al. 2022

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“…Moreover, 50–70% of these patients are diagnosed with advanced-stage disease [ 3 , 27 , 28 , 29 , 30 ]. Furthermore, in our series, 45.5% of women had mixed type endometrial cancer, which is another well-documented characteristic of uterine papillary serous carcinoma [ 31 ], as it has been described that mixed carcinomas are possibly serous carcinomas displaying endometrioid mimicry [ 32 ]. On multivariable analysis, mixed type was not found to be significantly associated with survival, and patients with mixed and pure USC had a comparable survival rate, which is a result that has been debated in the bibliography with contradicting results from varying studies [ 13 , 33 , 34 ].…”

Section: Discussionmentioning

confidence: 59%

What Has Changed in the Management of Uterine Serous Carcinomas? Two Decades of Experience

et al. 2021

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Uterine serous carcinoma accounts for 3–10% of endometrial cancers, but it is the most lethal histopathological subtype. The molecular characterization of endometrial carcinomas has allowed novel therapeutic approaches for these patients. We undertook a retrospective analysis of patients with uterine serous carcinomas treated in our hospital within the last two decades to identify possible changes in their management. The patients and their characteristics were evenly distributed across the two decades. Treatment modalities did not change significantly throughout this period. After adjuvant treatment, patients’ median disease-free survival was 42.07 months (95% CI: 20.28–63.85), and it did not differ significantly between the two decades (p = 0.059). The median overall survival was 47.51 months (95% Cl: 32.18–62.83), and it significantly favored the first decade’s patients (p = 0.024). In patients with de novo metastatic or recurrent disease, median progression-free survival was 7.8 months (95% Cl: 5.81–9.93), whereas both the median progression-free survival and the median overall survival of these patients did not show any significant improvement during the examined time period. Overall, the results of our study explore the minor changes in respect of uterine serous carcinoma’s treatment over the last two decades, which are reflected in the survival outcomes of these patients and consequently underline the critical need for therapeutic advances in the near future.

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“…The epithelial and sarcomatous components were initially thought to develop as a combination of cellular masses secondary to an early divergence from a common precursor cancer stem cell (combination theory) or as a result of the collision between independent but adjacent epithelial and mesenchymal progenitors (collision theory) 8 10. Recently, several molecular and clonality studies have suggested that the endometrial carcinosarcoma arises from a single malignant epithelial clone (carcinoma lineage) that subsequently undergoes sarcomatous trans-differentiation, through a process of epithelial-to-mesenchymal transition (conversion theory) 10–12. The monoclonal origin of endometrial carcinosarcoma is supported on genetic, molecular, and clinical grounds 10–13.…”

Section: Pathological Features: the Conversion Theorymentioning

confidence: 99%

“…Recently, several molecular and clonality studies have suggested that the endometrial carcinosarcoma arises from a single malignant epithelial clone (carcinoma lineage) that subsequently undergoes sarcomatous trans-differentiation, through a process of epithelial-to-mesenchymal transition (conversion theory) 10–12. The monoclonal origin of endometrial carcinosarcoma is supported on genetic, molecular, and clinical grounds 10–13. The epithelial and mesenchymal elements share common genetic mutational profiles, and stromal cells often show positive immunohistochemical staining for epithelial markers 10–13…”

Section: Pathological Features: the Conversion Theorymentioning

confidence: 99%

“…The majority of endometrial carcinosarcomas share molecular and genomic similarities with high-grade serous ovarian carcinoma and serous endometrial carcinoma, while only a minority resembles the endometrioid counterpart 3 4 10 12–15. In particular, TP53 (60–97%) FBXW (10–44%), PPP2R1A (11–30%), HER2 (9–18%) serous-like mutations are common, whereas endometrioid-like mutations such as ARID1A (10–25%), KRAS (8–15%), PTEN (10–50%), and PIK3CA (20–40%) are less frequent 3 4 10 12. The mutational rates vary across the studies depending on the different endometrial carcinosarcoma subtypes included (eg, low-grade vs high-grade carcinomas).…”

Section: Molecular Landscapementioning

confidence: 99%

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Endometrial carcinosarcoma

Bogani

Ray‐Coquard

Concin

et al. 2022

Int J Gynecol Cancer

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Endometrial carcinosarcoma is a rare and aggressive high-grade endometrial carcinoma with secondary sarcomatous trans-differentiation (conversion theory). The clinical presentation and diagnostic work-up roughly align with those of the more common endometrioid counterpart, although endometrial carcinosarcoma is more frequently diagnosed at an advanced stage. Endometrial carcinosarcoma is not a single entity but encompasses different histological subtypes, depending on the type of carcinomatous and sarcomatous elements. The majority of endometrial carcinosarcomas are characterized by p53 abnormalities. The proportion ofPOLEand microsatellite instablity-high (MSI-H) is directly related to the epithelial component, being approximately 25% and 3% in endometrioid and non-endometrioid components.The management of non-metastatic disease is based on a multimodal approach with optimal surgery followed by (concomitant or sequential) chemotherapy and radiotherapy, even for early stages. Palliative chemotherapy is recommended in the metastatic or recurrent setting, with carboplatin/paclitaxel doublet being the first-line regimen. Although the introduction of immunotherapy plus/minus a tyrosine kinase inhibitor shifted the paradigm of treatment of patients with recurrent endometrial cancer, patients with endometrial carcinosarcoma were excluded from most studies evaluating single-agent immunotherapy or the combination. However, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of pembrolizumab and lenvatinib in endometrial cancer (all histotypes) after progression on chemotherapy and single-agent immunotherapy in MSI-H cancers. In the era of precision medicine, emerging knowledge on molecular endometrial carcinosarcoma is opening new promising therapeutic options for more personalized treatment. The present review outlines state-of-the-art knowledge and future directions for patients with endometrial carcinosarcoma.

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Genomic alterations in gynecological malignancies: histotype-associated driver mutations, molecular subtyping schemes, and tumorigenic mechanisms

Cited by 7 publications

References 200 publications

Comprehensive Approach to Genomic and Immune Profiling: Insights of a Real-World Experience in Gynecological Tumors

Comprehensive Approach to Genomic and Immune Profiling: Insights of a Real-World Experience in Gynecological Tumors

What Has Changed in the Management of Uterine Serous Carcinomas? Two Decades of Experience

Endometrial carcinosarcoma

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