PIK3CA exon9 mutations associate with reduced survival, and are highly concordant between matching primary tumors and metastases in endometrial cancer

Mjos, Siv; Werner, Henrica M.J.; Birkeland, Even; Holst, Frederik; Berg, Ansgar; Halle, Mari K.; Tangen, Ingvild L.; Kusonmano, Kanthida; Mauland, Karen Klepsland; Øyan, Anne Margrete; Kalland, Karl‐Henning; Lewis, Aurélia E.; Mills, Gordon B.; Krakstad, Camilla; Trovik, Jone; Salvesen, Helga B.; Høivik, Erling A.

doi:10.1038/s41598-017-10717-z

Cited by 25 publications

(37 citation statements)

References 60 publications

(104 reference statements)

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“…As for survival, no signi cant association has been reported between PIK3CA mutations and disease-free survival in 94 EC patients [10]. On the other hand, associations have been reported between PIK3CA missense mutation and unfavorable outcome in grade 3 EEC tumors, and between PIK3CA exon 9 mutations and reduced survival in EC patients [23,24]. In the current study, there were no signi cant associations between the PIK3CA mutation and any clinicopathological features or survival.…”

Section: Discussioncontrasting

confidence: 66%

Clinical Relevance of Oncogenic Driver Mutations Identified in Endometrial Carcinoma

Watanabe

Nanamiya

Kojima

et al. 2020

Preprint

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Background: Endometrial carcinoma is a clinically heterogeneous disease characterized by a number of different histological subtypes, and its heterogeneity may be involved in the accumulation of multiple genetic alterations. The aim of this work is to investigate a comprehensive mutational profile of endometrial carcinoma tumors, and examine the correlations with somatic mutations and clinicopathological features or survival in endometrial carcinoma patients. Methods: A total of 100 surgical tumors were obtained from endometrial carcinoma patients who had undergone surgery at Fukushima Medical University Hospital between 2013 and 2017. Genomic DNA samples extracted form fresh-frozen tissues were analyzed using the Ion AmpliSeq Cancer Hotspot Panel v2 Kit covering 50 tumor-related genes.Results: Validated mutations were detected in 91 of the 100 tumors (91%) and identified in eight of the most frequently mutated genes, namely PTEN (57%), PIK3CA (51%) and TP53 (30%) KRAS (23%), CTNNB1 (21%), FBFR2 (13%), FBXW7(10%) and RB1 (9%). PTEN mutations correlated with young age (< 60), early-stage, endometrioid histology, non-recurrence and better overall survival. CTNNB1 mutations correlated with young age, endometrioid histology and better overall survival. On the other hands, TP53 mutations correlated with late-stage, non-endometrioid histology, high-grade, recurrence and worse overall survival. FBWX7 mutations correlated with late-stage, vascular invasion and lymph node metastasis. FGFR2 mutations correlated with deep (≥ 1/2) myometrial invasion. No statistically significant associations were found between clinicopathological characteristics or overall survival and PIK3CA, KRAS or RB1 mutations were found.Conclusion: Our study demonstrated that mutations in PTEN and CTNNB1 could be predictive biomarkers for favorable outcome, while mutations in TP53, FBXW7 and FGFR2 could be those for adverse outcome. Our comprehensive mutational profile is useful for understanding and evaluating the molecular characteristics of endometrial carcinoma patients, and will lead to the establishment of novel treatment strategies that improve the survival of patients with endometrial carcinoma in the future.

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Section: Discussioncontrasting

confidence: 66%

Clinical Relevance of Oncogenic Driver Mutations Identified in Endometrial Carcinoma

Watanabe

Nanamiya

Kojima

et al. 2020

Preprint

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“…The protein product of the PIK3CA gene is the catalytic subunit, p110a, in class IA of PI3K 24 . Mutations of PIK3CA have been found in multiple malignant tumors, such as breast cancer 25 , endometrial cancer 26 and bladder cancer 27 . Previous studies have reported that the frequency of PIK3CA mutation in CRC is 7%-32% 8 , 28 – 31 .…”

Section: Discussionmentioning

confidence: 99%

PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer

et al. 2018

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Chemotherapy represents an important treatment option for colorectal cancer (CRC), but only half of the patients benefit from these regimens. We explored the potential predicting value and mechanism of PIK3CA mutation in CRC chemotherapy. CRC specimens from 440 patients were retrospectively collected and examined with a fluorescence PCR-based method. The correlation of first-line chemotherapy response and PIK3CA mutation was evaluated according to follow-up and medical records. The underlying mechanism of PIK3CA mutation in chemotherapy resistance was assessed with CRC tumors and primary cells. The mutation frequency of the PIK3CA gene in CRC patients was 9.55%, which was correlated with late TNM staging and lower histological grade. The CRC patients with PIK3A mutation showed worse response to first-line chemotherapy than those without PIK3CA mutation. PIK3A mutation tumor cells showed poor sensitivity to first-line chemotherapy in vitro and in vivo. PIK3CA mutation induced PI3K/Akt signaling activation to increase LGR5+ CRC stem cells survival and proliferation, from which lead to chemotherapy resistance. Furthermore, PIK3CA mutation/LGR5+ expression was an independent detrimental factor for CRC patients. Our findings indicated that PIK3CA mutation induced PI3K/Akt activation contributed to CRC stem cells survival and proliferation, from which cells further resistance to chemotherapy. PIK3CA mutation/LGR5+ expression was a potential biomarker for monitoring chemotherapy resistance in CRC.

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“…Although there are multiple variations of PIK3CA mutation, the "hot-spot" mutations are located within the helical (exon 9) or kinase (exon [42]. While previous studies have investigated the potential associations between various PIK3CA mutations and clinical prognosis [43][44][45], prediction of pharmacological vulnerability based on these mutations remains elusive. Interestingly, when we evaluated drug sensitivities to PI3K compounds in PIK3CA-mutant tumors, we found that SNVs that lead to E542K amino acid substitution induced the most robust susceptibility to an AKT inhibitor (AZD5363) compared to other PIK3CA mutations (Fig.…”

Section: Pharmacogenomic Landscape Of Gastric Cancermentioning

confidence: 99%

Comprehensive pharmacogenomic characterization of gastric cancer

et al. 2020

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Background: Gastric cancer is among the most lethal human malignancies. Previous studies have identified molecular aberrations that constitute dynamic biological networks and genomic complexities of gastric tumors. However, the clinical translation of molecular-guided targeted therapy is hampered by challenges. Notably, solid tumors often harbor multiple genetic alterations, complicating the development of effective treatments. Methods: To address such challenges, we established a comprehensive dataset of molecularly annotated patient derivatives coupled with pharmacological profiles for 60 targeted agents to explore dynamic pharmacogenomic interactions in gastric cancers. Results: We identified lineage-specific drug sensitivities based on histopathological and molecular subclassification, including substantial sensitivities toward VEGFR and EGFR inhibition therapies in diffuse-and signet ring-type gastric tumors, respectively. We identified potential therapeutic opportunities for WNT pathway inhibitors in ALK-mutant tumors, a significant association between PIK3CA-E542K mutation and AZD5363 response, and transcriptome expression of RNF11 as a potential predictor of response to gefitinib. Conclusions: Collectively, our results demonstrate the feasibility of drug screening combined with tumor molecular characterization to facilitate personalized therapeutic regimens for gastric tumors.

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PIK3CA exon9 mutations associate with reduced survival, and are highly concordant between matching primary tumors and metastases in endometrial cancer

Cited by 25 publications

References 60 publications

Clinical Relevance of Oncogenic Driver Mutations Identified in Endometrial Carcinoma

Clinical Relevance of Oncogenic Driver Mutations Identified in Endometrial Carcinoma

PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer

Comprehensive pharmacogenomic characterization of gastric cancer

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