Clinical outcomes and differential effects of PI3K pathway mutation in obese versus non-obese patients with cervical cancer

Grigsby, Perry W.; Elhammali, Adnan; Ruiz, Fiona; Markovina, Stephanie; McLellan, Michael D.; Miller, Christopher A.; Chundury, Anupama; Ta, Ngoc Anh L.; Rashmi, Ramachandran; Pfeifer, John D.; Fulton, Robert S.; DeWees, T.A.

doi:10.18632/oncotarget.23664

Cited by 15 publications

(14 citation statements)

References 27 publications

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“…Grigsby et al [26] investigated the impact of PIK3CA mutations on OS rates of obese and normal-weight patients with cervical cancer. They found that the impact was significant in the obese population ( p = 0.09) but the effect was not significant in the normal-weight population.…”

Section: Resultsmentioning

confidence: 99%

PIK3CA Mutations and Their Impact on Survival Outcomes of Patients with Cervical Cancer: A Systematic Review

et al. 2020

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Introduction: Several studies have implicated the PIK3/AKT pathway in the pathophysiology of cancer progression as its activation seems to be aberrant in several forms of cancer. The purpose of the present systematic review is to evaluate the impact of PIK3CA mutations on survival outcomes of patients with cervical cancer. Methods: We used the Medline (1966–2020), Scopus (2004–2020), ClinicalTrials.gov (2008–2020), EMBASE (1980–2020), Cochrane Central Register of Controlled Trials (CENTRAL) (1999–2020), and Google Scholar (2004–2020) databases in our primary search along with the reference lists of electronically retrieved full-text papers. Statistical meta-analysis was performed with the RevMan 5.3 software. Results: Overall, 12 articles were included in the present study that comprised 2,196 women with cervical cancer. Of those, 3 studies did not report significant differences in survival outcomes among patients with mutated versus wild-type PIK3CA tumors, 5 studies reported decreased survival outcomes, and 3 studies revealed increased survival rates. The meta-analysis revealed that patients with the mutated PIK3CA genotypes had worse overall survival compared to patients with wild-type PIK3CA (HR 2.31; 95% CI: 1.51, 3.55; 95% PI: 0.54, 9.96; data from 3 studies) and the same was observed in the case of DFS rates (HR 1.82; 95% CI: 1.47, 2.25; 95% PI: 1.29, 2.56; data from 4 studies). Conclusion: Current evidence concerning the impact of PIK3CA mutations on survival outcomes of patients with cervical cancer is inconclusive, although the majority of included studies support a potential negative effect, primarily among those with squamous cell carcinoma tumors.

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Section: Resultsmentioning

confidence: 99%

PIK3CA Mutations and Their Impact on Survival Outcomes of Patients with Cervical Cancer: A Systematic Review

et al. 2020

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“…50,51 However, the nominal 60 cm bore diameters of the commercial PET/MRIs may not accommodate many of our patients since~40% of our patients are obese consistent with the National Health and Nutrition Examination Survey. 52,53 Of the institutional 70 cm diameter wide-bore systems we measured, the Siemens 3 T Vida and the Philips 1.5 T Ingenia had the highest field homogeneity for their respective field strengths. The Ingenia is our default MRI simulator and came equipped with RT features (flat table, external laser positioning, RT QA phantoms and sequences).…”

Section: D B 0 Field Homogeneity and Rtmentioning

confidence: 97%

B₀ field homogeneity recommendations, specifications, and measurement units for MRI in radiation therapy

et al. 2020

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Purpose: The purpose is: (a) Relate magnetic resonance imaging (MRI) quality recommendations for radiation therapy (RT) to B 0 field homogeneity; (b) Evaluate manufacturer specifications of B 0 homogeneity for 34 commercial whole-body MRI systems based on the MRI quality recommendations and RT application; (c) Measure field homogeneity in five commercial MRI systems and one commercial MRI-Linac used in RT and compare the results with their B 0 homogeneity specifications. Methods: Magnetic resonance imaging quality recommendations for spatial integrity, image blurring, fat saturation, and null banding in RT were developed based on the literature. Guaranteed (maximum) and typical B 0 field homogeneity specifications for various diameter spherical volumes (DSVs) were provided by GE, Philips, Siemens, and Canon. For each system, the DSV that conforms to each MRI quality recommendation and anatomical RT application was estimated based on the manufacturer specifications. B 0 field homogeneity was measured on six MRI systems including Philips (1.5 T), Siemens (1.5 and 3 T), and ViewRay MRI (0.35 T) systems using 24 and 35 cm DSV spherical phantoms. Two measurement techniques were used: (a) MRI using phase contrast field mapping to measure peak-to-peak (pk-pk), volume root mean square (VRMS), and standard deviation (SD); and (b) Magnetic resonance (MR) spectroscopy by acquiring a volumetric free induction decay (FID) to measure full width at half maximum (FWHM). The measurements were used to assess: (a) conformance with the manufacturer specifications; and (b) the relationship between the various field homogeneity measurement units. Measurements were made with and without gradient shimming (gradshim) or second-order active shimming. Multiple comparisons, analysis of variance (ANOVA), and Pearson correlations were performed to assess the dependence of pk-pk, VRMS, SD, and FWHM measurements of field homogeneity on shim volume, level of shim, and MRI system. Results: For a 40 cm DSV, the B 0 homogeneity specifications ranged from 0.35 to 5 ppm (median = 0.75 ppm) VRMS for 1.5 T systems and 0.2 to 1.4 ppm (median = 0.5 ppm) VRMS for 3 T systems. The usable DSVs ranged from 16 to 49 cm (median = 35 cm) based on the image quality recommendations and the manufacturer specifications. There was general compliance between the six measured field homogeneities and manufacturer specifications although signal dephasing was observed in two systems at < 35 cm DSV. The relationships between pk-pk, VRMS, SD, and FWHM varied based on MRI system, shim volume, and quality of shim. However, VRMS and SD measurements were highly correlated. Conclusions: The delineation of the diseased lesion from organs at risk is the main priority for RT. Therefore, field homogeneity performance for RT must minimize image blurring and image artifacts (null bands and signal dephasing) while optimizing spatial integrity and fat saturation. Based on the specifications and recommendations for field homogeneity, some MRI systems are not well suited to meet the stri...

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“…Pathways in the top right quadrant have significant marginal epistatic effects in both traits; while, points in the bottom right and top left quadrants are pathways that are uniquely enriched in height or BMI, respectively. The four highlighted pathways in blue represent a cluster of oncogenic and signaling pathways whose loci have been functionally connected to BMI in previous studies [122][123][124][125][126][127][128][129]. Across both databases, BMI results have lower MAPIT-R p-values than height results on average.…”

Section: Discussionmentioning

confidence: 87%

“…One particular gene in this group, AKT2, has been associated with multiple monogenic disorders of glucose metabolism, including severe insulin resistance and diabetes, and severe fasting hypoinsulinemic hypoglycemia [122][123][124], representing a possible driver of this cluster. Additionally, pharmacological inhibition of crosstalk between the PI3Ks has been shown to reduce adiposity and metabolic syndrome in both human beings and other model organisms [125][126][127][128][129].…”

Section: Stronger Epistatic Signals Underlie Bmi Than Heightmentioning

confidence: 99%

Pathway Analysis within Multiple Human Ancestries Reveals Novel Signals for Epistasis in Complex Traits

Turchin

Darnell

Crawford

et al. 2020

Preprint

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Genome-wide association (GWA) studies have identified thousands of significant genetic associations in humans across a number of complex traits. However, the majority of these studies focus on linear additive relationships between genotypic and phenotypic variation. Epistasis, or non-additive genetic interactions, has been identified as a major driver of both complex trait architecture and evolution in multiple model organisms; yet, this same phenomenon is not considered to be a significant factor underlying human complex traits. There are two possible reasons for this assumption. First, most large GWA studies are conducted solely with European cohorts; therefore, our understanding of broad-sense heritability for many complex traits is limited to just one ancestry group. Second, current epistasis mapping methods commonly identify significant genetic interactions by exhaustively searching across all possible pairs of SNPs. In these frameworks, estimated epistatic effects size are often small and power can be low due to the multiple testing burden. Here, we present a case study that uses a novel region-based mapping approach to analyze sets of variants for the presence of epistatic effects across six diverse subgroups within the UK Biobank. We refer to this method as the “MArginal ePIstasis Test for Regions” or MAPIT-R. Even with limited sample sizes, we find a total of 245 pathways within the KEGG and REACTOME databases that are significantly enriched for epistatic effects in height and body mass index (BMI), with 67% of these pathways being detected within individuals of African ancestry. As a secondary analysis, we introduce a novel region-based “leave-one-out” approach to localize pathway-level epistatic signals to specific interacting genes in BMI. Overall, our results indicate that non-European ancestry populations may be better suited for the discovery of non-additive genetic variation in human complex traits — further underscoring the need for publicly available, biobank-sized datasets of diverse groups of individuals.

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Clinical outcomes and differential effects of PI3K pathway mutation in obese versus non-obese patients with cervical cancer

Cited by 15 publications

References 27 publications

PIK3CA Mutations and Their Impact on Survival Outcomes of Patients with Cervical Cancer: A Systematic Review

PIK3CA Mutations and Their Impact on Survival Outcomes of Patients with Cervical Cancer: A Systematic Review

B₀ field homogeneity recommendations, specifications, and measurement units for MRI in radiation therapy

Pathway Analysis within Multiple Human Ancestries Reveals Novel Signals for Epistasis in Complex Traits

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Clinical outcomes and differential effects of PI3K pathway mutation in obese versus non-obese patients with cervical cancer

Cited by 15 publications

References 27 publications

PIK3CA Mutations and Their Impact on Survival Outcomes of Patients with Cervical Cancer: A Systematic Review

PIK3CA Mutations and Their Impact on Survival Outcomes of Patients with Cervical Cancer: A Systematic Review

B0 field homogeneity recommendations, specifications, and measurement units for MRI in radiation therapy

Pathway Analysis within Multiple Human Ancestries Reveals Novel Signals for Epistasis in Complex Traits

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Product

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B₀ field homogeneity recommendations, specifications, and measurement units for MRI in radiation therapy