Somatic alterations in a seven-gene DDR gene panel predicts platinum sensitivity in advanced prostate cancer patients.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 283-283
Author(s):  
Panagiotis J. Vlachostergios ◽  
Jyothi Manohar ◽  
Muhammad Junaid Niaz ◽  
Aileen Lee ◽  
Amy Hackett ◽  
...  
Keyword(s):  
Single Gene ◽  
Brca2 Gene ◽  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Kaplan Meier ◽  
Platinum Based Chemotherapy ◽  
Somatic Alterations ◽  
Brca1 Brca2 ◽  
Tissue Specimens ◽  
The Impact

283 Background: Genomic alterations in the DNA damage response and repair (DDR) pathways are common in advanced PC. Platinum compounds are active in CRPC pts. DDR-defective PC tumors have increased sensitivity to PARP inhibitors (PARPi); the mechanisms involved in sensitivity to platinum and PARPi may be similar but not identical. This study aimed to assess the impact of somatic DDR alterations on clinical outcome of platinum-treated patients with advanced PC. Methods: We reviewed records of advanced PC patients, who received platinum-based chemotherapy with available tumor tissue specimens. We used next generation sequencing (whole exome or targeted) to assess for mutations and copy number alterations in a selected panel of DDR genes, including BRCA1, BRCA2, ATM, ERCC3, ERCC5, TP53 and RB1. We used Kaplan Meier curves to predict PFS and OS after initiation of platinum chemotherapy. Results: Our cohort included 50 men, median age 69.5 years (45-91), median PSA 0.81 (0.008-2291.25), median LDH 264 (109-6714). 39 had visceral metastases (38 liver, 15 lung, 2 adrenal, 2 peritoneal, 1 brain). The majority or pts (33/50) received carboplatin, 17 received cisplatin (2 subsequently also received carbo with initial platinum used for data analysis). Most pts received chemotherapy doublets, and platinum was most frequently combined with etoposide (N=27) and paclitaxel (N=9). 39 pts had tumors harboring at least one DDR alteration. Somatic deletions in BRCA2 gene (N=18) were associated with a significantly longer PFS compared to men with wild-type BRCA2 (median PFS: 6 versus 3 months, P=0.019). No significant associations were identified between somatic DDR alterations and OS. Presence of ≥2 concomitant DDR somatic alterations predicted a favorable PFS compared to single-gene alterations or lack thereof (6 vs 3 months, P=0.006). Conclusions: Our study suggests that presence of ≥2 concomitant DDR somatic alterations from a 7-gene DDR panel, including BRCA1, BRCA2, ATM, ERCC3, ERCC5, TP53, and RB1, may predict longer PFS in pts with advanced PC treated with platinum-based chemotherapy. Further studies are needed to clinically qualify multiplex predictive biomarkers of DDR-defective PCs.

Comparative assessment of abiraterone or enzalutamide activity in the PROREPAIR-B study.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 164-164 ◽  
Author(s):  
Rebeca Lozano ◽  
Nuria Romero-Laorden ◽  
Angela del Pozo ◽  
Ana Medina ◽  
Maria Jose Mendez ◽  
...  
Keyword(s):  
Dna Repair ◽  
Progression Free Survival ◽  
Germline Mutations ◽  
Parp Inhibitors ◽  
Dna Repair Genes ◽  
Mutational Status ◽  
Platinum Based Chemotherapy ◽  
Brca1 Brca2 ◽  
The Impact ◽  
Repair Genes

164 Background: Germline mutations in DNA repair genes have been associated with poor prostate cancer outcomes in retrospectives studies. Such defects have been identified in 12% of mCRPC patients. Several studies are ongoing to assess the benefit of these patients from platinum-based chemotherapy and PARP inhibitors, but no conclusive data are available with regards to currently approved therapies for mCRPC, as Abiraterone or Enzalutamide. Methods: PROREPAIR-B (NCT03075735) is a prospective multicentre observational cohort study. Patients diagnosed with mCRPC, with unknown mutational status at study entry and who were going to start a first-line treatment for mCRPC were eligible. For this sub-analysis patients who received Abiraterone or Enzalutamide as first androgen receptor targeted therapy (ART) were selected. The endpoints of this sub-analysis included to assess the impact of BRCA1, BRCA2, ATM, PALB2 and other germline mutations in DNA repair genes on cause-specific survival (CSS), progression-free survival (PFS), time to PSA progression (bPFS) and response to the first ART received as 1st or 2nd line therapy. Results: 337 patients were eligible for this analysis. CSS from mCRPC was not significantly different between gDDR carriers and non-carriers. However, CSS from mCRPC in BRCA2 carriers was significantly shorter than in non-carriers (23.3 Vs 34.6 months, p = 0.02). CSS from first ART, PFS and response-rates were not significantly different between both groups. However, the bPFS was significantly shorter in patients harbouring gDDR mutations (7.3 Vs 3.8 months, p = 0.04), especially in BRCA2 carriers (7.3 Vs 3.0 months, p = 0.03). Conclusions: This is the first study to prospectively follow-up DNA repair germline mutations to determine the outcome on standard treatment for mCRPC. The results suggest that different gDDR defects may have different impact on mCRPC outcomes. Clinical trial information: NCT03075735.

ctDNA pathogenic variants (PVs) in homologous recombination repair (HRR) genes in patients with metastatic CRPC.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 138-138
Author(s):  
Ellen Jaeger ◽  
Elisa Marie Ledet ◽  
Marcus W. Moses ◽  
Charlotte Manogue ◽  
Brian E. Lewis ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Cancer Center ◽  
Small Subset ◽  
Published Data ◽  
Pathogenic Variants ◽  
Recombination Repair ◽  
Brca1 Brca2 ◽  
Allelic Fraction ◽  
Germline Testing

138 Background: HRR PVs can serve as predictive biomarkers and two PARP inhibitors are approved for metastasic CRPC (mCRPC) pts. Published data are predominantly focused on tissue-based assays, but obtaining tissue from mCRPC pts is problematic. In a large tissue based series (PROfound), 4047 mCRPC pts had tumor samples submitted for genomic testing but only 69% had interpretable results. No data were published from PROfound enumerating pts without available tissue to submit. Herein we assess frequency of PVs from selected HRR genes using a ctDNA assay. Methods: 292 mCRPC pts at Tulane Cancer Center were assessed for detectable HRR ctDNA changes using the Guardant 360 assay (which assesses the HRR genes BRCA1, BRCA2, and ATM). Results: 20/292 (6.8%) pts had a PV in ATM. However only 4/292 (1.4%) had > 1% mutant allelic fraction. Germline testing occurred in 18/20 of the ctDNA ATM PV pts and 0/18 had a germline PV. The PROfound series had 6.3% somatic PVs in ATM. 18/292 pts (6.2%) had a PV in BRCA2 and 12/292 (4.1%) had a mutant allelic fraction of > 1%. Germline testing was performed in 17/18 with BRCA2 ctDNA PVs and 9/17 had germline PVs. The PROfound series had 9.7% somatic BRCA2 PVs. BRCA1 PVs were detected in 6/292 (2.1%) pts and 3/292 (1%) had a mutant allelic fraction > 1%. 6/6 of the ctDNA PVs has germline testing and 1/6 had a BRCA1 PV. The PROfound series had 1.3% somatic PVs in BRCA1. Conclusions: Using ctDNA essay, it is feasible to measure PVs in only a small subset of HRR genes in mCRPC pts. These assays fail to detect deep deletions, a known and important mechanism of HRR gene loss. The ctDNA mutant allelic fractions are often low. The ability of ctDNA PVs using this assay to predict treatment effects are unknown.

Germline BRCA1/2, PALB2, and ATM mutations in 3,030 patients with pancreatic adenocarcinoma: Survival analysis of carriers and noncarriers.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 280-280
Author(s):  
Pashtoon Murtaza Kasi ◽  
Fergus Couch ◽  
William R Bamlet ◽  
Chunling Hu ◽  
Steven Hart ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Pancreatic Adenocarcinoma ◽  
Final Analysis ◽  
Parp Inhibitors ◽  
P Value ◽  
Pathogenic Variants ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Before And After ◽  
Brca1 Brca2

280 Background: Patients with pancreatic adenocarcinoma (PDAC) can have mutations in breast cancer associated genes ( BRCA1/2) and other homologous recombination (HR) pathway genes. The therapeutic significance of these mutations for PDAC patients is not yet established. We performed a comprehensive survival analysis of 3,030 unselected PDAC patients comparing non-carriers and carriers of BRCA1/2, PALB2, and ATM mutations. Methods: We analyzed germline DNA samples and outcomes from confirmed PDAC patients recruited from 1999-2014 into the Mayo Clinic SPORE in Pancreatic Cancer registry. A total of 3,046 genomic DNA samples were analyzed by next generation sequencing. All pathogenic variants were validated by Sanger sequencing. Survival analysis of PDAC patients with and without BRCA1, BRCA2, PALB2, or ATM germline mutations was performed using the Kaplan-Meier method and log-rank tests. Hazard ratios (HR) were calculated using Cox proportional hazard modeling adjusted for co-variates including age, sex, and stage. A p-value < 0.05 was considered statistically significant. Pre- and post-FOLFIRINOX eras were defined as before and after June 1, 2011. Results: A total of 139 (4.6%) patients were noted to have deleterious mutations in BRCA1, BRCA2, PALB2, or ATM genes. After exclusion of patients with missing data, final analysis was restricted to 2,452 PDAC patients. Overall survival was slightly better (14.2 months versus 11.3 months) in patients with mutations as compared to those without mutations, although this finding was not statistically significant (p = 0.07). When stratified by FOLFIRINOX era, 40 patients with these mutations in the post-FOLFIRINOX era had better outcomes than 668 non-carriers (adjusted HR 0.62; 95% CI 0.43-0.89; p = 0.0062). Conclusions: Deleterious germline BRCA1/2, PALB2, and ATM mutations were seen in approximately 5% of patients with PDAC. Post-FOLFIRINOX era patients with these mutations had improved outcomes, possibly secondary to exposure to DNA-damaging chemotherapies. Germline screening of PDAC patients and development of trials incorporating this information (e.g., PARP inhibitors) has potential value for PDAC patients.

A single arm phase II study of rucaparib maintenance in patients with advanced pancreatic adenocarcinoma and a known deleterious BRCA1, BRCA2 or PALB2 mutation who have achieved stability on platinum therapy.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS531-TPS531 ◽  
Author(s):  
Kim Anna Reiss ◽  
Kara Noelle Maxwell ◽  
Katharine Nathanson ◽  
Ursina R. Teitelbaum ◽  
Mark H. O'Hara ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Parp Inhibitor ◽  
Unmet Need ◽  
Parp Inhibitors ◽  
Ductal Adenocarcinoma ◽  
Cross Resistance ◽  
Platinum Resistance ◽  
Platinum Based Chemotherapy ◽  
Brca1 Brca2

TPS531 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a median overall survival of < 1 year. A subset of PDAC is characterized by a homologous recombination deficiency (HRD). The most well-defined patients within this group are those with deleterious mutations in BRCA1, BRCA2 and PALB2. This subset of tumors respond exceptionally well to treatment with platinum agents, leading to durable responses. However, cumulative toxicity can complicate or even prevent continued therapy, and there is an unmet need to establish maintenance strategies for such patients.Prior studies have shown that BRCA1 and BRCA2 associated PDACs respond to PARP inhibitors. Cross-resistance to platinum and PARP inhibitors exists, so initiating PARP inhibitor therapy after the development of platinum-resistance is an inferior approach. In this setting, we have designed a phase II trial of rucaparib as maintenance therapy for patients with deleterious BRCA1, BRCA2 or PALB2 who have sustained stability on platinum-based treatment. Methods: We have enrolled 2 of 42 planned patients on study NCT03140670. Eligibility criteria include inoperable PDAC, a known somatic or germline deleterious mutation in BRCA1, BRCA2 or PALB2 and stability on platinum-based chemotherapy for ≥16 weeks. Patients who have progressed on platinum-based treatment or who have received prior therapy with PARP inhibitors are excluded. Patients will receive oral rucaparib twice daily continuously in 28-day cycles. The primary endpoint is progression-free survival at 6 months. Secondary endpoints include response rate, duration of response and overall survival. A pre-treatment tumor biopsy and biopsy at progression will be obtained, as well as serial blood collections for circulating tumor material. Correlative assays will include tumor and circulating tumor DNA sequencing to identify genomic predictors of outcome and study resistance mechanisms. Clinical trial information: NCT03140670.

BRCA1 genetic variant to predict survival in metastatic colorectal cancer (mCRC) patients (pts) treated with FOLFIRI/bevacizumab (bev): Results from phase III TRIBE and FIRE-3 trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3145-3145 ◽  
Author(s):  
Madiha Naseem ◽  
Shu Cao ◽  
Sebastian Stintzing ◽  
Fotios Loupakis ◽  
Martin D. Berger ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Parp Inhibitors ◽  
Base Change ◽  
Phase Iii ◽  
Survival Outcomes ◽  
Discovery Cohort ◽  
Mutation Burden ◽  
Prospective Trials ◽  
Brca1 Brca2 ◽  
The Impact

3145 Background: BRCA muts in CRC are associated with a higher tumor mutation burden irrespective of microsatellite instability, which highlights the possibility of using PARP-inhibitors(i) in CRC in the future. Early phase studies have shown that combination of PARP-i with oxaliplatin or irinotecan enhances tumor lysis in CRC. In this study, we investigated the influence of mutations in the Homologous Repair Pathway genes on survival outcomes among mCRC pts treated with oxaliplatin or irinotecan-based regimens. Methods: The impact of selected SNPs within 4 genes (BRCA1, BRCA2, RAD51, BARD1) on OS/PFS was analyzed through the OncoArray, a custom array manufactured by Illumina, on genomic DNA from blood samples of 431 pts enrolled in 2 randomized trials. TRIBE FOLFIRI/bev arm (n = 215, mPFS/OS: 9.7/26.2 mo) served as discovery cohort, FIRE-3 FOLFIRI/bev arm (n = 107, mPFS/OS: 11.5/31.4 mo) as validation and TRIBE FOLFOX/bev arm (n = 109, mPFS/OS: 10.8/26 mo) as control. Results: Significant associations were found among carriers of BRCA1 rs8176318 SNP, where C > A base change is known to reduce BRCA1 expression among CRC cells. In the discovery cohort, pts with A/A had shorter OS (22.4 vs 27.3 mo, P = .009) and PFS (7.5 vs 10.5 mo, P = .0006) compared to carriers of any C allele in both univariate and multivariate analysis. Same results were observed in pts with left-sided CRCs (PFS-7.5 vs 11 mo, P = .005; OS- 25.6 vs 32.3, P = .034) and among males (PFS- 7.5 vs 10.3 mo, P = .008; OS- 25.7 vs 31.3 mo, P = .008) in both uni and multivariate analysis. These results were also seen in the validation cohort: A/A carriers in left-sided CRCs had poor OS (26.1 vs 36.0 mo, P = .027) and PFS (9.5 vs 11.7 mo, P = .002. Males with A/A genotype also had poor OS (24.7 vs 32.5 mo, P = .028) and PFS 96.9 vs 12.2 mo; P = .0002). In the control cohort, A/A genotype carriers had poor tumor response in overall (P = .011) and left-sided disease (P = .034). These outcomes were independent of KRAS mutation status. No significant relationship was observed among females with mCRC. Conclusions: This is the first study to report that BRCA1 mut influence survival outcomes among mCRC pts, particularly among males and those with left-sided disease. Prospective trials are warranted to assess the utility of routine BRCA mut testing and the role of PARP-i in improving survival outcomes in this pt population.

scholarly journals Transcriptional Expressions of CXCL9/10/12/13 as Prognosis Factors in Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Yan Li ◽  
Mingqiang Liang ◽  
Yuxiang Lin ◽  
Jinxing Lv ◽  
Minyan Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Predictive Biomarkers ◽  
Nodal Metastasis ◽  
Transcriptional Level ◽  
Breast Cancer Patients ◽  
Oncomine Database ◽  
Kaplan Meier ◽  
The Impact

CXCLs play critical roles in antitumor immunity by activating tumor-specific immune responses and stimulating tumor proliferation, thus affecting patient outcomes. However, the expression and prognostic values of CXCLs in breast cancer have not been well clarified. The aim of this study was to investigate the impact of CXCLs transcriptional expression on breast cancer patients. Oncomine database, GEPIA (Gene Expression Profiling Interactive Analysis), UALCAN, Kaplan–Meier Plotter, TIMER (Tumor Immune Estimation Resource), and DAVID were used in our study. The transcriptional levels of CXCL9/10/11/13 in breast cancer tissues were significantly elevated while the transcriptional levels of CXCL1/2/3/12 were decreased based on intersections of Oncomine database and GEPIA. Among them, breast cancer patients with high transcriptional levels of CXCL2/9/10/12/13 and low transcriptional level of CXCL3 were associated with a better prognosis. We also found that most of CXCLs expressions are significantly correlated with known prognostic factors, such as patient’s age, major subclasses, individual cancer stages, and nodal metastasis status. In addition, the expression of CXCL9/10/12/13 was also indicated to be correlated with the infiltration of six types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells). The functions of differentially expressed CXCLs are primarily related to the immune response and cytokine-cytokine receptor interactions. Our results may provide novel evidence of new prognostic or predictive biomarkers for breast cancer patients.

scholarly journals BRCA2 and Other DDR Genes in Prostate Cancer

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 352 ◽  
Author(s):  
Paz Nombela ◽  
Rebeca Lozano ◽  
Alvaro Aytes ◽  
Joaquin Mateo ◽  
David Olmos ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Germline Mutations ◽  
Parp Inhibitors ◽  
Brca1 And Brca2 ◽  
Damage Repair ◽  
Platinum Based Chemotherapy ◽  
History Of ◽  
Altered Gene ◽  
Tumor Types ◽  
The Impact

Germline and somatic aberrations in DNA damage repair (DDR) genes are more prevalent in prostate cancer than previously recognized, with BRCA2 as the most commonly altered gene. Germline mutations in BRCA2 have been linked to poor prognosis when patients are managed under the protocols currently approved for prostate cancer. The impact of germline mutations in other DDR genes beyond BRCA2 remain unclear. Importantly, a quarter of prostate cancer patients identified as germline mutation carriers lack a family history of cancer. The clinical implications of somatic DDR defects are yet to be elucidated. Poly ADP-ribose polymerase (PARP) inhibitors and platinum-based chemotherapy have proven to be effective in the treatment of other tumor types linked to BRCA1 and BRCA2 alterations and several trials are currently evaluating their efficacy in prostate cancer. Here, we summarize the available evidence regarding the prevalence of somatic and germline DDR defects in prostate cancer; their association with clinical outcomes; the trials assessing the efficacy of new therapies that exploit DDR defects in prostate cancer and briefly discuss some uncertainties about the most appropriate management for these patients.

scholarly journals QOL-49. THE IMPACT OF OTOTOXICITY AND VISUAL IMPAIRMENT ON EDUCATION IN CHILDREN TREATED FOR CNS TUMOURS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii440-iii440
Author(s):  
Harriet Dulson ◽  
Rachel McAndrew ◽  
Mark Brougham
Keyword(s):  
Visual Impairment ◽  
Impaired Hearing ◽  
Cranial Radiotherapy ◽  
Radiotherapy Group ◽  
Platinum Based Chemotherapy ◽  
Cns Tumours ◽  
Group 3 ◽  
Group 2 ◽  
The Impact ◽  
Group 1

Abstract INTRODUCTION Children treated for CNS tumours experience a very high burden of adverse effects. Platinum-based chemotherapy and cranial radiotherapy can cause ototoxicity, which may be particularly problematic in patients who have impaired vision and cognition as a result of their tumour and associated treatment. This study assessed the prevalence of impaired hearing and vision and how this may impact upon education. METHODS 53 patients diagnosed with solid tumours in Edinburgh, UK between August 2013–2018 were included in the study. Patients were split into three groups according to treatment received: Group 1 – cisplatin-based chemotherapy and cranial radiotherapy; Group 2 - platinum-based chemotherapy, no cranial radiotherapy; Group 3 – benign brain tumours treated with surgery only. Data was collected retrospectively from patient notes. RESULTS Overall 69.5% of those treated with platinum-based chemotherapy experienced ototoxicity as assessed by Brock grading and 5.9% of patients had reduced visual acuity. Patients in Group 1 had the highest prevalence of both. 44.4% of patients in Group 1 needed increased educational support following treatment, either with extra support in the classroom or being unable to continue in mainstream school. 12.5% of Group 2 patients required such support and 31.3% in Group 3. CONCLUSIONS Children with CNS tumours frequently require support for future education but those treated with both platinum-based chemotherapy and cranial radiotherapy are at particular risk, which may be compounded by co-existent ototoxicity and visual impairment. It is essential to provide appropriate support for this patient cohort in order to maximise their educational potential.

Malnutrition and biological frailty are independent and complementary predictors of one-year mortality in women after primary angioplasty for ST-segment elevation myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Arroyo-Espliguero ◽  
M.C Viana-Llamas ◽  
A Silva-Obregon ◽  
A Estrella-Alonso ◽  
C Marian-Crespo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Mortality Rate ◽  
Primary Angioplasty ◽  
Prognostic Impact ◽  
St Segment Elevation ◽  
Segment Elevation Myocardial Infarction ◽  
Kaplan Meier ◽  
St Segment ◽  
One Year ◽  
The Impact

Abstract Background Malnutrition and sarcopenia are common features of frailty. Prevalence of frailty among ST-segment elevation myocardial infarction (STEMI) patients is higher in women than men. Purpose Assess gender-based differences in the impact of nutritional risk index (NRI) and frailty in one-year mortality rate among STEMI patients following primary angioplasty (PA). Methods Cohort of 321 consecutive patients (64 years [54–75]; 22.4% women) admitted to a general ICU after PA for STEMI. NRI was calculated as 1.519 × serum albumin (g/L) + 41.7 × (actual body weight [kg]/ideal weight [kg]). Vulnerable and moderate to severe NRI patients were those with Clinical Frailty Scale (CFS)≥4 and NRI&lt;97.5, respectively. We used Kaplan-Meier survival model. Results Baseline and mortality variables of 4 groups (NRI-/CFS-; NRI+/CFS-; NRI+/CFS- and NRI+/CFS+) are depicted in the Table. Prevalence of malnutrition, frailty or both were significantly greater in women (34.3%, 10% y 21.4%, respectively) than in men (28.9%, 2.8% y 6.0%, respectively; P&lt;0.001). Women had greater mortality rate (20.8% vs. 5.2%: OR 4.78, 95% CI, 2.15–10.60, P&lt;0.001), mainly from cardiogenic shock (P=0.003). Combination of malnutrition and frailty significantly decreased cumulative one-year survival in women (46.7% vs. 73.3% in men, P&lt;0.001) Conclusion Among STEMI patients undergoing PA, the prevalence of malnutrition and frailty are significantly higher in women than in men. NRI and frailty had an independent and complementary prognostic impact in women with STEMI. Kaplan-Meier and Cox survival curves Funding Acknowledgement Type of funding source: None

scholarly journals Mitochondrial O-GlcNAc Transferase Interacts with and Modifies Many Proteins and Its Up-Regulation Affects Mitochondrial Function and Cellular Energy Homeostasis

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2956
Author(s):  
Paweł Jóźwiak ◽  
Piotr Ciesielski ◽  
Piotr K. Zakrzewski ◽  
Karolina Kozal ◽  
Joanna Oracz ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Energy Homeostasis ◽  
Glucose Sensor ◽  
Single Gene ◽  
Mitochondrial Proteins ◽  
Mitochondrial Activity ◽  
Ros Generation ◽  
Inner Mitochondrial Membrane ◽  
Glcnac Transferase ◽  
The Impact

O-GlcNAcylation is a cell glucose sensor. The addition of O-GlcNAc moieties to target protein is catalyzed by the O-Linked N-acetylglucosamine transferase (OGT). OGT is encoded by a single gene that yields differentially spliced OGT isoforms. One of them is targeted to mitochondria (mOGT). Although the impact of O-GlcNAcylation on cancer cells biology is well documented, mOGT’s role remains poorly investigated. We performed studies using breast cancer cells with up-regulated mOGT or its catalytic inactive mutant to identify proteins specifically modified by mOGT. Proteomic approaches included isolation of mOGT protein partners and O-GlcNAcylated proteins from mitochondria-enriched fraction followed by their analysis by mass spectrometry. Moreover, we analyzed the impact of mOGT dysregulation on mitochondrial activity and cellular metabolism using a variety of biochemical assays. We found that mitochondrial OGT expression is glucose-dependent. Elevated mOGT expression affected the mitochondrial transmembrane potential and increased intramitochondrial ROS generation. Moreover, mOGT up-regulation caused a decrease in cellular ATP level. We identified many mitochondrial proteins as mOGT substrates. Most of these proteins are localized in the mitochondrial matrix and the inner mitochondrial membrane and participate in mitochondrial respiration, fatty acid metabolism, transport, translation, apoptosis, and mtDNA processes. Our findings suggest that mOGT interacts with and modifies many mitochondrial proteins, and its dysregulation affects cellular bioenergetics and mitochondria function.

Sign in / Sign up

Export Citation Format

Share Document