Acquired resistance to HSP90 inhibitor 17-AAG and increased metastatic potential are associated with MUC1 expression in colon carcinoma cells

Heat shock protein 90 (HSP90) is a molecular chaperone required for the stability and function of many proteins. The chaperoning of oncoproteins by HSP90 enhances the survival, growth, and invasive potential of cancer cells. HSP90 inhibitors are promising new anticancer agents, in which the benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in clinical evaluation. However, the implications of acquired resistance to this class of drug remain largely unexplored. In the present study, we have generated isogenic human colon cancer cell lines that are resistant to 17-AAG by continued culturing in the compound. Cross-resistance was found with another HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin. The resistant cells showed obvious morphology changes with a metastatic phenotype and significant increases in migration and adhesion to collagens. Western blotting analysis of epithelial–mesenchymal transition molecular markers found that expression of E-cadherin downregulated, whereas expression of N-cadherin and β-catenin upregulated in the resistant cells. Mucin 1 (MUC1) has been reported to mediate metastasis as well as chemical resistance in many cancers. Here, we found that MUC1 expression was significantly elevated in the acquired drug resistance cells. 17-AAG treatment could decrease MUC1 more in parental cells than in acquired 17-AAG-resistant cells. Further study found that knockdown of MUC1 expression by small interfering RNA could obviously re-sensitize the resistant cells to 17-AAG treatment, and decrease the cell migration and adhesion. These were coupled with a downregulation in N-cadherin and β-catenin. The results indicate that HSP90 inhibitor therapies in colon carcinomas could generate resistance and increase metastatic potential that might mediated by upregulation of MUC1 expression. Findings from this study further our understanding of the potential clinical effects of HSP90-directed therapies in colon carcinomas.

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Efficacy and safety analysis of chemotherapy for advanced colitis-associated colorectal cancer in Japan

Chemotherapy for advanced colitis-associated colorectal cancer (CAC) has been insufficiently evaluated. The goal of this study was to clarify the efficacy and safety of chemotherapy for CAC in Japan. CAC patients who were treated with chemotherapy between 2005 and 2015 were retrospectively examined. Twenty-nine patients (median age, 48 years; 23 men) were assessed. Eighteen patients had ulcerative colitis, and 11 had Crohn's disease. Three ulcerative colitis and four Crohn's disease patients were in the active disease phase. Primary tumors were located in the rectum/anus (n=16), the left colon (n=9), or the right colon (n=4). Palliative or adjuvant chemotherapy was performed in 13 and 16 patients, respectively. First-line palliative chemotherapy regimens were as follows: fluorouracil, leucovorin, and oxaliplatin (FOLFOX; n=6), FOLFOX+bevacizumab (n=3), and others (n=4). Adjuvant chemotherapy regimens were S-1 (n=7), oxaliplatin-based (n=4) and others (n=5). In palliative chemotherapy, the objective response rate was 15%, and the median progression-free survival and overall survival were 182 and 315 days, respectively. In adjuvant chemotherapy, the 5-year relapse-free survival rate was 78%. Grade 3/4 adverse events (AEs) were observed in 16 patients (55%). Active and remission inflammatory bowel disease patients suffered grade 3/4 nonhematological AEs at an incidence of 71 and 23%, respectively (P

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Changes over time in the impact of gene-expression profiles on the administration of adjuvant chemotherapy in estrogen receptor positive early stage breast cancer patients – a nationwide study

ABSTRACT

Ten years ago gene-expression profiles were introduced to aid adjuvant chemotherapy decision-making in breast cancer. Since then subsequent national guidelines gradually expanded the indication area for adjuvant chemotherapy. In this nation-wide study the evolution of the proportion of patients with estrogen-receptor positive (ER+) tumors receiving adjuvant chemotherapy in relation to gene-expression profile use in patient groups that became newly eligible for chemotherapy according to national guideline changes over time is assessed.

Data on all surgically treated early breast cancer patients diagnosed between 2004–2006 and 2012-2014 were obtained from the Netherlands Cancer Registry. ER+/Her2- patients with tumor-characteristics making them eligible for gene-expression testing in both cohorts and a discordant chemotherapy recommendation over time (2004 guideline not recommending and 2012 guideline recommending chemotherapy) were identified.

We identified 3864 patients eligible for gene-expression profile use during both periods. Gene-expression profiles were deployed in 5% and 35% of the patients in the respective periods. In both periods the majority of patients was assigned to a low genomic risk-profile (67% and 69% respectively) and high adherence rates to the test result were observed (86% and 91% respectively). Without deploying a gene-expression profile 8% and 52% (p <0.001) of the respective cohorts received chemotherapy while 21% and 28% of these patients received chemotherapy when a gene-expression profile was used (p 0.177).

In conclusion, in ER+/Her2- early stage breast cancer patients gene-expression profile use was associated with a consistent proportion of patients receiving chemotherapy despite an adjusted guideline-based recommendation to administer chemotherapy. This article is protected by copyright. All rights reserved.

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IL17 producing γδT cells induce angiogenesis and are associated with poor survival in gallbladder cancer patients

Abstract

Despite conventional treatment modalities, gallbladder cancer (GBC) remains a highly lethal malignancy. Prognostic biomarkers and effective adjuvant immunotherapy for GBC are not available. In the recent past, immunotherapeutic approaches targeting tumor associated inflammation have gained importance but the mediators of inflammatory circuit remain unexplored in GBC patients. In the current prospective study we investigated the role of IL17 producing TCRγδ⁺ (Tγδ17), CD4⁺ (Th17), CD8⁺ (Tc17) and regulatory T cells (Tregs) in pathogenesis of GBC. Analysis by multi-color flow cytometry revealed that compared to healthy individuals (HI), Tγδ17, Th17 and Tc17 cells were increased in peripheral blood mononuclear cells (PBMCs) and tumor infiltrating lymphocytes (TIL) of GBC patients. Tregs were decreased in PBMCs but increased in TILs of GBC patients. The suppressive potential of Tregs from GBC patients and HI were comparable. Serum cytokines profile of GBC patients showed elevated levels of cytokines (IL6, IL23 and IL1β) required for polarization and/or stabilization of IL17 producing cells. We demonstrated that Tγδ17 cells migrate towards tumor bed using CXCL9-CXCR3 axis. IL17 secreted by Tγδ17 induced productions of vascular endothelial growth factor and other angiogenesis related factors in GBC cells. Tγδ17 cells promote vasculogenesis as studied by chick chorioallantoic membrane assay. Survival analysis showed that Tγδ17, Th17 and Treg cells in peripheral blood were associated with poor survival of GBC patients. Our findings suggest that Tγδ17 is a pro-tumorigenic subtype of γδT cells which induces angiogenesis. Tγδ17 may be considered as a predictive biomarker in GBC thus opening avenues for targeted therapies. This article is protected by copyright. All rights reserved.

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“Tumor immunology meets oncology” (TIMO) XI, May 22–23, 2015, Halle/Saale, Germany

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Opportunities for immunotherapy in microsatellite instable colorectal cancer

Abstract

Microsatellite instability (MSI), the somatic accumulation of length variations in repetitive DNA sequences called microsatellites, is frequently observed in both hereditary and sporadic colorectal cancer (CRC). It has been established that defects in the DNA mismatch repair (MMR) pathway underlie the development of MSI in CRC. After the inactivation of the DNA MMR pathway, misincorporations, insertions and deletions introduced by DNA polymerase slippage are not properly recognized and corrected. Specific genomic regions, including microsatellites, are more prone for DNA polymerase slippage and, therefore, more susceptible for the introduction of these mutations if the DNA MMR capacity is lost. Some of these susceptible genomic regions are located within the coding regions of genes. Insertions and deletions in these regions may alter their reading frame, potentially resulting in the transcription and translation of frameshift peptides with c-terminally altered amino acid sequences. These frameshift peptides are called neoantigens and are highly immunogenic, which explains the enhanced immunogenicity of MSI CRC. Neoantigens contribute to increased infiltration of tumor tissue with activated neoantigen-specific cytotoxic T lymphocytes, a hallmark of MSI tumors. Currently, neoantigen-based vaccination is being studied in a clinical trial for Lynch syndrome and in a trial for sporadic MSI CRC of advanced stage. In this Focussed Research Review, we summarize current knowledge on molecular mechanisms and address immunological features of tumors with MSI. Finally, we describe their implications for immunotherapeutic approaches and provide an outlook on next-generation immunotherapy involving neoantigens and combinatorial therapies in the setting of MSI CRC.

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Peptide receptor radionuclide therapy for metastatic paragangliomas

Abstract

There is little evidence to direct the management of malignant paragangliomas (mPGL) beyond initial surgical treatment. Peptide receptor radionuclide therapy (PRRT), using somatostatin analogues, is effective in other neuroendocrine tumours, but data on its efficacy in treating mPGL are scarce. We report safety and efficacy outcomes from a case series of five patients with advanced mPGLs treated with ¹⁷⁷Lu-DOTATATE PRRT. The mean age of our cohort was 34 years (range 16–47); 4 patients were male with bone disease being the most prevalent metastatic site. PRRT scheme varied between 1 and 4 cycles, with premature cessation due to suspected pneumonitis in one case and disease progression in another. Three patients with previously documented progressive disease achieved stabilization following treatment; one had partial response and one was treatment refractory. Median progression-free survival was 17 months (range 0–78 months). 177-Lu-DOTATATE is an effective therapy in mPGLs in this molecularly defined patient cohort, warranting further investigation in larger studies including hereditary and sporadic mPGL.

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Variation in National Use of Long-Term ADT by Disease Aggressiveness Among Men With Unfavorable-Risk Prostate Cancer

Background: The current NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer recommend long-term androgen deprivation therapy (ADT) for all men with high-risk prostate cancer treated with external-beam radiation therapy (EBRT). We determined whether the use of long-term ADT varied by the recently defined subcategories of high-risk disease (favorable, other, and very high) versus unfavorable intermediate-risk disease. Methods: We identified 5,524 patients with unfavorable-risk prostate cancer diagnosed from 2004 to 2007 and managed with EBRT using the SEER-Medicare linked database. Patients were stratified by risk group: unfavorable intermediate-risk, favorable high-risk (previously defined and validated as clinical stage T1c, Gleason score of 4 + 4 = 8, and prostate-specific antigen [PSA] level <10 ng/mL, or clinical stage T1c, Gleason score of 6, and PSA level >20 ng/mL), very-high-risk (clinical stage T3b–T4 or primary Gleason pattern 5), or other high risk (ie, neither favorable nor very high). We used multivariable competing risks regression to estimate the rates of long-term (≥2 years) ADT by group. Results: Men with favorable high-risk prostate cancer were significantly less likely to receive long-term ADT than those with other high-risk disease (15.4% vs 24.6%, adjusted hazard ratio [AHR], 0.68; 95% CI, 0.60–0.76; P<.001), and similarly likely as those with unfavorable intermediate-risk disease (AHR, 1.10; 95% CI, 0.99–1.23; P=.087). Other high-risk disease was less likely to receive long-term ADT than very high-risk cancer (24.6% vs 30.8%; AHR, 0.83; 95% CI, 0.74–0.93; P=.002). Conclusions: Despite current guidelines, patients with EBRT-managed high-risk prostate cancer received significantly different rates of long-course ADT based on subclassification. Our results suggest that oncologists view these patients as a heterogeneous group with favorable high-risk cancer warranting less aggressive therapy than other high-risk or very high-risk disease.

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NCCN News

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Molecular Profiling in Cutaneous Melanoma

Molecular profiling of malignant tumors is gaining increasing interest in oncology. In recent years, several molecular techniques have been studied in melanoma, with the goal to improve upon the diagnostic and prognostic abilities of currently available clinical and histopathologic parameters. Reliable tests performed early in the diagnosis and management of melanoma could lead to decreased morbidity and mortality by selecting appropriate patients for more-aggressive therapy and sparing those for whom it is not indicated. This article reviews the molecular diagnostic and prognostic techniques currently available for melanoma and evaluates their potential role in clinical practice.

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Letting Nature Loose

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Patterns of Palliative Care Consultation Among Elderly Patients With Cancer

Background: The role of palliative care has expanded over the past several decades, although the oncology-specific regional evolution of this specialty has not been characterized at the population-based level. Methods: This study defined the patterns of palliative care delivery using a retrospective cohort of patients with advanced cancer within the SEER-Medicare linked database. We identified 83,022 patients with metastatic breast, prostate, lung, and colorectal cancers. We studied trends between 2000 through 2009, and determined patient-level and regional-level predictors of palliative care delivery. Results: Palliative care consultation rates increased from 3.0% in 2000 to 12.9% in 2009, with most consultations occurring in the last 4 weeks of life (77%) in the inpatient hospital setting. The rates of palliative care delivery were highest in the West (7.6%) and lowest in the South (3.2%). The likelihood of palliative care consultation increased with decreasing numbers of regional acute care hospital beds per capita. The use of palliative care consultation increased with increasing numbers of regional physicians. The use of palliative care decreased with increasing regional Medicare expenditure with a $1,387 difference per beneficiary between the first and fourth quartiles of palliative care use. Conclusions: Geographic location influences a patient's options for palliative care in the United States. Although the overall rates of palliative care are increasing, future effort should focus on improving palliative care services in regions with the least access.

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NCCN Guidelines and Quality Cancer Care: Where Have We Come From, and Where Should We Be Going?

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Oncology Research Program

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Imatinib Treatment of Lymphangiomatosis (Generalized Lymphatic Anomaly)

Lymphangiomatosis (eg, generalized lymphatic anomaly) is an abnormal proliferation of lymphatic endothelial cells. It is often a childhood disease, but it may present in adulthood by infiltrating organs and cause obstruction, bleeding, or disruption of lymphatic flow. Pulmonary involvement may be mild or cause diffuse interstitial lung disease, airway obstruction, hemoptysis, chylothorax, chylopericardium, and culminate in respiratory failure. Treatment has been limited to surgical resection or drainage procedures because there is no accepted effective systemic therapy. This report presents a patient with lymphangiomatosis and life-threatening hemoptysis in whom positive immunostaining for c-KIT suggested upregulation of tyrosine kinase and whose disease was controlled with imatinib.

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The Cost of Initial Care for Medicare Patients With Advanced Ovarian Cancer

Objectives: In preparation for payment reform, we evaluated Medicare payments for the initial treatment of patients with advanced ovarian cancer and assessed factors responsible for variation. Methods: Using the linked SEER-Medicare database, we identified a cohort of 9,491 women aged 65 years or older with stage III/IV epithelial ovarian cancer diagnosed between 1995 and 2007. Diagnostic and procedural codes specific to the care of ovarian cancer were used to estimate total medical costs for the treatment of ovarian cancer. Costs were adjusted for geography and for inflation to the 2009 US dollar. NCCN Guideline–consistent care was defined as surgery and 6 cycles of chemotherapy. A generalized linear regression was performed to assess factors associated with variability in cost. Results: The mean total payment per patient in the initial treatment period was $65,908 (range of means, $30,745–$96,360). Increasing medical comorbidity, use of PET/CT, surgical complications, and readmissions were associated with increased costs. Treatment with NCCN Guideline–consistent surgery and chemotherapy had a mean annual cost of $85,987 compared with $89,149 for non–NCCN Guideline–consistent treatment with surgery and chemotherapy. The cost of surgery and chemotherapy that was not consistent with NCCN Guidelines was approximately $7,000 more than the cost of therapy that was consistent (P<.001) Conclusions: The financial burden of caring for patients with ovarian cancer is substantial. Treatment that is consistent with NCCN recommendations for treating advanced ovarian cancer, which is shown to have improved outcomes, is not associated with higher cost.

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NCCN Guidelines Insights: Multiple Myeloma, Version 3.2016

These NCCN Guidelines Insights highlight the important updates/changes specific to the 2016 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include updated recommendations to the overall management of multiple myeloma from diagnosis and staging to new treatment options.

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Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections.

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Guiding Lay Navigation in Geriatric Patients With Cancer Using a Distress Assessment Tool

Background: There is growing interest in psychosocial care and evaluating distress in patients with cancer. As of 2015, the Commission on Cancer requires cancer centers to screen patients for distress, but the optimal approach to implementation remains unclear. Methods: We assessed the feasibility and impact of using distress assessments to frame lay navigator interactions with geriatric patients with cancer who were enrolled in navigation between January 1, 2014, and December 31, 2014. Results: Of the 5,121 patients enrolled in our lay patient navigation program, 4,520 (88%) completed at least one assessment using a standardized distress tool (DT). Navigators used the tool to structure both formal and informal distress assessments. Of all patients, 24% reported distress scores of 4 or greater and 5.5% reported distress scores of 8 or greater. The most common sources of distress at initial assessment were pain, balance/mobility difficulties, and fatigue. Minority patients reported similar sources of distress as the overall program population, with increased relative distress related to logistical issues, such as transportation and financial/insurance questions. Patients were more likely to ask for help with questions about insurance/financial needs (79%), transportation (76%), and knowledge deficits about diet/nutrition (76%) and diagnosis (66%) when these items contributed to distress. Conclusions: Lay navigators were able to routinely screen for patient distress at a high degree of penetration using a structured distress assessment.

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Treatment Disparities Faced by Undocumented Workers From Low- and Middle-Income Countries in the United States With Hematologic Malignancies

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Silence of long noncoding RNA UCA1 inhibits malignant proliferation and chemotherapy resistance to adriamycin in gastric cancer

Abstract

Purpose

Urothelial carcinoma associated 1 (UCA1) gene is a long noncoding RNA (lncRNA), which shows expression and function abnormality in some kinds of malignant cancers. This study aimed to investigate its clinical significance and to examine its regulative effects of malignant proliferation and chemosensitivity to doxorubicin in gastric cancer cells.

Methods

The expression of UCA1 was detected by quantitative real-time PCR. Statistical analysis was used to determine the relationship between UCA1 expression and clinical features and the prognostic value of UCA1 for disease-free survival. MTT assay was used to detect cell proliferation ability and chemosensitivity. Dual-color flow cytometric method was used to detect cell apoptosis. The expression of cleaved PARP and Bcl-2 protein was examined by Western blot.

Results

UCA1 was highly expressed in gastric cancer tissues and cells, and its high expression level had a positive correlation with some malignant pathological characteristics of gastric cancer, such as higher grade and poor differentiation. Moreover, UCA1 was an independent prognostic biomarker of disease-free survival for gastric cancer patients. Silence of UCA1 could significantly inhibit the cell proliferation of gastric cancer BGC-823 and SGC7901 cells. The chemotherapy resistance to adriamycin of SGC7901/ADR cells was depressed by UCA1 silence, and IC50 for adriamycin presented a conspicuous depression. UCA1 silence advanced apoptosis induced by adriamycin in SGC7901/ADR cells, up-regulated cleaved PARP protein expression and depressed the expression of anti-apoptosis protein Bcl-2. These results demonstrated that chemotherapy resistance changes induced by UCA1 silence might be mediated by the cell apoptosis pathway.

Conclusions

In summary, lncRNA UCA1 was an independent prognostic biomarker of disease-free survival in gastric cancer patients and acted as an oncogene to regulate the malignant proliferation and resistance to adriamycin in gastric cancer cells. UCA1 might provide a new potential therapeutic target and stratagem for gastric cancer.

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Favorable outcome of primary mediastinal large B-cell lymphoma patients treated with sequential RCHOP-RICE regimen without radiotherapy

Abstract

Purpose

Outcomes in primary mediastinal B cell lymphoma (PMBL) improved with the introduction of dose intense treatments, consolidation radiotherapy and rituximab. DA-EPOCH-R, which omits radiotherapy has been adopted with worldwide enthusiasm, despite lack of proven superiority in randomized trials. We aimed to evaluate the course and outcome of PMBL using an alternative intensive rituximab-containing regimen, RCHOP-RICE. We also evaluated the prognostic value of ¹⁸FDG-PET-CT (PET-CT).

Methods

We reviewed the clinical, laboratory and imaging data of PMBL patients receiving 1st-line treatment in Hadassah Medical Center between 8/2002 and 10/2014.

Results

Of 47 PMBL patients, 24 (51 %) were treated with RCHOP-RICE and 23 (49 %) with other protocols. Overall, the 5-year progression-free survival was 93 % and the overall survival was 98 % (87 and 100 %, respectively, for the RCHOP-RICE regimen). Patient characteristics and treatment toxicities were balanced among protocols. A mean of 11.1 ± 1.3 hospitalization days/patient were needed to administer RCHOP-RICE regimen compared to 37 ± 2 days/patient for DA-EPOCH-R (n = 2). Radiotherapy was given to 3 patients (12 %) treated with RCHOP-RICE compared to 18 patients (78 %) treated with other protocols (p < 0.01). For patients followed with interim and end of treatment (EOT) PET-CT, we observed a significant reduction in the uptake between the two (p < 0.0001). Using a Deauville score cutoff of 3, the negative and positive predictive values (NPV and PPV) of EOT PET-CT were 94 and 33 %, respectively.

Conclusions

The RCHOP-RICE protocol results in excellent survival outcomes, generally permits omission of RT and is simpler to administer than DA-EPOCH-R. Interim PET-CT in PMBL may be unjustified; however, EOT Deauville scores ≤3 predicts a favorable outcome.

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The difference in Ezrin–pAkt signaling axis between lepidic and papillary predominant invasive adenocarcinomas of the lung

Abstract

Purpose

Histologic classification of invasive lung adenocarcinomas by predominant subtype has prognostic value. Papillary predominant adenocarcinoma (PPA) reportedly shows poorer prognosis than lepidic predominant adenocarcinoma (LPA); however, biological differences between PPA and LPA are unclear. The purpose of this study was to clarify biological differences between PPA and LPA.

Methods

Clinicopathological characteristics of invasive 62 PPAs and 117 LPAs smaller than 30 mm were investigated. Furthermore, we compared immunochemical staining scores of 9 molecular markers (E-cadherin, S100A4, fibronectin, integrinβ1, ezrin, GLUT1, ALDH1, SOX2 and Nanog) between PPA and LPA. We performed Western blot analysis using ezrin shRNA-knockdown lung adenocarcinoma cell lines to examine whether molecules that are highly expressed in PPA, such as ezrin, affect pAkt. Finally, we performed immunochemical staining to compare pAkt expression level in PPA and LPA.

Results

Lymphovascular and pleural invasion and lymph node metastasis were significantly more often detected in PPA than in LPA (lymphatic permeation: 31 vs 3 %, vascular invasion: 35 vs 3 %, pleural invasion: 29 vs 5 %, lymph node metastasis: 18 vs 1 %; all P < 0.01). Immunohistochemical (IHC) study revealed that expression score of ezrin was significantly higher in PPA than in LPA (38.3 vs 15.0; P < 0.01). The level of pAkt decreased in shEzrin-induced PC-9 and A549 cancer cells. Moreover, the IHC staining score of pAkt was significantly higher in PPA than in LPA (13.3 vs 0.0; P < 0.01).

Conclusions

Our results show that the activation of the ezrin–pAkt signaling axis is associated with the more aggressive clinicopathological features of PPA compared with LPA.

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The HLA-DRB1 allele polymorphisms and nasopharyngeal carcinoma

Abstract

Human leukocyte antigen (HLA)-DRB1 has been reported to influence individual's susceptibility to nasopharyngeal carcinoma (NPC) by many studies in recent years; however, these studies provided controversial results. The meta-analysis was thus conducted here to estimate the relationship between HLA-DRB1 polymorphisms and NPC. After an extensive review of journals from various databases (PubMed, the Web of Science, Embase, China National Knowledge Internet (CNKI), and Wanfang Database), 8 out of 69 case-control studies, including 778 cases and 1148 controls, were extracted. The results showed that 4 of 13 polymorphisms allele are statistically significantly associated with NPC, among them, HLA-DRB1*3, HLA-DRB1*9, and HLA-DRB1*10 may increase the risk of NPC while HLA-DRB1*01 has the opposite effect. The pooled odds ratio and 95 % confidence interval (CI) were 1.702 [95 % CI (1.047, 2.765)], 1.363 [95 % CI (1.029, 1.806)], 1.989 [95 % CI (1.042, 3.799)], and 0.461 [95 % CI (0.315, 0.676)], respectively. In a further ethnicity-based subgroup analysis, HLA-DRB1*08, HLA-DRB1*11, and HLA-DRB1*16 were found to be linked with NPC in Asian, Tunisian, and Caucasian, respectively. In Asian, HLA-DRB1*03, 08, and 10 may elevate the risk whereas HLA-DRB1*09 could lower it. In Tunisian, HLA-DRB1*01 and 11 are the protective factors while HLA-DRB1*03 is the only risk factor. In Caucasian, HLA-DRB1*01 and 03 increase the risk and HLA-DRB1*16 lowers it. The most frequent statistically associated gene is found to be HLA-DRB1*03 which has protective influence on Asian and Tunisian. In conclusion, HLA-DRB1*01, DRB1*03, DRB1*09, and DRB1*10 are related with NPC susceptibility, and the association of HLA-DRB1*08, DRB1*11, and DRB1*16 with NPC risk are significantly different in different ethnicities.

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Genome-wide mitochondrial DNA sequence variations and lower expression of OXPHOS genes predict mitochondrial dysfunction in oral cancer tissue

Abstract

Several studies reported that mtDNA mutations may play important roles in carcinogenesis although the mechanism is not clear yet. Most of the studies compared mtDNA sequences in a tumor with those in normal tissues from different individuals ignoring inter-individual variations. In this study, 271 SNPs, 7 novel SNPs (or SNVs), and 15 somatic mutations were detected in mtDNA of 8 oral cancer tissues with respect to reference (rCRS) and adjacent normal tissues, respectively, using Ion PGM next generation sequencing method. Most of the sequence variations (76 SNPs and 1 somatic) are present in D-loop region followed by CyB (36 SNPs), ATP6 (24 SNPs), ND5 (17 SNPs and 5 somatic), ND4 (18 coding and 2 somatic) and other non-coding and coding DNA sequences. A total of 53 and 8 non-synonymous SNPs and somatic mutations, respectively, were detected in tumor tissues and some of these variations may have deleterious effects on the protein function as predicted by bioinformatic analysis. Moreover, significantly low mtDNA contents and expression of several mitochondrial genes in tumor compared to adjacent normal tissues may have also affected mitochondrial functions. Taken together, this study suggests that mtDNA mutations as well as low expression of mtDNA coded genes may play important roles in tumor growth. Although the sample size is low, an important aspect of the study is the use of adjacent control tissues to find out somatic mutations and a change in the expression of mitochondrial genes, to rule out inter-individual and inter-tissue variations which are important issues in the study of mitochondrial genomics.

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