BMC Cancer

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ISSN / EISSN : 1471-2407 / 1471-2407
Current Publisher: Springer Science and Business Media LLC (10.1186)
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Guang-Liang Chen, Li Guo, Shun’E Yang, Dong-Mei Ji
BMC Cancer, Volume 21, pp 1-7; doi:10.1186/s12885-021-08391-6

Abstract:
Background Tuberculosis (TB) may facilitate carcinogenesis. We performed a case-control study of the association between TB and cancer in Xinjiang, a high TB endemic area of China. Methods From January 2016 to December 2018, a total of 45,455 patients hospitalized in Xinjiang Cancer Hospital were consecutively enrolled and divided into a malignant tumor group (n = 32,539) and a benign tumor group (n = 12,916). Patients with active and previous TB before the diagnosis of cancer were retrospectively identified in the two groups. Results A significantly higher proportion of TB was found in the malignant tumor group (n = 1776, 5.46%) than in the control (benign tumor) group (n = 175, 1.35%) (p < 0.0001). The highest and lowest proportions of TB in the malignant group were in patients with non-Hodgkin’s lymphoma (16.74%) and thyroid cancer (0.77%), respectively. In multivariate analysis adjusting for age, sex, and ethnicity, TB remained an independent risk factor for all cancers (odds ratio (OR) 1.68; 95% confidence interval (CI) 1.43–1.97). Furthermore, TB was associated with a significantly higher risk of non-Hodgkin’s lymphoma, cervical cancer, esophageal cancer, “other” cancers, ovarian cancer, and breast cancer. Moreover, females with TB were more likely to develop cancer than males (p < 0.0001), except for esophageal cancer and lymphoma. Conclusion TB patients have an elevated cancer risk. A screening strategy for TB should be taken into consideration before treatment in patients with some cancer types that are associated with a high proportion of TB.
, Qian Zhang, Luis E. Rodriguez, Claudie M. Hecquet, Cherrie K. Donawho, Peter J. Ansell, Edward B. Reilly
BMC Cancer, Volume 21, pp 1-11; doi:10.1186/s12885-021-08403-5

Abstract:
Background Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. Antibody efficacy, however, may be limited to subtypes with either PRLR overexpression and/or those where estradiol no longer functions as a mitogen and are, therefore, reliant on PRLR signaling for growth. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations. Methods We derived a novel ADC targeting PRLR, ABBV-176, that delivers a pyrrolobenzodiazepine (PBD) dimer cytotoxin, an emerging class of warheads with enhanced potency and broader anticancer activity than the clinically validated auristatin or maytansine derivatives. This agent was tested in vitro and in vivo cell lines and patient derived xenograft models. Results In both in vitro and in vivo assays, ABBV-176 exhibits potent cytotoxicity against multiple cell line and patient-derived xenograft breast tumor models, including triple negative and low PRLR expressing models insensitive to monomethyl auristatin (MMAE) based PRLR ADCs. ABBV-176, which cross links DNA and causes DNA breaks by virtue of its PBD warhead, also demonstrates enhanced anti-tumor activity in several breast cancer models when combined with a poly-ADP ribose polymerase (PARP) inhibitor, a potentiator of DNA damage. Conclusions Collectively the efficacy and safety profile of ABBV-176 suggest it may be an effective therapy across a broad range of breast cancers and other cancer types where PRLR is expressed with the potential to combine with other therapeutics including PARP inhibitors.
Fang Yu, Babu Gajendran, Ning Wang, Klarke M. Sample, Wuling Liu, Chunlin Wang, Anling Hu, Eldad Zacksenhaus, Xiaojiang Hao, Yaacov Ben-David
BMC Cancer, Volume 21, pp 1-12; doi:10.1186/s12885-021-08402-6

Abstract:
Background Cholesterol plays vital roles in human physiology; abnormal levels have deleterious pathological consequences. In cancer, elevated or reduced expression of cholesterol biosynthesis is associated with good or poor prognosis, but the underlying mechanisms are largely unknown. The limonoid compounds A1542 and A1543 stimulate ERK/MAPK by direct binding, leading to leukemic cell death and suppression of leukemia in mouse models. In this study, we investigated the downstream consequences of these ERK/MAPK agonists in leukemic cells. Methods We employed RNAseq analysis combined with Q-RT-PCR, western blot and bioinformatics to identify and confirm genes whose expression was altered by A1542 and A1543 in leukemic cells. ShRNA lentiviruses were used to silence gene expression. Cell culture and an animal model (BALB/c) of erythroleukemia induced by Friend virus were utilized to validate effects of cholesterol on leukemia progression. Results RNAseq analysis of A1542-treated cells revealed the induction of all 18 genes implicated in cholesterol biosynthesis. Expression of these cholesterol genes was blocked by cedrelone, an ERK inhibitor. The cholesterol inhibitor lovastatin diminished ERK/MAPK activation by A1542, thereby reducing leukemic cell death induced by this ERK1/2 agonist. Growth inhibition by cholesterol was observed both at the intracellular level, and when orally administrated into a leukemic mouse model. Both HDL and LDL also suppressed leukemogenesis, implicating these lipids as important prognostic markers for leukemia progression. Mechanistically, knockdown experiments revealed that the activation of SREBP1/2 by A1542-A1543 was responsible for induction of only a sub-set of cholesterol biosynthesis genes. Induction of other regulatory factors by A1542-A1543 including EGR1, AP1 (FOS + JUN) LDLR, IER2 and others may cooperate with SREBP1/2 to induce cholesterol genes. Indeed, pharmacological inhibition of AP1 significantly inhibited cholesterol gene expression induced by A1542. In addition to leukemia, high expression of cholesterol biosynthesis genes was found to correlate with better prognosis in renal cancer. Conclusions This study demonstrates that ERK1/2 agonists suppress leukemia and possibly other types of cancer through transcriptional stimulation of cholesterol biosynthesis genes.
HongBin Zhou, Jiuke Li, Zhewen Chen, Ying Chen,
BMC Cancer, Volume 21, pp 1-13; doi:10.1186/s12885-021-08430-2

Abstract:
Background Nitric oxide (NO) plays an important role in lung cancer. However, the results of previous studies about NO in the occurrence, progress and therapy were not consistent. Therefore, we conducted a meta-analysis to evaluate the relationship between NO and lung cancer. Method We carried out comprehensive search in the databases, and collected related studies. The data of fraction of exhaled nitric oxide (FeNO) or blood NO in different populations (lung cancer patients and control subjects) and different time points (before therapy and after therapy) were extracted by two investigators. A random effect model was applied to analyze the differences of FeNO and blood NO in different populations and different time points. To further compare NO level of each subgroup with different pathological types and different stages, a network meta-analysis (NMA) was performed. Results Fifty studies including 2551 cases and 1691 controls were adopted in this meta-analysis. The FeNO (SMD 3.01, 95% CI 1.89–4.13, p < 0.00001) and blood NO (SMD 1.34, 95% CI 0.84–1.85, p < 0.00001) level in lung cancer patients was much higher than that in control subjects. NMA model indicated blood NO level in each cancer type except SCLC was higher than that in control patients. There was no significant difference of blood NO level among four kinds of lung cancer patients. Blood NO level in LCC patients (SUCRA = 83.5%) was the highest. Blood NO level in advanced stage but not early stage was higher than that in control subjects. Patients in advanced stage (SUCRA = 95.5%) had the highest blood NO level. No significant difference of FeNO (SMD -0.04, 95% CI -0.46-0.38, p > 0.05) and blood NO level (SMD -0.36, 95% CI -1.08-0.36, p > 0.05) was observed between pretreatment and posttreatment in all patients. However, FeNO level elevated (SMD 0.28, 95% CI 0.04–0.51, p = 0.02) and blood NO level decreased in NSCLC patients (SMD -0.95, 95% CI -1.89-0.00, p = 0.05) after therapy. Conclusion FeNO and blood NO level would contribute to diagnosis of lung cancer and evaluation of therapy effect, especially for NSCLC patients.
Yuan-Jun Cai, Long-Feng Ke, Wen-Wen Zhang, Jian-Ping Lu,
BMC Cancer, Volume 21, pp 1-9; doi:10.1186/s12885-021-08427-x

Abstract:
Background Malignant melanoma of the female genital tract is relatively uncommon and accounts for 3–7% of all melanoma localizations. This study aimed to identify driver genes in melanoma of the female genital tract with the purpose of enhancing understanding of disease pathogenesis and identifying potential new therapeutic targets to develop effective therapies. Methods KIT (CD117) and BRAF expression were detected immunohistochemically. Polymerase Chain Reaction (PCR) and Sanger sequencing techniques were performed to identify the mutational status of BRAF, NRAS, KRAS, NF1, KIT, PDGFRA and SF3B1 on 19 melanomas of the female genital tract, paired with 25 cutaneous melanomas, 18 acral melanomas and 11 melanomas of nasal cavity. Results Somatic variant analysis identified KRAS (6/19; 32%) as the most commonly mutated gene, followed by KIT (4/19; 21%), SF3B1 (3/19; 16%) and NRAS (1/19; 5%). None of the cases were found to harbor BRAF, NF1 and PDGFRA mutations in melanomas of the female genital tract. However, none of the cases were found to harbor SF3B1 and KIT mutations in cutaneous melanomas, acral melanomas and melanomas of nasal cavity. Recurrent KIT mutations, as well as mutations in the less frequently mutated genes NRAS and SF3B1, were exclusively detected in vulvovaginal melanomas, but not in tumors arising in the cervix. However, recurrent KRAS mutations were detected in similar frequencies in tumors of the vulva, vagina, and cervix. Additionally, recurrent KRAS and KIT mutations occurred predominantly in polygonal and epithelioid cell types of melanoma in the female genital tract. Immunohistochemistry revealed moderate or strong cytoplasmic CD117 expression in 6 of the 19 cases (31.6%). Conclusions We observed that gynecologic melanoma harbored distinct mutation rates in the KIT, BRAF, SF3B1, KRAS, and NRAS genes. Our findings support the notion that gynecologic melanoma is a distinct entity from non-gynecologic melanoma, and these findings offer insights into future therapeutic options for these patients.
J. Ripoll, , J. Montaño, J. Pons, A. Ameijide, P. Franch
BMC Cancer, Volume 21, pp 1-8; doi:10.1186/s12885-021-08418-y

Abstract:
Background Information about survival by stage in bladder cancer is scarce, as well as about survival of non-invasive bladder cancer. The aims of this study are: 1) to find out the distribution of bladder cancer by stage; 2) to determine cancer-specific survival by stage of bladder cancer; 3) to identify factors that explain and predict the likelihood of survival and the risk of dying from these cancers. Methods Incident bladder cancer cases diagnosed between 2006 and 2011 were identified through the Mallorca Cancer Registry. Inclusion criteria: cases with code C67 according to the ICD-O 3rd edition with any behaviour and any histology, except lymphomas and small cell carcinomas. Cases identified exclusively through the death certificate were excluded. We collected the following data: sex; age; date and method of diagnosis; histology according to the ICD-O 3rd edition; T, N, M and stage at the time of diagnosis; and date of follow-up or death. End point of follow-up was 31 December 2015. Multiple imputation (MI) was performed to estimate cases with unknown stage. Cases with benign or indeterminate behaviour were excluded for the survival analysis. Actuarial and Kaplan-Meier methods and Cox regression models were used for survival analysis. Results One thousand nine hundred fourteen cases were identified. 14% were women and 65.4% were 65 years or older. 3.9% had no stage (benign or undetermined behaviour) and 11.5% had unknown stage. After MI, 37.5% were in stage Ta (non-invasive papillary carcinoma), 3.2% in stage Tis (carcinoma in situ), 34.3% in stage I, 11.7% in Stage II, 4.3% in stage III, and 9.0% in stage IV. Survival was 76% at 5 years. Survival by stage: 98% at stage Ta, 90% at stage Tis, 85% at stage I, 45% at stage II, 35% at stage III, and 7% at stage IV. The Cox model showed that age, histology, and stage, but not sex, were associated with survival. Conclusion Bladder cancer survival vary greatly with stage, among both non-invasive and invasive cases. The percentage of non-invasive cancers is high. Stage, age, and histology are associated to survival.
Jiujie Cui, Haiyan Yang, Jue Liu, Donghui Chen, Jiong Hu, Haiyan Zhang, Yu Wang, Ting Han, Tiebo Mao, Feng Jiao, et al.
BMC Cancer, Volume 21, pp 1-9; doi:10.1186/s12885-021-08375-6

Abstract:
Background Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that lack of effective therapeutic drugs. K-001 is an oral antitumor drug made from active ingredients of marine microorganisms. The current study aimed to evaluate safety and antitumor activity of K-001 in patients with advanced PDAC. Methods In this phase I, open-label trial, patients with advanced PDAC were recruited to a dose-escalation study in a standard 3 + 3 design. K-001 was administered twice daily in four-week cycles, and dose escalation from 1350 mg to 2160 mg was evaluated twice daily. Physical examination and laboratory tests were done at screening and then weekly. The safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of K-001 were assessed while tumor response was estimated by Response Evaluation Criteria in Solid Tumor (RECIST). Results Eighteen patients with advanced PDAC were screened, and twelve eligible patients were analyzed in the study. No DLT was observed. Totally, 47 adverse events (AEs) presented, and 14 drug-related AEs were reported in 7 patients, including 8 grade 1 events (57.1%) and 6 grade 2 events (42.9%). There was no grade 3 or 4 drug-related AE. In these 14 drug-related AEs, the most frequent ones were dyspepsia (21.4%), followed by flatulence, constipation, and hemorrhoid bleeding (above 10% of each). Among all 12 patients, 10 patients (83.3%) maintained stable disease (SD), and 2 patients (16.7%) had progressive disease (PD). The objective response rate (ORR) was 0% and the disease control rate (DCR) was 83.3%. Conclusions K-001 manifests satisfactory safety and tolerability, as well as meaningful antitumor activity in advanced PDAC patients. Further evaluation of K-001 in phase II/III appears warranted. Trial registration NCT02720666. Registered 28 Match 2016 - Retrospectively registered.
Hiromichi Nakajima, Daisuke Kotani, Hideaki Bando, Takeshi Kato, Eiji Oki, Eiji Shinozaki, Yu Sunakawa, Kentaro Yamazaki, Satoshi Yuki, Yoshiaki Nakamura, et al.
BMC Cancer, Volume 21, pp 1-6; doi:10.1186/s12885-021-08395-2

Abstract:
Background Previous clinical trials have demonstrated the potential efficacy of rechallenge with anti- epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) for patients with RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). Moreover, post hoc biomarker analyses of clinical trials has suggested that RAS status in circulating tumor DNA (ctDNA) has a high probability to select patients who could benefit from anti-EGFR mAb rechallenge. Methods This trial is composed of 2 phases: a monitoring phase (REMARRY) and a trial phase (PURSUIT). A monitoring phase, the REMARRY study, aims to evaluate the dynamics of plasma RAS status during the subsequent treatments after refractory to anti-EGFR therapy in patients with mCRC with RAS/BRAF V600E wild-type tumors who have progressed after a response to previous anti-EGFR therapy, using a highly sensitive digital polymerase chain reaction OncoBEAM RAS CRC kit in a central laboratory (Sysmex, Japan). A trial phase, the PURSUIT trial, is a multicenter, single-arm phase II trial to assess the efficacy and safety of rechallenge therapy with panitumumab plus irinotecan in patients without RAS mutations in ctDNA (plasma RAS negative) in the REMARRY study. Key eligibility criteria of the PURSUIT trial include RAS/BRAF V600E wild-type mCRC in tumor tissue refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; progression after complete or partial response to previous anti-EGFR therapy; plasma RAS negative (defined as plasma mutant allele frequencies [MAF] of all RAS ≤ 0.1%) within 28 days prior to enrollment; 4 months or more between the last administration of previous anti-EGFR mAb and the start of protocol treatment; and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. The primary endpoint is the confirmed objective response rate (ORR). The target sample size of the PURSUIT trial is 50 patients. Biomarker analyses will be performed in parallel using the OncoBEAM RAS CRC kit and a next-generation sequencing-based ctDNA analysis (Guardant360). Discussion Our trial aims to confirm the clinical benefit of anti-EGFR mAb rechallenge therapy in patients with plasma RAS negative. Moreover, through biomarker analyses, our trial will shed light on which patients would benefit from rechallenge in addition to being plasma RAS negative. Trial registration The REMARRY study: UMIN, UMIN000036424. Registered date: April 5, 2019. The PURSUIT trial: jRCT, jRCTs031190096. Registered date: October 1, 2019.
, László Antal, Eszter Gyöngyösi, Anita Szalmás, Szilárd Póliska, György Veress, József Kónya
BMC Cancer, Volume 21, pp 1-19; doi:10.1186/s12885-021-08361-y

Abstract:
Background miRNAs and lncRNAs can regulate cellular biological processes both under physiological and pathological conditions including tumour initiation and progression. Interactions between differentially expressed diverse RNA species, as a part of a complex intracellular regulatory network (ceRNA network), may contribute also to the pathogenesis of HPV-associated cancer. The purpose of this study was to investigate the global expression changes of miRNAs, lncRNAs and mRNAs driven by the E6 and E7 oncoproteins of HPV16, and construct a corresponding ceRNA regulatory network of coding and non-coding genes to suggest a regulatory network associated with high-risk HPV16 infections. Furthermore, additional GO and KEGG analyses were performed to understand the consequences of mRNA expression alterations on biological processes. Methods Small and large RNA deep sequencing were performed to detect expression changes of miRNAs, lncRNAs and mRNAs in primary human keratinocytes expressing HPV16 E6, E7 or both oncoproteins. The relationships between lncRNAs, miRNAs and mRNAs were predicted by using StarBase v2.0, DianaTools-LncBase v.2 and miRTarBase. The lncRNA-miRNA-mRNA regulatory network was visualized with Cytoscape v3.4.0. GO and KEEG pathway enrichment analysis was performed using DAVID v6.8. Results We revealed that 85 miRNAs in 21 genomic clusters and 41 lncRNAs were abnormally expressed in HPV E6/E7 expressing cells compared with controls. We constructed a ceRNA network with members of 15 lncRNAs – 43 miRNAs – 358 mRNAs with significantly altered expressions. GO and KEGG functional enrichment analyses identified numerous cancer related genes, furthermore we recognized common miRNAs as key regulatory elements in biological pathways associated with tumorigenesis driven by HPV16. Conclusions The multiple molecular changes driven by E6 and E7 oncoproteins resulting in the malignant transformation of HPV16 host cells occur, at least in part, due to the abnormal alteration in expression and function of non-coding RNA molecules through their intracellular competing network.
Jing Zhao, Huiling Cao, Wenfan Zhang, Yongjuan Fan, Shujuan Shi,
BMC Cancer, Volume 21, pp 1-10; doi:10.1186/s12885-021-08406-2

Abstract:
Background The association between SOX14 and cancer has been reported. The aim of this study was to identify and validate the potential value of SOX14 methylation in the early detection of cervical cancer. Methods First, we extracted the data for SOX14 methylation and expression within cervical cancer from The Cancer Genome Atlas (TCGA) database and analysed them via UALCAN, Wanderer, MEXPRESS and LinkedOmics. Subsequently, according to the bioinformatics findings, primers and probes were designed for the most significantly differentiated methylation CpG site and synthesized for methylation-specific PCR (MSP) and quantitative methylation-specific PCR (QMSP) to verify SOX14 methylation in both cervical tissuses and liquid-based cell samples. Eventually, the clinical diagnostic efficacy of SOX14 methylation in the normal, cervical intraepithelial neoplasia, and cancer groups was analysed by ROCAUC. Results Pooled analysis demonstrated that SOX14 methylation levels were significantly increased in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) compared to normal tissues (P < 0.001). Both the verification and validation cohorts indicated that the methylation level and the positive rate of SOX14 gradually increased with increasing severity from normal to cancer samples (P < 0.01). When the cut-off value was set as 128.45, the sensitivity and specificity of SOX14 hypermethylation in the diagnosis of cervical cancer were 94.12 and 86.46%, respectively. When taken as a screening biomarker (>CINII), the sensitivity was 74.42% and the specificity was 81.48%, with a cut-off value of 10.37. Conclusion SOX14 hypermethylation is associated with cervical cancer and has the potential to be a molecular biomarker for the screening and early diagnosis of cervical cancer.
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