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Δευτέρα 12 Αυγούστου 2019

Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome
In the original publication, part d of Figure 2 was mistakenly not included.

Correction to: Real-world treatment of over 1600 Japanese patients with EGFR mutation-positive non-small cell lung cancer with daily afatinib
The original article can be found online.

Introduction: Lynch syndrome—its molecular mechanism and current topics

Cell-type-specific sensitivity of bortezomib in the methotrexate-resistant primary central nervous system lymphoma cells

Abstract

Background

Methotrexate (MTX) is used in first-line treatment of primary central nervous system lymphoma (PCNSL), but most cases result in relapse-acquired resistance to MTX. However, only few studies have reported on internal changes and chemotherapies in PCNSL.

Methods

In this study, we generated two MTX-resistant PCNSL cell lines, designated MTX-HKBML and MTX-TK, in addition to a MTX-resistant Burkitt lymphoma cell line, designated MTX-RAJI. We examined gene expression changes and drug sensitivity to a proteasome inhibitor, bortezomib, in these cells.

Results

Cytotoxic tests revealed that the 50% inhibitory concentration for MTX in MTX-HKBML is markedly higher than that in the other two cell lines. Expression of the genes in MTX and folate metabolisms, including gamma-glutamyl hydrolase and dihydrofolate reductase, are upregulated in both MTX-HKBML and MTX-TK, whereas the gene expression of folylpolyglutamate synthetase, thymidylate synthase, and methylenetetrahydrofolate dehydrogenase 1 were upregulated and downregulated in MTX-HKBML and MTX-TK, respectively, on the other hand, bortezomib sensitivity was observed in MTX-TK, as compared with control TK, but not in MTX-HKBML.

Conclusion

These results indicate the cell-type-specific changes downstream of metabolic pathways for MTX and folate, bortezomib sensitivity, and purine and pyrimidine syntheses, in each PCNSL cell line. The MTX-resistant lymphoma cell lines established may be useful for in vitro relapse models for MTX and development of salvage chemotherapy and drug discovery.

Prognostic value of serum C-reactive protein level prior to second-line treatment in intermediate risk metastatic renal cell carcinoma patients

Abstract

Background

The later-line treatment of metastatic renal cell carcinoma (mRCC) has been drastically changing by the development of immune-oncology drugs and molecular targeted treatment in recent years. Although the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is useful for second-line setting, this model has the problem that over 50% patients are classified as intermediate risk group. The aim of this study is to evaluate whether the serum C-reactive protein (CRP) levels prior to second-line treatment could divide intermediate risk group patients.

Methods

We retrospectively reviewed 82 consequent intermediate-risk mRCC patients who received second-line molecular targeted therapy. We classified patients who had serum CRP higher than 0.5 mg/dl in elevated CRP group because the median baseline serum CRP level before second-line treatment was 0.51 mg/dl. We assessed the prognostic impact of serum CRP levels prior to second-line treatment initiation to predict overall survival (OS).

Results

Thirty-three out of 82 (40%) patients demonstrated elevated baseline CRP levels. The median OS of elevated and non-elevated CRP group was 11.5 (95% CI 5.4–17.5) and 29.4 (95% CI 25.5–33.5) months, respectively (p = 0.001). The serum CRP elevation could predict prognosis in intermediate risk patients treated with second-line treatment (HR 2.5, 95% CI 1.4–4.2, p = 0.001).

Conclusions

The serum CRP levels after first-line treatment termination could divide intermediate risk group mRCC patients into two prognostic subgroups in second-line targeted treatment setting.

Association of SNPs in the OBFC1 gene and laryngeal carcinoma in Chinese Han male population

Abstract

Background

Laryngeal carcinoma (LC) is one of common diagnosed head and neck malignancies. Telomere length has been reported involved in malignant transformation and tumorigenesis. We speculate that single nucleotide polymorphisms (SNPs) in telomere length-related gene oligonucleotide/oligosaccharide-binding folds containing 1 (OBFC1) may have an association with LC in Chinese Han male population.

Methods

To prove this hypothesis, we performed a case–control study to analyze the OBFC1 polymorphisms in 172 LC patients and 180 healthy controls. A total of five SNPs (i.e., rs9325507, rs3814220, rs12765878, rs11191865, rs9420707) were selected for further genotyping.

Results

There was a significant difference in rs9325507 T allele frequency (OR = 0.88, 95% CI 0.64–1.21, P = 0.036) and rs11191865 A allele frequency (OR = 0.86, 95% CI 0.62–1.18, P = 0.009) between patient and control groups. In addition, the rs9325507 T/C genotype, rs3814220 G/A genotype, rs12765878 C/T genotype and rs11191865 A/G genotype had a lower risk of LC based on the results of logistic regression model analysis.

Conclusions

The results indicate a potential association between OBFC1 and LC risk in Chinese Han male population. Further work is required to confirm these results and explore the mechanisms of these effects.

High diagnostic efficacy of 5-aminolevulinic acid-induced fluorescent urine cytology for urothelial carcinoma

Abstract

Background

In general, urine cytology is often problematic because of its low sensitivity, especially for low-grade urothelial carcinoma (UC) in clinical practice. To improve the sensitivity, we focused on 5-aminolevulinic acid (5-ALA), because recent studies suggested that 5-ALA-induced urine cytology can be used for photodynamic diagnosis. In this study, we evaluated the diagnostic efficacy of 5-ALA-induced fluorescent urine cytology for UC.

Methods

We included in this study 318 patients comprising 158 non-cancer patients, 84 bladder tumor patients, and 76 upper urinary tract urothelial carcinoma (UUT-UC) patients treated in our institution from March 2013 to September 2018. Using the same voided urine sample, we compared sensitivity and specificity between conventional urine cytology and 5-ALA-induced fluorescent urine cytology.

Results

Overall, the sensitivity of 5-ALA-induced fluorescent urine cytology was significantly higher than that of conventional urine cytology (86.9% vs. 69.4%; p = 0.0002), and the specificity was equivalently high (96.2% vs. 95.6%; p = 1.0). In subgroup analysis, the high sensitivity of 5-ALA-induced fluorescent urine cytology was also detected regardless of age, sex, and tumor type. However, in terms of stage and grade, differences were only detected in patients with less than pTa stage (89.2% vs. 52.1%; p = 0.0001) and low-grade tumor (91.5% vs. 51.1%; p < 0.0001).

Conclusions

5-ALA-induced fluorescent urine cytology was significantly more effective for UC diagnosis when compared with the conventional cytology, especially in patients with low-stage and low-grade tumors. These findings indicate that 5-ALA-induced fluorescent urine cytology may potentially be a very useful tool for clinical use.

Current clinical topics of Lynch syndrome

Abstract

Lynch syndrome (LS) is one of the most common genetic cancer syndromes, occurring at a rate of 1 per 250–1000 in the general population. This autosomal dominant disease is caused by a germline variant in one of the four mismatch repair genes, MSH2, MLH1, MSH6, PMS2, or the EPCAM gene. LS develops at early ages in colorectal cancer (CRC), endometrial cancer, and various other associated tumors. Accurate diagnosis of LS and utilization of various risk-reduction strategies such as surveillance, prophylactic surgery, and chemoprevention could improve clinical outcomes. The efficacy of surveillance has only been proven for CRC; however, specialists have proposed surveillance for other LS associated tumors. Universal screening for tumor tissue using microsatellite instability testing or the mismatch repair protein immunochemistry in all CRC or endometrial cancers is recommended not only as a diagnostic tool for LS, but also as a predictive, prognostic, and therapeutic marker. Next-generation sequencing methods have revealed several conditions with phenotypes similar to LS, such as Lynch-like syndrome, constitutional mismatch repair deficiency syndrome, and polymerase proofreading-associated polyposis. Distinguishing LS from these similar conditions is clinically important, since clinical management for patients differs according to the conditions. Recently, immune checkpoint inhibitors have been shown to be a promising treatment against mismatch repair-deficient (dMMR) solid tumors. The efficacy of immune-checkpoint inhibitors in LS-associated tumors has been shown to be similar to that in sporadic dMMR tumors. This review discusses current clinical topics related to LS screening, diagnosis, surveillance, and therapy.

Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome

Abstract

Lynch syndrome is a cancer-predisposing syndrome inherited in an autosomal-dominant manner, wherein colon cancer and endometrial cancer develop frequently in the family, it results from a loss-of-function mutation in one of four different genes (MLH1MSH2MSH6, and PMS2) encoding mismatch repair proteins. Being located immediately upstream of the MSH2 gene, EPCAM abnormalities can affect MSH2 and cause Lynch syndrome. Mismatch repair proteins are involved in repairing of incorrect pairing (point mutations and deletion/insertion of simple repetitive sequences, so-called microsatellites) that can arise during DNA replication. MSH2 forms heterodimers with MSH6 or MSH3 (MutSα, MutSβ, respectively) and is involved in mismatch-pair recognition and initiation of repair. MLH1 forms a complex with PMS2, and functions as an endonuclease. If the mismatch repair system is thoroughly working, genome integrity is maintained completely. Lynch syndrome is a state of mismatch repair deficiency due to a monoallelic abnormality of any mismatch repair genes. The phenotype indicating the mismatch repair deficiency can be frequently shown as a microsatellite instability in tumors. Children with germline biallelic mismatch repair gene abnormalities were reported to develop conditions such as gastrointestinal polyposis, colorectal cancer, brain cancer, leukemia, etc., and so on, demonstrating the need to respond with new concepts in genetic counseling. In promoting cancer genome medicine in a new era, such as by utilizing immune checkpoints, it is important to understand the genetic and genomic molecular background, including the status of mismatch repair deficiency.

Identification of SERPINE1, PLAU and ACTA1 as biomarkers of head and neck squamous cell carcinoma based on integrated bioinformatics analysis

Abstract

Background

Head and neck squamous cell carcinoma (HNSCC) is the six leading cancer by incidence worldwide. The 5-year survival rate of HNSCC patients remains less than 65% due to lack of symptoms in the early stage. Hence, biomarkers which can improve detection of HNSCC should improve clinical outcome.

Methods

Gene expression profiles (GSE6631, GSE58911) and the Cancer Genome Atlas (TCGA) HNSCC data were used for integrated bioinformatics analysis; the differentially expressed genes (DEGs) were then subjected to functional and pathway enrichment analysis, protein–protein interaction (PPI) network construction. Subsequently, module analysis of the PPI network was performed and overall survival (OS) analysis of hub genes in subnetwork was studied. Finally, immunohistochemistry was used to verify the selected markers.

Results

A total of 52 up-regulated and 80 down-regulated DEGs were identified, which were mainly associated with ECM–receptor interaction and focal adhesion signaling pathways. Importantly, a set of prognostic signatures including SERPINE1, PLAU and ACTA1 were screened from DEGs, which could predict OS in HNSCC patients from TCGA cohort. Experiment of clinical samples further successfully validated that these three signature genes were aberrantly expressed in the oral epithelial dysplasia and HNSCC, and correlated with aggressiveness of HNSCC patients.

Conclusions

SERPINE1, PLAU and ACTA1 played important roles in regulating the initiation and progression of HNSCC, and could be identified as key biomarkers for precise diagnosis and prognosis of HNSCC, which will provide potential targets for clinical therapies.

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