Integrative Analysis of Germline Rare Variants in Clear and Non-clear Cell Renal Cell Carcinoma.

Background and objective: Previous germline studies on renal cell carcinoma (RCC) have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification, which might have led to an inaccurate estimation of genetic risk. Here, we aim to analyze the major germline drivers of RCC risk and clinically relevant but underexplored germline variant types. Methods: We first characterized germline pathogenic variants (PVs), cryptic splice variants, and copy number variants (CNVs) in 1436 unselected RCC patients. To evaluate the enrichment of PVs in RCC, we conducted a case-control study of 1356 RCC patients ancestry matched with 16 512 cancer-free controls using approaches accounting for population stratification and histological subtypes, followed by characterization of secondary somatic events. Key findings and limitations: Clear cell RCC patients (n = 976) exhibited a significant burden of PVs in VHL compared with controls (odds ratio [OR]: 39.1, p = 4.95e-05). Non-clear cell RCC patients (n = 380) carried enrichment of PVs in FH (OR: 77.9, p = 1.55e-08) and MET (OR: 1.98e11, p = 2.07e-05). In a CHEK2-focused analysis with European participants, clear cell RCC (n = 906) harbored nominal enrichment of low-penetrance CHEK2 variants-p.Ile157Thr (OR: 1.84, p = 0.049) and p.Ser428Phe (OR: 5.20, p = 0.045), while non-clear cell RCC (n = 295) exhibited nominal enrichment of CHEK2 loss of function PVs (OR: 3.51, p = 0.033). Patients with germline PVs in FH, MET, and VHL exhibited significantly earlier age of cancer onset than patients without germline PVs (mean: 46.0 vs 60.2 yr, p < 0.0001), and more than half had secondary somatic events affecting the same gene (n = 10/15, 66.7%). Conversely, CHEK2 PV carriers exhibited a similar age of onset to patients without germline PVs (mean: 60.1 vs 60.2 yr, p = 0.99), and only 30.4% carried somatic events in CHEK2 (n = 7/23). Finally, pathogenic germline cryptic splice variants were identified in SDHA and TSC1, and pathogenic germline CNVs were found in 18 patients, including CNVs in FH, SDHA, and VHL. Conclusions and clinical implications: This analysis supports the existing link between several RCC risk genes and RCC risk manifesting in earlier age of onset. It calls for caution when assessing the role of CHEK2 due to the burden of founder variants with varying population frequency. It also broadens the definition of the RCC germline landscape of pathogenicity to incorporate previously understudied types of germline variants. Patient summary: In this study, we carefully compared the frequency of rare inherited mutations with a focus on patients' genetic ancestry. We discovered that subtle variations in genetic background may confound a case-control analysis, especially in evaluating the cancer risk associated with specific genes, such as CHEK2. We also identified previously less explored forms of rare inherited mutations, which could potentially increase the risk of kidney cancer.

Plasmonic Nanoparticles on Graphene Absorber for Broadband High Responsivity 2D/3D Photodiode.

To overcome the image deterioration caused by pixel miniaturization resulting from the high-resolution trend of CIS (CMOS image sensor) technology, a photodiode working with an enhanced mechanism based on a distinctive device structure from the existing one is considerably required. In this study, our photodiode, consisting of gold nanoparticles/monolayer graphene/n-type trilayer MoS2/p-type Si bulk, achieved ultrafast rising/falling times of 28.6 ns/30.4 ns due to the spatially confined narrow depletion width (DW) resulting from the 2D/3D heterojunction. To compensate for the expected low absorbance due to the narrow DW, plasmonic gold nanoparticles on monolayer graphene are introduced, revealing broadband enhanced EQE of an average of 187% in the spectral range of 420-730 nm and the maximum EQE reaching 847% at 5 nW for a 520 nm wavelength. The broadband enhancement was further investigated through multiphysics simulation, and carrier multiplication in graphene was discussed for the reason for exceeding 100% EQE in our reverse biased photodiode.

Reciprocal interactions among Cobll1, PACSIN2, and SH3BP1 regulate drug resistance in chronic myeloid leukemia.

Cobll1 affects blast crisis (BC) progression and tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML). PACSIN2, a novel Cobll1 binding protein, activates TKI-induced apoptosis in K562 cells, and this activation is suppressed by Cobll1 through the interaction between PACSIN2 and Cobll1. PACSIN2 also binds and inhibits SH3BP1 which activates the downstream Rac1 pathway and induces TKI resistance. PACSIN2 competitively interacts with Cobll1 or SH3BP1 with a higher affinity for Cobll1. Cobll1 preferentially binds to PACSIN2, releasing SH3BP1 to promote the SH3BP1/Rac1 pathway and suppress TKI-mediated apoptosis and eventually leading to TKI resistance. Similar interactions among Cobll1, PACSIN2, and SH3BP1 control hematopoiesis during vertebrate embryogenesis. Clinical analysis showed that most patients with CML have Cobll1 and SH3BP1 expression at the BC phase and BC patients with Cobll1 and SH3BP1 expression showed severe progression with a higher blast percentage than those without any Cobll1, PACSIN2, or SH3BP1 expression. Our study details the molecular mechanism of the Cobll1/PACSIN2/SH3BP1 pathway in regulating drug resistance and BC progression in CML.

Deciphering the molecular mechanisms of epitranscriptome regulation in cancer.

Post-transcriptional regulation is an indispensable cellular mechanism of gene expression control that dictates various cellular functions and cell fate decisions. Recently, various chemical RNA modifications, termed the "epitranscriptome," have been proposed to play crucial roles in the regulation of post-transcriptional gene expression. To date, more than 170 RNA modifications have been identified in almost all types of RNA. As with DNA modification-mediated control of gene expression, regulation of gene expression via RNA modification is also accomplished by three groups of proteins: writers, readers, and erasers. Several emerging studies have revealed that dysregulation in RNA modification is closely associated with tumorigenesis. Notably, the molecular outcomes of specific RNA modifications often have opposite cellular consequences. In this review, we highlight the current progress in the elucidation of the mechanisms of cancer development due to chemical modifications of various RNA species. [BMB Reports 2021; 54(2): 89-97].

Association between the IL-6, IL-10, and TNFα gene polymorphisms and preterm-birth in Korean women.

BACKGROUND: Preterm birth (PTB) is a major adverse pregnancy outcome and largely contributes to increasing neonatal and maternal mortality. Genetic and environmental factors may play an important role in the development of PTB. Numerous studies have shown that immune genes related to the immune system, such as IL-6, IL-10, and TNFα, are associated with the occurrence of PTB. OBJECTIVE: We examined genetic associations between IL-6 rs1800796, IL-10 rs1800872, and TNFα rs1800630 polymorphisms and PTB in Korean women. METHODS: In this study, 115 PTB patients and 147 controls were analyzed. The genotyping of three SNPs was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Our result showed that the rs1800872 polymorphism was significantly associated with the development of PTB in genotype frequency (odds ratio (OR) 1.71, 95% confidence interval (CI) 1.01-2.90, p = 0.046). We also found a significant association in an analysis of combined genotypes (rs1800796 CC, rs1800872 CA, and rs1800630 CA) (OR 7.43, 95% CI 2.06-26.84, p = 0.001). In a correlation analysis, rs1800630 A allele was significantly related with the increased birth weight (g) within PTB patients (p = 0.005). CONCLUSION: Our results imply possible relationships between the rs1800796, rs1800872, and rs1800630 polymorphisms and the development of PTB.

Diverse molecular functions of m6A mRNA modification in cancer.

N6-methyladenosine (m6A), the most prevalent chemical modification found on eukaryotic mRNA, is associated with almost all stages of mRNA metabolism and influences various human diseases. Recent research has implicated the aberrant regulation of m6A mRNA modification in many human cancers. An increasing number of studies have revealed that dysregulation of m6A-containing gene expression via the abnormal expression of m6A methyltransferases, demethylases, or reader proteins is closely associated with tumorigenicity. Notably, the molecular functions and cellular consequences of m6A mRNA modification often show opposite results depending on the degree of m6A modification in specific mRNA. In this review, we highlight the current progress on the underlying mechanisms of m6A modification in mRNA metabolism, particularly the functions of m6A writers, erasers, and readers in the context of tumorigenesis.

GCA links TRAF6-ULK1-dependent autophagy activation in resistant chronic myeloid leukemia.

Imatinib is the first molecularly targeted compound for chronic myeloid leukemia (CML) capable to inhibit BCR-ABL kinase activity. However, recent clinical evidence indicates that a substantial proportion of CML patients exhibit BCR-ABL-dependent or independent resistance to imatinib. Despite the importance of imatinib resistance in CML, the underlying molecular mechanisms of this resistance are largely unknown. Here, we identified GCA (grancalcin) as a critical regulator of imatinib resistance in chronic phase CML via activation of autophagy. Mechanistically, we demonstrated that GCA activates TRAF6 ubiquitin ligase activity to induce Lys63 ubiquitination of ULK1, a crucial regulator of autophagy, resulting in its stabilization and activation. We also highlighted the role of GCA-TRAF6-ULK1 autophagy regulatory axis in imatinib resistance. Our findings represent the basis for novel therapeutic strategies against CML.Abbreviation: ACTB/ß-actin: actin beta; ADM: adrenomedullin; AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; ANXA5: annexin A5; CP: cytogenetic response; CML: chronic myeloid leukemia; CUL3: cullin 3; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GCA: grancalcin; Dx: at diagnosis; E-64-d: (2S,3S)-trans-Epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester; IMres: Imatinib resistance; KLHL20: Kelch-like protein 20; LRMP: lymphoid-restricted membrane protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MMR: major molecular response; NH4Cl: ammonium chloride; PBMCs: peripheral blood mononuclear cells; PTPRC: protein tyrosine phosphatase, receptor type, C; SQSTM1/p62: sequestosome 1; SYK: spleen associated tyrosine kinase; TAP1: transporter 1, ATP binding cassette subfamily B member; TKIs: ABL-specific tyrosine kinase inhibitors; TLR9: toll- like receptor 9; TRAF6: TNF receptor associated factor 6; ULK1: unc-51 like autophagy activating kinase 1.

Assessment of associations between mitochondrial DNA haplogroups and attention deficit and hyperactivity disorder in Korean children.

Attention deficit hyperactivity disorder (ADHD) is a multifactorial disorder with multiple environmental and biological etiologies, including genetic factors. Until now, several genetic variants have been reported to be significantly associated with ADHD. Recently, the relationship between mitochondrial DNA (mtDNA) haplogroups and psychiatric disorders such as schizophrenia has also been reported. However, currently there are no reports pertaining to the genetic association between mtDNA haplogroups and ADHD. Therefore, we performed an mtDNA haplogroup analysis of a total of 472 Korean children (150 Children with ADHD and 322 controls). The 20 East Asian specific mtDNA haplogroups were determined using the SNaPshot assay. We also sequenced the displacement loop (D-loop) region, position 15,971-613. Our results showed that haplogroup B4 was significantly associated with ADHD (OR, 1.90; 95% CI, 1.055-3.429; p = 0.031). A marginally significant association was found in subjects with ADHD and haplogroup B5 (OR, 0.26; 95% CI, 0.059-1.139; p = 0.041). When stratified based on gender, an association was also observed between haplogroup B5 and boys diagnosed with ADHD (OR, 0.17; 95% CI, 0.022-1.340; p = 0.048). Compared with boys, girls with ADHD carried an excess of the haplogroup D4b (OR, 4.83; 95% CI, 1.352-17.272; p = 0.014). Stratified analysis of subtypes also showed significant results (combined: haplogroup B4, p = 0.007; inattentive: haplogroup F, p = 0.022). Our results showed a possible role of mtDNA haplogroups in the genetic etiology of ADHD and ADHD symptoms in Korean children.

Association of glutathione S-transferase M1 and T1 null/present polymorphism with physical performance in the Korean population.

Human physical performance is a highly complex phenotype that is influenced by various factors. In particular, genetic factors related to muscle fiber type, bone density, muscle performance, and metabolic processes are known to contribute in varying degrees to athlete status and physical performance in various ethnic groups. To investigate the relationship between these genetic factors and physical performances, we genotyped five genetic polymorphisms (ACE Ins/Del, ACTN3 R577X, ER-α C/T, GSTM1 null/present, and GSTT1 null/present) in 111 Korean athletes and 145 controls. We examined genotype and allele frequency differences between athletes and control groups, along with the odds ratios, using Chi square. One-way analysis of variance (ANOVA) was used to test the significance of differences in continuous variables between the multiple genetic polymorphisms and physical performance test results. The GSTM1 polymorphism exhibited a highly significant association in athletes (p = 0.017). Combined analysis of GSTM1 and GSTT1 also revealed significant differences between athletes and controls (p < 0.05). In the analysis of physical performance within athletes, the ER-α gene polymorphism was associated with the sargent jump and the side-step (p < 0.05), and the GSTM1 gene polymorphism was significantly associated with the 20 m shuttle run and sit-up (p < 0.05). Thus, our data imply that GSTM1 and ER-α gene polymorphisms were associated with physical performance in Korean athletes, although functional studies with larger sample sizes are necessary to elaborate upon these findings.

Genetic variations of MTHFR gene and their association with preterm birth in Korean women.

BACKGROUND AND OBJECTIVE: The MTHFR gene encodes the methylenetetrahydrofolate reductase known to be involved in the homocysteine-methionine pathway. It has been reported that the deficiency of MTHFR activity may cause hyperhomocysteinemia which results in adverse pregnancy outcomes. Previous studies reported a correlation between the MTHFR gene polymorphisms (677 T/C and 1298 A/C) and lower MTHFR activity and its association with preterm birth in various populations. Since these results were conflicting, we analyzed the genetic association of MTHFR gene 677 T/C and 1298 A/C polymorphisms with preterm birth in Korean women. MATERIALS AND METHODS: The subjects for case-control study were collected a total of 226 Korean women (98 preterm-birth patients and 128 controls). Genotype frequency differences between the case and the control were assessed using chi-square tests. Mann-Whitney t-test was used to estimate the effects of 1298 A/C genotype on clinicopathological characteristics (systolic blood pressure, diastolic blood pressure, birth weight, and gestational age at delivery) in preterm-birth patients. RESULTS: Our results showed that the MTHFR 677 C/T polymorphism was significantly associated with preterm-birth patients in the analysis of genotype frequency (P=0.044) and the over-dominant model (OR=0.54; 95% CI, 0.320-0.920; P=0.023). The recessive model showed a marginal trend toward significance (OR=0.47; 95% CI, 0.220-1.010; P=0.046). The 1298 A/C polymorphism was also associated with reduced preterm-birth risk in the recessive model (P=0.032). In the correlation analysis, the 1298 C allele was significantly associated with increasing of gestational age at delivery in preterm-birth patients (P=0.034). CONCLUSIONS: Our findings suggested that the MTHFR gene 677 C/T and 1298 A/C polymorphisms might have protective effects for preterm birth in the Korean women.