The use of multigene panel testing for patients with a predisposition to breast/ovarian cancer is increasing as the identification of variants is useful for diagnosis and disease management. We ...identified pathogenic and likely pathogenic (P/LP) variants of high‐and moderate‐risk genes using a 23‐gene germline cancer panel in 518 patients with hereditary breast and ovarian cancers (HBOC). The frequency of P/LP variants was 12.4% (64/518) for high‐ and moderate‐penetrant genes, namely, BRCA2 (5.6%), BRCA1 (3.3%), CHEK2 (1.2%), MUTYH (0.8%), PALB2 (0.8%), MLH1 (0.4%), ATM (0.4%), BRIP1 (0.4%), TP53 (0.2%), and PMS2 (0.2%). Five patients possessed two P/LP variants in BRCA1/2 and other genes. We also compared the results from in silico splicing predictive tools and exon splicing patterns from patient samples by analyzing RT‐PCR product sequences in six P/LP intronic variants and two intronic variants of unknown significance (VUS). Altered transcriptional fragments were detected for P/LP intronic variants in BRCA1, BRIP1, CHEK2, PARB2, and PMS2. Notably, we identified an in‐frame deletion of the BRCA1 C‐terminal (BRCT) domain by exon skipping in BRCA1 c.5152+6T>C—as known VUS—indicating a risk for HBOC. Thus, exon splicing analysis can improve the identification of veiled intronic variants that would aid decision making and determination of hereditary cancer risk.
This study identified 12.4% (64/518) pathogenic or likely pathogenic (P/LP) variants using a comprehensive multi‐gene panel including 23 cancer susceptibility genes and analyzed the pathogenic effects in the intronic variants identified by analyzing exon splicing patterns. These analyses would help further identify the uncharacterized variants that are expected to increase hereditary breast/ovarian cancer risk.
We prospectively investigated the association between a change of serum vascular endothelial growth factor (VEGF) level after transcatheter arterial chemoembolization (TACE) and hepatocellular ...carcinoma (HCC) patient prognosis. The study involved 147 patients with unresectable HCC treated at the National Cancer Center, Korea, between July and December 2005. Serum samples were collected from each patient before TACE, and 1–2 days and 1 month after TACE. Serum VEGF concentrations were measured using an enzyme‐linked immunosorbent assay (ELISA). The loge(VEGF/platelets) increased transiently 1–2 days after TACE and declined thereafter. Frequency of previous TACE did not correlate with loge(VEGF/platelets). This study found that loge(VEGF/platelets) 1–2 days after TACE, but not loge(VEGF/platelets) at baseline, was strongly correlated with vascular or nodal invasion and AJCC (American Joint Committee on Cancer)/UICC (International Union Against Cancer) stage, and was significantly greater in men. Relative changes in serum VEGF/platelet levels 1–2 days after TACE (ΔVEGF) > 0.5 were directly correlated with tumor size, vascular invasion and modified UICC and AJCC/UICC stage (P < 0.05 for each). Additionally, ΔVEGF > 0.5 was significantly correlated with newly developed extrahepatic metastases one and six months after TACE (P = 0.005 and 0.003, respectively). Progression free survival of patients with ΔVEGF > 0.5 was significantly worse (P < 0.001) and ΔVEGF > 0.5 was an independent prognostic factor for PFS (hazard ratio, 3.111; P < 0.001). This study showed that a high increment in serum VEGF level 1–2 days after TACE in HCC patients was associated with distant metastasis and unfavorable outcomes. (Cancer Sci 2008; 99: 2037–2044)
Our purpose is to investigate the impact of circadian and melatonin pathway genes as well as their interactions with night-shift work (NSW) on breast cancer risk in Korean women. Information about ...NSW and other covariates was collected using a structured questionnaire and twenty-two polymorphisms in 11 genes were analyzed in a hospital-based case-control study with 941 cases of breast cancer and 959 controls. In analysis of the main effects of each single nucleotide polymorphisms(SNPs), variants in CLOCK rs11133373 was associated with breast cancer risk even after false discovery rate (FDR) correction (Odd Ratios (OR) = 1.38 (95% Confident Interval (CI) 1.14-1.69) in CG and CC compared to GG genotype. Analysis of MTNR1A rs2119882 demonstrated a decreased risk of breast cancer in CC compared to TT (p-FDR = 0.043). A correlation between NSW and breast cancer interaction was found in two loci. NSW increased risk of breast cancer in women who carried the heterozygote genotype of CRY2 rs2292912 (OR = 1.98, 95% CI = 1.14-3.44) or carried at least one minor allele of RORA rs1482057 (OR = 2.20, 95% CI = 1.10-4.37). Our study results support a putative role for several loci of circadian genes and genes of melatonin biosynthesis and their interaction, and the gene interactions with NSW in the development of breast cancer.
Immunomodulatory cytokines and systemic inflammatory markers are important during cancer development and progression. This study investigated the association and prognostic impact of systemic ...cytokine profiles and inflammatory markers in colorectal cancer (CRC).
Interleukin (IL)-1β, IL-6, IL-8, IL-9, IL-10, tumour necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) serum levels were measured using multiplex bead assays in CRC patients. Data on systemic inflammatory markers, such as the modified Glasgow prognostic score (mGPS), the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index (PNI) and fibrinogen, were collected. Survival analysis was performed to identify factors associated with progression-free survival (PFS) and overall survival (OS).
There were moderate-to-strong correlations within serum cytokines, as well as within systemic inflammatory markers, whereas the associations between serum cytokines and systemic inflammatory markers were generally weak. IL-8 and the LMR were independent significant prognostic factors for PFS and OS. The low IL-8 and high LMR group had the best survival (both PFS and OS) of all groups.
Systemic cytokine profiles and inflammatory markers have relatively weak intergroup correlations. A composite classification of systemic cytokine profiles and inflammatory markers has an enhanced prognostic value in CRC.
Although sorafenib is the global standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC), it does not have reliable predictive or prognostic biomarkers. Circulating ...cell-free DNA (cfDNA) has shown promise as a biomarker for various cancers. We investigated the use of cfDNA to predict clinical outcomes in HCC patients treated with sorafenib.
This prospective biomarker study analyzed plasma cfDNA from 151 HCC patients who received first-line sorafenib and 14 healthy controls. The concentration and VEGFA-to-EIF2C1 ratios (the VEGFA ratio) of cfDNA were measured. Low depth whole-genome sequencing of cfDNA was used to identify genome-wide copy number alteration (CNA), and the I-score was developed to express genomic instability. The I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. The primary aim of this study was to develop cfDNA biomarkers predicting treatment outcomes of sorafenib, and the primary study outcome was the association between biomarkers with treatment efficacy including disease control rate (DCR), time to progression (TTP) and overall survival (OS) in these patients.
The cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/μL; P < 0.0001). Patients who did not achieve disease control with sorafenib had significantly higher cfDNA levels (0.82 vs. 0.63 ng/μL; P = 0.006) and I-scores (3405 vs. 1024; P = 0.0017) than those achieving disease control. The cfDNA-high group had significantly worse TTP (2.2 vs. 4.1 months; HR = 1.71; P = 0.002) and OS (4.1 vs. 14.8 months; HR = 3.50; P < 0.0001) than the cfDNA-low group. The I-score-high group had poorer TTP (2.2 vs. 4.1 months; HR = 2.09; P < 0.0001) and OS (4.6 vs. 14.8 months; HR = 3.35; P < 0.0001). In the multivariable analyses, the cfDNA remained an independent prognostic factor for OS (P < 0.0001), and the I-score for both TTP (P = 0.011) and OS (P = 0.010). The VEGFA ratio was not significantly associated with treatment outcomes.
Pretreatment cfDNA concentration and genome-wide CNA in cfDNA are potential biomarkers predicting outcomes in advanced HCC patients receiving first-line sorafenib.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
N6‐Methyladenosine (m6A) is the most abundant epitranscriptomic mark and plays a fundamental role in almost every aspect of mRNA metabolism. Although m6A writers and readers have been widely studied, ...the roles of m6A erasers are not well‐understood. Here, we investigate the role of FTO, one of the m6A erasers, in natural killer (NK) cell immunity. We observe that FTO‐deficient NK cells are hyperactivated. Fto knockout (Fto−/−) mouse NK cells prevent melanoma metastasis in vivo, and FTO‐deficient human NK cells enhance the antitumor response against leukemia in vitro. We find that FTO negatively regulates IL‐2/15‐driven JAK/STAT signaling by increasing the mRNA stability of suppressor of cytokine signaling protein (SOCS) family genes. Our results suggest that FTO is an essential modulator of NK cell immunity, providing a new immunotherapeutic strategy for allogeneic NK cell therapies.
Synopsis
The m6A RNA demethylase FTO suppresses the cytotoxic activity of natural killer cells by negatively regulating IL‐2/15‐driven JAK/STAT signaling.
FTO‐deficient natural killer (NK) cells are hyper‐activated.
FTO negatively regulates IL‐2/15‐driven JAK/STAT signaling in NK cells.
FTO removes m6A marks from the mRNA of Suppressor of cytokine signaling proteins (SOCS) family genes increasing their stability.
The m6A RNA demethylase FTO suppresses the cytotoxic activity of natural killer cells by negatively regulating IL‐2/15‐driven JAK/STAT signaling.
Background: The increased demand for genetic testing and counseling necessitates healthcare professionals (HCPs) to improve their genetic competency through training programs. This systematic review ...identified HCPs’ learning needs and their perspectives on essential information for families with hereditary cancer. Methods: This review covered studies published from 2013 to 2024 across five databases. Data were analyzed using a content analysis. Results: Thirteen studies involving 332 HCPs were analyzed. Most studies focused on the learning needs of physicians caring for families affected by Hereditary Breast and Ovarian Cancer in North America and Europe. HCPs required training emphasizing practical counseling skills over the basics of genetics. Learning needs varied by profession: physicians needed training in assessing cancer risk and supporting decision-making in risk management; nurses required information on resources and the genetic care system; genetic counselors sought guidance on family communication and planning. Essential information identified for families included risk-reducing strategies, personalized cancer risk assessment, family implications, psychological issues, (cascade) genetic testing, and social concerns. Conclusions: The findings have implications for the development of training programs for HCPs, emphasizing the need for tailored training based on professions. Future research should explore the needs of HCPs caring for families with diverse hereditary cancers and cultural backgrounds.
Very young breast cancer patients are more common in Asian countries than Western countries and are thought to have worse prognosis than older patients. The aim of the current study was to identify ...molecular characteristics of young patients with estrogen receptor (ER)‐positive breast cancer by analyzing mutations and copy number variants (CNV), and by applying expression profiling. The whole exome and transcriptome of 47 Korean young breast cancer (KYBR) patients (age <35) were analyzed. Genomic profiles were constructed using mutations, CNV and differential gene expression from sequencing data. Pathway analyses were also performed using gene sets to identify biological processes. Our data were compared with young ER+ breast cancer patients in The Cancer Genome Atlas (TCGA) dataset. TP53, PIK3CA and GATA3 were highly recurrent somatic mutation genes. APOBEC‐associated mutation signature was more frequent in KYBR compared with young TCGA patients. Integrative profiling was used to classify our patients into 3 subgroups based on molecular characteristics. Group A showed luminal A‐like subtype and IGF1R signal dysregulation. Luminal B patients were classified into groups B and C, which showed chromosomal instability and enrichment for APOBEC3A/B deletions, respectively. Group B was characterized by 11q13 (CCND1) amplification and activation of the ubiquitin‐mediated proteolysis pathway. Group C showed 17q12 (ERBB2) amplification and lower ER and progesterone receptor expression. Group C was also distinguished by immune activation and lower epithelial‐mesenchyme transition (EMT) degree compared with group B. This study showed that integrative genomic profiling could classify very young patients with breast cancer into molecular subgroups that are potentially linked to different clinical characteristics.
Very young patients with breast cancer are much more common in Asian countries. We analyzed whole exomes and transcriptomes of 47 Korean young breast cancer (KYBR) patients, and classified patients into 3 subgroups based on molecular characteristics, including IGF1R dysregulation, chromosomal instability and APOBEC deletion enrichment.
This study aimed to analyze the proportion, characteristics and prognosis of untreated hepatocellular carcinoma (HCC) patients in a large representative nationwide study. A cohort study was conducted ...using the National Health Insurance Service (NHIS) database in Korea. A total of 63,668 newly-diagnosed HCC patients between January 2008 and December 2013 were analyzed. Patients were categorized into treatment group and no treatment group using claim codes after HCC diagnosis. The proportion of untreated HCC patients was 27.6%, decreasing from 33.4% in 2008 to 24.8% in 2013. Compared to treated patients, untreated patients were more likely to be older (P < 0.001), female (P < 0.01), to have a distant SEER stage (P < 0.001), severe liver disease (P < 0.001), and lower income (P < 0.001). The fully-adjusted hazard ratio for all-cause mortality comparing untreated to treated patients was 3.11 (95% CI, 3.04-3.18). The risk of mortality was higher for untreated patients in all pre-defined subgroups, including those with distant SEER stage and those with severe liver disease. About one fourth of newly diagnosed HCC patients did not receive any HCC-specific treatment. Untreated patients showed higher risk of mortality compared to treated patients in all subgroups. Further studies are needed to identify obstacles for HCC treatment and to improve treatment rates.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
