Deep learning model integrating cfDNA methylation and fragment size profiles for lung cancer diagnosis.

Detecting aberrant cell-free DNA (cfDNA) methylation is a promising strategy for lung cancer diagnosis. In this study, our aim is to identify methylation markers to distinguish patients with lung cancer from healthy individuals. Additionally, we sought to develop a deep learning model incorporating cfDNA methylation and fragment size profiles. To achieve this, we utilized methylation data collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. Then we generated methylated DNA immunoprecipitation sequencing and genome-wide Enzymatic Methyl-seq (EM-seq) form lung cancer tissue and plasma. Using these data, we selected 366 methylation markers. A targeted EM-seq panel was designed using the selected markers, and 142 lung cancer and 56 healthy samples were produced with the panel. Additionally, cfDNA samples from healthy individuals and lung cancer patients were diluted to evaluate sensitivity. Its lung cancer detection performance reached an accuracy of 81.5% and an area under the receiver operating characteristic curve of 0.87. In the serial dilution experiment, we achieved tumor fraction detection of 1% at 98% specificity and 0.1% at 80% specificity. In conclusion, we successfully developed and validated a combination of methylation panel and a deep learning model that can distinguish between patients with lung cancer and healthy individuals.

Plasma Circulating Cell-free DNA in Advanced Hepatocellular Carcinoma Patients Treated With Radiation Therapy.

BACKGROUND/AIM: Although radiation therapy (RT) is an effective and safe treatment when administered locally for various stages of hepatocellular carcinoma (HCC), adequate biomarkers that are predictive of therapeutic efficacy have not been identified. We evaluated the clinical utility of circulating cell-free DNA (cfDNA) to predict treatment response of patients with HCC treated with RT. PATIENTS AND METHODS: We prospectively recruited 37 patients diagnosed with HCC between March 2019 and May 2020. All patients were treated with RT as salvage therapy. Whole peripheral blood was collected twice, one before RT (baseline; V1) and another aliquot one week after the end of RT (V2). We determined whether cfDNA genomic copy number variations (CNVs) could predict treatment outcome. An I-score was calculated from the plasma cfDNA that reflected CNVs of cfDNA, which is evidence of genomic instability. RESULTS: The I-score at V1 exhibited a strong correlation with the planning target volume (PTV) (coefficient=0.65) and was a predictive marker for progression-free survival (PFS). In particular, a mean I-score value at V1 of ≥6.3 had a significant positive correlation with PFS (p=0.017). Compared with patients who had a complete response (CR) following RT, non-CR patients had a higher mean I-score value at V2 ≥6.2 (p=0.034). Furthermore, I-score values at V1 and V2 and the delta I-score ratio were significantly associated with a pre-RT alpha-fetoprotein level ≥200 among non-CR patients. CONCLUSION: I-score values calculated from plasma cfDNA represent a potential biomarker for predicting treatment outcomes in patients with advanced HCC receiving RT.

Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA.

Multi-cancer early detection remains a key challenge in cell-free DNA (cfDNA)-based liquid biopsy. Here, we perform cfDNA whole-genome sequencing to generate two test datasets covering 2125 patient samples of 9 cancer types and 1241 normal control samples, and also a reference dataset for background variant filtering based on 20,529 low-depth healthy samples. An external cfDNA dataset consisting of 208 cancer and 214 normal control samples is used for additional evaluation. Accuracy for cancer detection and tissue-of-origin localization is achieved using our algorithm, which incorporates cancer type-specific profiles of mutation distribution and chromatin organization in tumor tissues as model references. Our integrative model detects early-stage cancers, including those of pancreatic origin, with high sensitivity that is comparable to that of late-stage detection. Model interpretation reveals the contribution of cancer type-specific genomic and epigenomic features. Our methodologies may lay the groundwork for accurate cfDNA-based cancer diagnosis, especially at early stages.

Prevalence and Risk Factors of Germline Pathogenic Variants in Pancreatic Ductal Adenocarcinoma.

PURPOSE: The genetic attribution for pancreatic ductal adenocarcinoma (PDAC) has been reported as 5%-10%. However, the incidence of germline pathogenic variants (PVs) in Korean PDAC patients has not been thoroughly investigated. Therefore, we studied to identify the risk factors and prevalence of PV for future treatment strategies in PDAC. MATERIALS AND METHODS: Total of 300 (155 male) patients with a median age of 65 years (range, 33 to 90 years) were enrolled in National Cancer Center in Korea. Cancer predisposition genes, clinicopathologic characteristics, and family history of cancer were analyzed. RESULTS: PVs were detected in 20 patients (6.7%, median age 65) in ATM (n=7, 31.8%), BRCA1 (n=3, 13.6%), BRCA2 (n=3), and RAD51D (n=3). Each one patient showed TP53, PALB2, PMS2, RAD50, MSH3, and SPINK1 PV. Among them, two likely PVs were in ATM and RAD51D, respectively. Family history of various types of cancer including pancreatic cancer (n=4) were found in 12 patients. Three patients with ATM PVs and a patient with three germline PVs (BRCA2, MSH3, and RAD51D) had first-degree relatives with pancreatic cancer. Familial pancreatic cancer history and PVs detection had a significant association (4/20, 20% vs. 16/264, 5.7%; p=0.035). CONCLUSION: Our study demonstrated that germline PVs in ATM, BRCA1, BRCA2, and RAD51D are most frequent in Korean PDAC patients and it is comparable to those of different ethnic groups. Although this study did not show guidelines for germline predisposition gene testing in patients with PDAC in Korea, it would be emphasized the need for germline testing for all PDAC patients.

Liquid biopsy using cfDNA to predict radiation therapy response in solid tumors.

PURPOSE: This study explored the potential feasibility of cell-free DNA (cfDNA) in monitoring treatment response through the measurement of chromosomal instabilities using I-scores in the context of radiation therapy (RT) for other solid tumors. MATERIALS AND METHODS: This study enrolled 23 patients treated with RT for lung, esophageal, and head and neck cancer. Serial cfDNA monitoring was performed before RT, 1 week after RT, and 1 month after RT. Low-depth whole-genome sequencing was done using Nano kit and NextSeq 500 (Illumina Inc.). To measure the extent of genome-wide copy number instability, I-score was calculated. RESULTS: Pretreatment I-score was elevated to more than 5.09 in 17 patients (73.9%). There was a significant positive correlation between the gross tumor volume and the baseline I-score (Spearman rho = 0.419, p = 0.047). The median I-scores at baseline, post-RT 1 week (P1W), and post-RT 1 month (P1M) were 5.27, 5.13, and 4.79, respectively. The I-score at P1M was significantly lower than that at baseline (p = 0.002), while the difference between baseline and P1W was not significant (p = 0.244). CONCLUSION: We have shown the feasibility of cfDNA I-score to detect minimal residual disease after RT in patients with lung cancer, esophageal cancer, and head and neck cancer. Additional studies are ongoing to optimize the measurement and analysis of I-scores to predict the radiation response in cancer patients.

Narcolepsy is associated with an increased risk of HLA-related autoimmune diseases: Evidence from a nationwide healthcare system data in South Korea.

STUDY OBJECTIVES: To determine the incidence rate of narcolepsy in South Korea and closely examine the relationship between narcolepsy, which is believed to be an autoimmune response, and other systemic autoimmune diseases. METHODS: We examined data from the South Korean nationwide health insurance claims database from 2010 to 2019. Our study included patients with narcolepsy as well as age- and sex-matched controls without narcolepsy. We estimated the incidence of narcolepsy and the odds ratio of narcolepsy and associated autoimmune comorbidities in South Korea. RESULTS: We identified 8710 patients with narcolepsy (59.8% men and 40.2% women). The incidence of narcolepsy was 0.05%. Patients with narcolepsy were at a significantly high risk of ankylosing spondylitis, rheumatoid arthritis, and Sjögren's syndrome, which diseases are known to be related to human leukocyte antigen (HLA) genes. CONCLUSIONS: Narcolepsy is closely related to systemic autoimmune diseases, particularly those related to HLA genes.

Shallow Whole-Genome Sequencing of Cell-Free DNA (cfDNA) Detects Epithelial Ovarian Cancer and Predicts Patient Prognosis.

Despite the progress in diagnostics and therapeutics, epithelial ovarian cancer (EOC) remains a fatal disease. Using shallow whole-genome sequencing of plasma cell-free DNA (cfDNA), we investigated biomarkers that could detect EOC and predict survival. Plasma cfDNA from 40 EOC patients and 20 healthy subjects were analyzed by shallow whole-genome sequencing (WGS) to identify copy number variations (CNVs) and determine the Z-scores of genes. In addition, we also calculated the genome-wide scores (Gi scores) to quantify chromosomal instability. We found that the Gi scores could distinguish EOC patients from healthy subjects and identify various EOC histological subtypes (e.g., high-grade serous carcinoma). In addition, we characterized EOC CNVs and demonstrated a relationship between RAB25 amplification (alone or with CA125), and disease-free survival and overall survival. This study identified RAB25 amplification as a predictor of EOC patient survival. Moreover, we showed that Gi scores could detect EOC. These data demonstrated that cfDNA, detected by shallow WGS, represented a potential tool for diagnosing EOC and predicting its prognosis.

Osteoarthritis improvement effect of Chrysanthemum zawadskii var. latilobum extract in relation to genotype.

Objectives: To determine whether SNPs of osteoarthritis (OA)-related genes predict the effect of Chrysanthemum zawadskii var. latilobum (CZ) extract in OA patients with OA. Subjects/methods: To analyze correlations between CZ extract effects in humans and their genotypes, 121 Korean patients with OA were recruited. Patients ingested 600 mg/day of the CZ extract GCWB106 (one tablet daily), including 250-mg CZ, or placebo (one tablet daily) for 12 weeks. Twenty SNPs were genotyped in 11 genes associated with OA pathogenesis, including tumor necrosis factor-alpha (TNF-α) and matrix metalloproteinases (MMPs), and 9 genes involved in OA-related dietary intervention. The Visual Analogue Scale (VAS) and Korean Western Ontario and McMaster Universities (K-WOMAC) were measured as indicators of GCWB106 effect. Statistical comparisons were performed using Kruskal-Wallis tests to identify associations between these scales and genotyped loci in patients with OA. Results: Three SNPs (PPARG rs3856806, MMP13 rs2252070, and ZIP2 rs2234632) were significantly associated with the degree of change in VAS pain score. Homozygous CC genotype carriers of rs3856806, G allele carriers (GA or GG) of rs2252070, and T allele carriers (GT or TT) of rs2234632 showed lower VAS score (i.e., less severe symptoms) in the GCWB106 group (n=53) than the placebo group (n=57) (p=0.026, p=0.009, and p=0.025, respectively). Gene-gene interaction effects on GCWB106-mediated pain relief were then examined, and it was found that the addition of each genotype resulted in a greater decrease in VAS pain score in the GCWB106 group (p=0.0024) but not the placebo group (p=0.7734). Conclusions: These novel predictive markers for the pain-relieving effects of GCWB106 may be used in the personalized treatment of patients with OA.

Chromosomal Instability in Cell-free DNA as a Prognostic Biomarker of Metastatic Hormone-sensitive Prostate Cancer Treated with Androgen Deprivation Therapy.

BACKGROUND: Although patients with metastatic hormone-sensitive prostate cancer (mHSPC) undergo androgen deprivation therapy (ADT), the disease can progress to metastatic castration-resistant prostate cancer (mCRPC). There are no reliable biomarkers for predicting this progression. Chromosomal instability resulting in copy number alterations (CNAs) is characteristically observed in patients with various cancers. OBJECTIVE: To investigate the role of chromosomal instability in patients with mHSPC. DESIGN, SETTING, AND PARTICIPANTS: This prospective study analyzed cell-free DNA (cfDNA) in pretreatment plasma samples from 75 patients with elevated prostate-specific antigen. Low-depth whole-genome sequencing of cfDNA was performed to identify CNAs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The I score (sum of the product of the absolute Z score and the corresponding chromosome length) was used as a measure of chromosomal instability. Kaplan-Meier and Cox proportional-hazard regression analyses were performed to evaluate the association between the I score and time to progression (TTP) and the prognostic value of chromosomal instability in predicting castration resistance, respectively. RESULTS AND LIMITATIONS: Of 22 patients with a positive I score, 86.4% (19/22) had metastatic prostate cancer. Of these 19 cases, 94.7% (18/19) were mHSPC, which was high-volume mHSPC in 83.3% (15/18). None of the patients with localized prostate cancer had a positive I score. TTP in patients with mHSPC was significantly shorter in the positive than in the negative I-score group (16.4 vs 36.9 mo; p = 0.001). Only the I score could independently predict mCRPC development (hazard ratio 10.315, 95% confidence interval 1.141-93.208; p = 0.038). CONCLUSIONS: The I score could be a biomarker for ADT response and progression to mCRPC in patients with mHSPC. PATIENT SUMMARY: We investigated whether genetic changes in cell-free DNA can predict outcomes for patients with metastatic prostate cancer that still responds to hormone therapy. We found that chromosomal instability could be a potential predictor of the development of metastatic castration-resistant prostate cancer.

Development and performance evaluation of an artificial intelligence algorithm using cell-free DNA fragment distance for non-invasive prenatal testing (aiD-NIPT).

With advances in next-generation sequencing technology, non-invasive prenatal testing (NIPT) has been widely implemented to detect fetal aneuploidies, including trisomy 21, 18, and 13 (T21, T18, and T13). Most NIPT methods use cell-free DNA (cfDNA) fragment count (FC) in maternal blood. In this study, we developed a novel NIPT method using cfDNA fragment distance (FD) and convolutional neural network-based artificial intelligence algorithm (aiD-NIPT). Four types of aiD-NIPT algorithm (mean, median, interquartile range, and its ensemble) were developed using 2,215 samples. In an analysis of 17,678 clinical samples, all algorithms showed >99.40% accuracy for T21/T18/T13, and the ensemble algorithm showed the best performance (sensitivity: 99.07%, positive predictive value (PPV): 88.43%); the FC-based conventional Z-score and normalized chromosomal value showed 98.15% sensitivity, with 40.77% and 36.81% PPV, respectively. In conclusion, FD-based aiD-NIPT was successfully developed, and it showed better performance than FC-based NIPT methods.

Early detection of norovirus outbreak using machine learning methods in South Korea.

BACKGROUND: The norovirus is a major cause of acute gastroenteritis at all ages but particularly has a high chance of affecting children under the age of five. Given that the outbreak of norovirus in Korea is seasonal, it is important to try and predict the start and end of norovirus outbreaks. METHODS: We predicted weekly norovirus warnings using six machine learning algorithms using test data from 2017 to 2018 and training data from 2009 to 2016. In addition, we proposed a novel method for the early detection of norovirus using a calculated norovirus risk index. Further, feature importance was calculated to evaluate the contribution of the estimated weekly norovirus warnings. RESULTS: The long short-term memory machine learning (LSTM) algorithm proved to be the best algorithm for predicting weekly norovirus warnings, with 97.2% and 92.5% accuracy in the training and test data, respectively. The LSTM algorithm predicted the observed start and end weeks of the early detection of norovirus within a 3-week range. CONCLUSIONS: The results of this study show that early detection can provide important insights for the preparation and control of norovirus outbreaks by the government. Our method provides indicators of high-risk weeks. In particular, last norovirus detection rate, minimum temperature, and day length, play critical roles in estimating weekly norovirus warnings.

Pharmacokinetics and Genetic Factors of Atorvastatin in Healthy Korean Subjects.

Background: Statins are the most popular agents for the primary and secondary prevention of cardiovascular disease; however, the pharmacokinetic parameters and associated genetic factors in the Korean population have not been fully elucidated. This study explored the pharmacokinetic properties of atorvastatin and the association between genetic variations and atorvastatin pharmacokinetics in healthy Korean subjects. Methods: Atorvastatin (80 mg) was administered to 35 healthy Korean volunteers. Plasma levels of atorvastatin and its metabolites were measured sequentially using liquid chromatography-tandem mass spectrometry from 0 to 24 h after atorvastatin administration. Customized next-generation sequencing analysis was performed covering all coding exons of 15 genes, as well as 46 single-nucleotide variants in 29 genes related to statin pharmacokinetics. Results: The mean area under the concentration-time (AUC) and Cmax (maximum peak concentration) were 269.0 ng/ml∙h and 84.3 ng/ml, respectively, which were approximately two times higher than those reported in Caucasians. Genetic analysis revealed that eight genetic variants in ABCB1, ABCG2, APOA5, CETP, and CYP7A1 contributed to the AUC of atorvastatin. The atorvastatin AUC0-24 h prediction model was developed based on age and eight genetic variants using multivariate linear regression (adjusted R 2 = 0.878, p < 0.0001). Conclusion: This study shows that the pharmacokinetic properties of atorvastatin in Koreans are different from those in Caucasians and that atorvastatin AUC0-24 h could be predicted based on age and eight genetic variants of ABCB1, ABCG2, APOA5, CETP, and CYP7A1.

Targeted next generation sequencing of circulating tumor DNA provides prognostic information for management in breast cancer patients.

Background: Circulating tumor DNA (ctDNA) is a non-invasive biomarker for evaluating cancer prognosis. The aim of this study was to analyze the genomic profile of circulating tumor DNA (ctDNA) in breast cancer patients, and evaluate its clinical implications. Methods: Targeted sequencing of ctDNA was performed in 38 patients using commercially available Oncomine Breast cfDNA panel. Whole exome sequencing was performed on matched tumor DNA (n=20). Survival analysis and response to chemotherapy in the study population were evaluated. The detected genomic variants were validated and serially monitored with droplet digital polymerase chain reaction (ddPCR) in 5 patients. Results: At least one variant or copy number alteration was detected in the ctDNA of 31 of 38 (82%) breast cancer patients, with the most common variants being in TP53 (50%), PIK3CA (15%) and ESR1 (14%). When comparing genomic profiles of ctDNA and those of matched tumor DNA in 20 patients, the concordance rate was 9.7% among positives. The patients with variants in TP53 showed significantly poorer overall survival than those without [hazard ratio (HR) =3.90, 95% confidence interval (CI): 1.10-13.84, P=0.035] and its impact was also statistically significant in multivariate analysis with breast cancer subtype included. In serially monitored results, changes in the allele frequency of somatic variants (PI3KCA, TP53) of ctDNA were found to be reflective of response to chemotherapy. Conclusions: The genomic profile of ctDNA reflects and provides additional information to the tumor DNA genome profile. Follow-up monitoring of mutations detected in ctDNA is useful in the clinical management of breast cancer patients.

Aberrant Transcript Usage Is Associated with Homologous Recombination Deficiency and Predicts Therapeutic Response.

BRCA1/2 mutations account for only a small fraction of homologous recombination (HR) deficiency (HRD) cases. Recently developed genomic HRD (gHRD) tests suffer confounding factors that cause low precision in predicting samples that will respond to PARP inhibitors and DNA damaging agents. Here we present molecular and clinical evidence of transcriptional HRD (tHRD) that is based on aberrant transcript usage (aTU) of minor isoforms. Specifically, increased TU of nonfunctional isoforms of DNA repair genes was prevalent in breast and ovarian cancer with gHRD. Functional assays validated the association of aTU with impaired HR activity. Machine learning-based tHRD detection by the transcript usage (TU) pattern of key genes was superior to directly screening for gHRD or BRCA1/2 mutations in accurately predicting responses of cell lines and patients with cancer to PARP inhibitors and genotoxic drugs. This approach demonstrated the capability of tHRD status to reflect functional HR status, including in a cohort of olaparib-treated ovarian cancer with acquired platinum resistance. Diagnostic tests based on tHRD are expected to broaden the clinical utility of PARP inhibitors. SIGNIFICANCE: A novel but widespread transcriptional mechanism by which homologous recombination deficiency arises independently of BRCA1/2 mutations can be utilized as a companion diagnostic for PARP inhibitors.

Genomic Instability of Circulating Tumor DNA as a Prognostic Marker for Pancreatic Cancer Survival: A Prospective Cohort Study.

Genomic instability of circulating tumor DNA (ctDNA) as a prognostic biomarker has not been evaluated in pancreatic cancer. We investigated the role of the genomic instability index of ctDNA in pancreatic ductal adenocarcinoma (PDAC). We prospectively enrolled 315 patients newly diagnosed with resectable (n = 110), locally advanced (n = 78), and metastatic (n = 127) PDAC from March 2015 through January 2020. Low-depth whole-genome cell-free DNA sequencing identified genome-wide copy number alterations using instability score (I-score) to reflect genome-wide instability. Plasma cell-free and matched tumor tissue DNA from 15 patients with resectable pancreatic cancer was sequenced to assess the concordance of chromosomal copy number alteration profiles. Associations of I-score with clinical factors or survival were assessed. Seventy-six patients had high genomic instability with I-score > 7.3 in pre-treatment ctDNA; proportions of high I-score were 5.5%, 5.1%, and 52% in resectable, locally advanced, and metastatic stages, respectively. Correlation coefficients between Z-scores of plasma and tissue DNA at segment resolution were high (r2 = 0.82). Univariable analysis showed the association of I-score with progression-free survival in each stage. Multivariable analyses demonstrated that clinical stage-adjusted I-scores were significant factors for progression-free and overall survival. In these patients, ctDNA genomic I-scores provided prognostic information relevant to progression-free survival in each clinical stage.

Prenatal diagnosis of combined methylmalonic acidemia and homocystinuria cobalamin C type using clinical exome sequencing and targeted gene analysis.

BACKGROUND: Combined methylmalonic acidemia and homocystinuria is a rare inherited disorder of intracellular cobalamin metabolism caused by biallelic variants in one of the following genes: MMACHC (cblC), MMADHC (cblD), LMBRD1 (cblF), ABCD4 (cblJ), THAP11 (cblX-like), and ZNF143 (cblX-like), or a hemizygous variant in HCFC1 (cblX). Prenatal diagnosis of combined methylmalonic acidemia with homocystinuria is crucial for high-risk couples since the disorder can be life-threatening for offspring. We would like to describe two infant deaths both of which are likely attributable to cblC despite not having a genetic confirmation, and subsequent pregnancy and prenatal genetic testing. METHODS: Parental clinical exome sequencing and targeted Sanger sequencing of MMACHC gene in amniotic fluid was performed to check the carrier status of the fetus. RESULTS: Parental clinical exome sequencing revealed a heterozygous pathogenic variant [NM_015506.2:c.217C>T (p.Arg73*)] in the MMACHC gene of the mother and [NM_015506.2:c.609G>A (p.Trp203*)] in the MMACHC gene of the father. Targeted Sanger sequencing of MMACHC gene in amniotic fluid revealed that the fetus carried only one nonsense variant [NM_015506.2:c.609G>A (p.Trp203*)], which was inherited from the father. The mother delivered a healthy baby and the neonate did not show any symptoms or signs of combined methylmalonic acidemia and homocystinuria after birth. CONCLUSION: We present a case of prenatal diagnosis with parental exome sequencing, which successfully diagnosed the carrier status of the fetus and parents in a combined methylmalonic acidemia and homocystinuria family.

Improvement in the Assessment of Response to Preoperative Chemoradiotherapy for Rectal Cancer Using Magnetic Resonance Imaging and a Multigene Biomarker.

The response to preoperative chemoradiotherapy (PCRT) is correlated with oncologic outcomes in patients with locally advanced rectal cancer. Accurate prediction of PCRT response before surgery can provide crucial information to aid clinicians in further treatment planning. This study aimed to develop an evaluation tool incorporating a genetic biomarker and magnetic resonance imaging (MRI) to improve the assessment of response in post-CRT patients with locally advanced rectal cancer. A total of 198 patients who underwent PCRT followed by surgical resection for locally advanced rectal cancer between 2010 and 2016 were included in this study. Each patient's response prediction index (RPI) score, a multigene biomarker developed in our previous study, and magnetic resonance tumor regression grade (mrTRG) score were added to create a new predictive value for pathologic response after PCRT, called the combined radiation prediction value (cRPV). Based on the new value, 121 and 77 patients were predicted to be good and poor responders, respectively, showing significantly different cRPV values (p = 0.001). With an overall predictive accuracy of 84.8%, cRPV was superior to mrTRG and RPI for the prediction of pathologic chemoradiotherapy response (mrTRG, 69.2%; RPI, 77.3%). In multivariate analysis, cRPV was found to be the sole predictor of tumor response (odds ratio, 32.211; 95% confidence interval, 14.408-72.011; p = 0.001). With its good predictive value for final pathologic regression, cRPV may be a valuable tool for assessing the response to PCRT before surgery.

Case report of juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome: first report in Korea with a novel mutation in the SMAD4 gene.

Juvenile polyposis/hereditary hemorrhagic telangiectasia (JPS/HHT) syndrome is a rare, autosomal dominant disorder caused by mutations in the SMAD4 gene, presenting with features of both juvenile polyposis syndrome (JPS) and HHT. Reports and studies of JPS/HHT syndrome are mostly from Western countries, while there are scarce reports from East Asian countries. We report a case of a Korean boy who had been previously diagnosed with JPS at 7 years and had first visited to our center at 15 years of age. Genetic studies of the patient and parents revealed a novel variant in the SMAD4 gene, SMAD4 c.1146_1163del; p.His382_Val387del (NM_005359.5), which had developed de novo. Numerous pedunculated and sessile polyps were observed throughout the gastrointestinal (GI) tract. Mucocutaneous telangiectases were observed on the lips, tongue, and jejunum, and arteriovenous malformations (AVMs) were observed in both lungs. This is the first case report of JPS/HHT syndrome in Korea, with a novel deletion variant in the SMAD4 gene. Patients with JPS should undergo genetic evaluation of associated genes including SMAD4, and those with genetically confirmed SMAD4 variants should undergo further evaluation for coexisting asymptomatic AVMs in order to prevent life-threatening complications of thrombotic emboli and pulmonary hemorrhage.

Impact of the COVID-19 Pandemic on Surgical Treatment Patterns for Colorectal Cancer in a Tertiary Medical Facility in Korea.

Because of their reluctance to visit the hospital due to concerns about contracting coronavirus disease 2019 (COVID-19), patients with colorectal cancer have been affected by delays in care during the pandemic. This study assessed the effects of the pandemic on the clinical characteristics and surgical treatment patterns of colorectal cancer patients at a tertiary medical facility in Korea. Patients who underwent colorectal cancer surgery at our institution between March and September 2020 were analyzed. Clinicopathological and treatment characteristics were compared with those of patients who underwent surgery in 2018 and 2019. The patients who did not undergo tumor resection (4.1% vs. 1.8%, p < 0.001) and who received neoadjuvant treatment (16.7% vs. 14.7%, p = 0.039) were significantly higher during the COVID period. The minimally invasive approach was performed less during the COVID period (81.2% vs. 88%, p < 0.001). More patients in the COVID period required combined resection of organs adjacent to the tumor (4.8% vs. 2.8%, p = 0.017). Surgical aggressiveness, as shown by the proportion of patients undergoing minimally invasive surgery and adjacent organ resection, was significantly influenced by the pandemic. In addition, resectability decreased during the COVID period. These characteristics will likely influence long-term oncological outcomes, indicating the need for long-term monitoring of this cohort.

A Population-Based Analysis of BRCA1/2 Genes and Associated Breast and Ovarian Cancer Risk in Korean Patients: A Multicenter Cohort Study.

In this study, we performed a comprehensive analysis of BRCA1/2 variants and associated cancer risk in Korean patients considering two aspects: variants of uncertain significance (VUS) and pathogenic or likely pathogenic variants (PLPVs) in BRCA1 and BRCA2. This study included 5433 Korean participants who were tested for BRCA1/2 genes. The BRCA1/2 variants were classified following the standards/guidelines for interpretation of genetic variants and using a multifactorial probability-based approach. In Korea, 15.8% of participants had BRCA1 or BRCA2 PLPVs. To estimate the additional sample numbers needed to resolve unclassified status, we applied a simulation analysis. The simulation study for VUS showed that the smaller the number of samples, the more the posterior probability was affected by the prior probability; in addition, more samples for BRCA2 VUS than those of BRCA1 VUS were required to resolve the unclassified status, and the presence of clinical information associated with their VUS was an important factor. The cumulative lifetime breast cancer risk was 59.1% (95% CI: 44.1-73.6%) for BRCA1 and 58.3% (95% CI: 43.2-73.0%) for BRCA2 carriers. The cumulative lifetime ovarian cancer risk was estimated to be 36.9% (95% CI: 23.4-53.9%) for BRCA1 and 14.9% (95% CI: 7.4-28.5%) for BRCA2 carriers.