Korea4K: whole genome sequences of 4,157 Koreans with 107 phenotypes derived from extensive health check-ups.

BACKGROUND: Phenome-wide association studies (PheWASs) have been conducted on Asian populations, including Koreans, but many were based on chip or exome genotyping data. Such studies have limitations regarding whole genome-wide association analysis, making it crucial to have genome-to-phenome association information with the largest possible whole genome and matched phenome data to conduct further population-genome studies and develop health care services based on population genomics. RESULTS: Here, we present 4,157 whole genome sequences (Korea4K) coupled with 107 health check-up parameters as the largest genomic resource of the Korean Genome Project. It encompasses most of the variants with allele frequency >0.001 in Koreans, indicating that it sufficiently covered most of the common and rare genetic variants with commonly measured phenotypes for Koreans. Korea4K provides 45,537,252 variants, and half of them were not present in Korea1K (1,094 samples). We also identified 1,356 new genotype-phenotype associations that were not found by the Korea1K dataset. Phenomics analyses further revealed 24 significant genetic correlations, 14 pleiotropic associations, and 127 causal relationships based on Mendelian randomization among 37 traits. In addition, the Korea4K imputation reference panel, the largest Korean variants reference to date, showed a superior imputation performance to Korea1K across all allele frequency categories. CONCLUSIONS: Collectively, Korea4K provides not only the largest Korean genome data but also corresponding health check-up parameters and novel genome-phenome associations. The large-scale pathological whole genome-wide omics data will become a powerful set for genome-phenome level association studies to discover causal markers for the prediction and diagnosis of health conditions in future studies.

A method for early diagnosis of lung cancer from tumor originated DNA fragments using plasma cfDNA methylome and fragmentome profiles.

Early detection is critical for minimizing mortality from cancer. Plasma cell-free DNA (cfDNA) contains the signatures of tumor DNA, allowing us to quantify the signature and diagnose early-stage tumors. Here, we report a novel tumor fragment quantification method, TOF (Tumor Originated Fragment) for the diagnosis of lung cancer by quantifying and analyzing both the plasma cfDNA methylation patterns and fragmentomic signatures. TOF utilizes the amount of ctDNA predicted from the methylation density information of each cfDNA read mapped on 6243 lung-tumor-specific CpG markers. The 6243 tumor-specific markers were derived from lung tumor tissues by comparing them with corresponding normal tissues and healthy blood from public methylation data. TOF also utilizes two cfDNA fragmentomic signatures: 1) the short fragment ratio, and 2) the 5' end-motif profile. We used 298 plasma samples to analyze cfDNA signatures using enzymatic methyl-sequencing data from 201 lung cancer patients and 97 healthy controls. The TOF score showed 0.98 of the area under the curve in correctly classifying lung cancer from normal samples. The TOF score resolution was high enough to clearly differentiate even the early-stage non-small cell lung cancer patients from the healthy controls. The same was true for small cell lung cancer patients.

PLC-gamma1 for Differentiating Adenocarcinoma from Reactive Mesothelial Cells in Effusions / 대한세포병리학회지

Cytologic diagnosis of reactive or malignant effusion is sometimes difficult. Espe- cially, differentiation of benign reactive mesothelial cells from malignant cells in body effusion is more difficult. Recently, immunohistochemistry has been used to diagnose difficult cases. Phospholipase C(PLC)-gamma 1 is one of the isoenzyme of the PLC which plays central role in signal transduction involving cellular growth, differentiation and transformation by phosphorylating many protein component. Increased expression of PLC-gamma 1 in human breast carcinoma, colorectal carcinoma and stomach cancers are reported. To evaluate the efficacy of positive PLC-gamma 1 immunostaining in the diagnosis of malignancy in effusions, paraffin-embedded cell blocks of pleural fluid and ascites from 10 patients(5 metastatic adenocarcinomas, and 5 reactive mesothelial cells) were immunostained with a monoclonal antibody to PLC-gamma 1. PLC-gamma 1 immuostained all the adenocarcinomas in cell block(5/5) with intense membrane pattern, however, none of the reactive mesothelial proliferations stained with the diagnostic membrane pattern. Thus, our study strongly supports the conclusion that PLC-gamma 1 immunopositivity is likely to become a useful adjunct for the diagnosis of malignancy in effusions.