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Abstract Background Cancer is a major cause of death, and its early identification and intervention have potential for clinical actionability and benefits for human health. The studies using whole‐genome sequencing (WGS) and large samples analysis of cancer‐related genes have been rarely done. Methods We performed WGS to explore germline mutations in coding and non‐coding areas of cancer‐related genes and non‐coding driver genes and regulatory areas. Structural variants (SVs) was also analyzed. We used several tools and a subgrouping method to analyze the variants in 1491 healthy participants. Moreover, 275 cancer‐related genes sequencing was carried out in 125 cancer patients. Results The incidence of familial cancer in the Taiwanese general population is 8.79% (131/1491). Cancer carrier rate of cancer‐related genes is about 7.04% (105/1491) for pathogenic/likely pathogenic variants (P/LP) on ClinVar database only, and 28.24% (421/1491) for P/LP and loss of function variants. The carrier frequencies of cancer‐related genes P/LP on ClinVar database were as follows: 8.40% (11/131), 7.11% (28/394), and 6.83% (66/966) in FC, 1MC, and nMC, respectively. The SVs and non‐coding driver gene variants are uncommon. There are 1.54% (23/1491) of actionable cancer genes in American College of Medical Genetics and Genomics (ACMG), and the germline mutation rate of 275 cancer‐related genes is 7.2% (9/125) in cancer patients including 4.0% (5/125) of actionable cancer genes in ACMG. After analyzing the frequencies of P/LP variants on GJB2 and SLC25A13 genes, we suggest that these two genes may not be cancer‐related genes and need be re‐evaluated. Conclusions WGS analysis can completely detect germline mutations in cancer carriers. This study use subgrouping approach for samples provides a strategy to study whether a gene or variant is a cancer‐related gene or variant in the future studies.

Abstract Next‐generation sequencing (NGS) technology is currently used to establish mutational profiles in many heterogeneous diseases. The aim of this study was to evaluate the mutational spectrum in Taiwanese patients with colorectal cancer (CRC) to help clinicians identify the best treatment method. Whole‐exome sequencing was conducted in 32 surgical tumor tissues from patients with CRC. DNA libraries were generated using the Illumina TruSeq DNA Exome, and sequencing was performed on the Illumina NextSeq 500 system. Variants were annotated and compared to those obtained from publicly available databases. The analysis revealed frequent mutations in APC (59.38%), TP53 (50%), RAS (28.13%), FBXW7 (18.75%), RAF (9.38%), PIK3CA (9.38%), SMAD4 (9.38%), and SOX9 (9.38%). A mutation in TCF7L2 was also detected, but at lower frequencies. Two or more mutations were found in 22 (68.75%) samples. The mutation rates for the WNT, P53, RTK‐RAS, TGF‐β, and PI3K pathways were 78.13%, 56.25%, 40.63%, 18.75%, and 15.63%, respectively. RTK‐RAS pathway mutations were correlated with tumor size (P = 0.028). We also discovered 23 novel mutations in NRAS, PIK3CA, SOX9, APC, SMAD4, MSH3, MSH4, PMS1 PMS2, AXIN2, ERBB2, PIK3R1, TGFBR2, and ATM that were not reported in the COSMIC, The Cancer Genome Atlas, and dbSNP databases. In summary, we report the mutational landscape of CRC in a Taiwanese population. NGS is a cost‐effective and time‐saving method, and we believe that NGS will help clinicians to treat CRC patients in the near future.