Dataset Information

The Clinical Relevance of Frequent Germline Genetic Variants Detected by Targeted Sequencing in Patients With Rectal Adenocarcinoma (READ).

ABSTRACT: BACKGROUND:The progression of colorectal cancer (CRC) mainly stems from the occurrence of somatic mutation. However, there is little information that can be used to comprehensively analyse the importance of germline variants in CRC patients. PATIENTS AND METHODS:The candidate germline variants between tumor relapse and cured rectal adenocarcinoma (READ) were firstly filtered by whole-exome sequencing (n=4), and validated by targeted sequencing and associated with clinical outcome in READ (n=48). RESULTS:We identified 9 pathogenic germline variants that were clinically associated with survival outcome in READ, including TIPIN, TLR1, TLR10, OR4D6, IGSF3, UBBP4, OR6J1, FAM208A and DISC1. Patients carrying these germline susceptibility variants had an increased risk of poor survival outcome compared to those without these variants. CONCLUSION:Not only the tumor genome, but also the germline sequence must be analysed to depict the overall genetic profile, providing potential therapeutic strategies for personalized medicine.

SUBMITTER: Huang KC

PROVIDER: S-EPMC7259889 | biostudies-literature | 2020 May-Jun

REPOSITORIES: biostudies-literature

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The Clinical Relevance of Frequent Germline Genetic Variants Detected by Targeted Sequencing in Patients With Rectal Adenocarcinoma (READ).

Huang Kevin Chih-Yang KC Chiang Shu-Fen SF Ke Tao-Wei TW Chen William Tzu-Liang WT Chen Tsung-Wei TW Chao Kun-San Clifford KC

Cancer genomics & proteomics 20200501 3

<h4>Background</h4>The progression of colorectal cancer (CRC) mainly stems from the occurrence of somatic mutation. However, there is little information that can be used to comprehensively analyse the importance of germline variants in CRC patients.<h4>Patients and methods</h4>The candidate germline variants between tumor relapse and cured rectal adenocarcinoma (READ) were firstly filtered by whole-exome sequencing (n=4), and validated by targeted sequencing and associated with clinical outcome ...[more]

PMID: 32345670

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Project description:ImportanceTumor genetic sequencing identifies potentially targetable genetic alterations with therapeutic implications. Analysis has concentrated on detecting tumor-specific variants, but recognition of germline variants may prove valuable as well.ObjectiveTo estimate the burden of germline variants identified through routine clinical tumor sequencing.Design, setting, and participantsPatients with advanced cancer diagnoses eligible for studies of targeted agents at Memorial Sloan Kettering Cancer Center are offered tumor-normal sequencing with MSK-IMPACT, a 341-gene panel. We surveyed the germline variants seen in 187 overlapping genes with Mendelian disease associations in 1566 patients who had undergone tumor profiling between March and October 2014.Main outcomes and measuresThe number of presumed pathogenic germline variants (PPGVs) and variants of uncertain significance per person in 187 genes associated with single-gene disorders and the proportions of individuals with PPGVs in clinically relevant gene subsets, in genes consistent with known tumor phenotypes, and in genes with evidence of second somatic hits in their tumors.ResultsThe mean age of the 1566 patients was 58 years, and 54% were women. Presumed pathogenic germline variants in known Mendelian disease-associated genes were identified in 246 of 1566 patients (15.7%; 95% CI, 14.0%-17.6%), including 198 individuals with mutations in genes associated with cancer susceptibility. Germline findings in cancer susceptibility genes were concordant with the individual's cancer type in only 81 of 198 cases (40.9%; 95% CI, 34.3%-47.9%). In individuals with PPGVs retained in the tumor, somatic alteration of the other allele was seen in 39 of 182 cases (21.4%; 95% CI, 16.1%-28.0%), of which 13 cases did not show a known correlation of the germline mutation and a known syndrome. Mutations in non-cancer-related Mendelian disease genes were seen in 55 of 1566 cases (3.5%; 95% CI, 27.1%-45.4%). Almost every individual had more than 1 variant of uncertain significance (1565 of 1566 patients; 99.9%; 95% CI, 99.6%-99.9%).Conclusions and relevanceGermline variants are common in individuals undergoing tumor-normal sequencing and may reveal otherwise unsuspected syndromic associations.

Project description:BackgroundKrüppel-like factor 1 (KLF1), a crucial erythroid transcription factor, plays a significant role in various erythroid changes and haemolytic diseases. The rare erythrocyte Lutheran inhibitor (In(Lu)) blood group phenotype serves as an effective model for identifying KLF1 hypomorphic and loss-of-function variants. In this study, we aimed to analyse the genetic background of the In(Lu) phenotype in a population-based sample group by high-throughput technologies to find potentially clinically significant KLF1 variants.ResultsWe included 62 samples with In(Lu) phenotype, screened from over 300,000 Chinese blood donors. Among them, 36 samples were sequenced using targeted Next Generation Sequencing (NGS), whereas 19 samples were sequenced using High Fidelity (HiFi) technology. In addition, seven samples were simply sequenced using Sanger sequencing. A total of 29 hypomorphic or loss-of-function variants of KLF1 were identified, 21 of which were newly discovered. All new variants discovered by targeted NGS or HiFi sequencing were validated through Sanger sequencing, and the obtained results were found to be consistent. The KLF1 haplotypes of all new variants were further confirmed using clone sequencing or HiFi sequencing. The lack of functional KLF1 variants detected in the four samples indicates the presence of additional regulatory mechanisms. In addition, some samples exhibited BCAM polymorphisms, which encodes antigens of the Lutheran (LU) blood group system. However, no BCAM mutations which leads to the absence of LU proteins were detected.ConclusionsHigh-throughput sequencing methods, particularly HiFi sequencing, were introduced for the first time into genetic analysis of the In(Lu) phenotype. Targeted NGS and HiFi sequencing demonstrated the accuracy of the results, providing additional advantages such as simultaneous analysis of other blood group genes and clarification of haplotypes. Using the In(Lu) phenotype, a powerful model for identifying hypomorphic or loss-of-function KLF1 variants, numerous novel variants have been detected, which have contributed to the comprehensive understanding of KLF1. These clinically significant KLF1 mutations can serve as a valuable reference for the diagnosis of related blood cell diseases.

Dataset Information

The Clinical Relevance of Frequent Germline Genetic Variants Detected by Targeted Sequencing in Patients With Rectal Adenocarcinoma (READ).

Publications

The Clinical Relevance of Frequent Germline Genetic Variants Detected by Targeted Sequencing in Patients With Rectal Adenocarcinoma (READ).

Similar Datasets

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