Analysis of germline mutations in Chinese colorectal cancer patients with next-generation sequencing.

e13651 Background: Colorectal cancer (CRC) remains one of the leading causes of morbidity and mortality around the world. Familial cancer syndromes are common in CRC, inherited syndromes including Lynch syndrome (LS), familial adenomatous polyposis (FAP), and MutY human homolog (MUTYH)-associated polyposis (MAP) were well defined. But still, there are not well-established evidence between other several genes and CRC risk. Expanded multi-gene testing may be an alternative to find out the underlying mechanism for genetic susceptibility. Our study aims to assess the germline alternation landscape of Chinese CRC patients. Methods: We performed hybrid capture-based next-generation sequencing (NGS) of 381 genes on tissues from patients with CRC between January 01, 2017 and December 02, 2019 in 3D Medicines database. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations, gene rearrangement and fusions were assessed. Results: 1360 CRC patients were included for analysis, in which 95 (7.0%) patients harbored pathogenic (80/95) and likely pathogenic (15/95) germline mutations in 28 cancer predisposition genes. 33 subjects had pathogenic variants associated with Lynch syndrome (15 mutations in MLH1, 9 mutations in MSH2, 6 mutations in MSH6, 3 mutations in PMS2, respectively). 8 subjects had pathogenic variants associated with FAP (3 APC), MAP (3 MUTYH) and Li-Fraumeni syndrome (2 TP53). In addition, 14 pathogenic mutations in moderate penetrance genes (5 ATM, 3 BLM and 6 CHEK2) were found. The frequency of pathogenic BRCA mutations were 1 alternation in BRCA1 and 3 alternations in BRCA2. Conclusions: 7.0 % of patients with Chinese CRC carried germline cancer susceptibility gene mutations. Multi-gene testing would provide references for assessing genetic susceptibility and managing increased surveillance.

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Next-generation Sequencing of Colorectal Cancer Somatic Cells to Guide Genetic Susceptibility Gene Mutations Screening.

Case Medical Research ◽

10.31525/ct1-nct04280666 ◽

2020 ◽

Author(s):

Keyword(s):

Colorectal Cancer ◽

Next Generation Sequencing ◽

Genetic Susceptibility ◽

Susceptibility Gene ◽

Somatic Cells ◽

Gene Mutations ◽

Next Generation ◽

Generation Sequencing

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Next Generation Sequencing in Molecular Diagnosis of Lynch Syndrome – a Pilot Study Using New Stratification Criteria

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2018.125 ◽

2018 ◽

Vol 61 (3) ◽

pp. 98-102 ◽

Cited By ~ 3

Author(s):

Ivana Kašubová ◽

Veronika Holubeková ◽

Katarína Janíková ◽

Barbora Váňová ◽

Zuzana Sňahničanová ◽

...

Keyword(s):

Colorectal Cancer ◽

Next Generation Sequencing ◽

Pilot Study ◽

Lynch Syndrome ◽

New Technologies ◽

Braf V600e ◽

Sporadic Colorectal Cancer ◽

Next Generation ◽

Gene Panel Testing ◽

Generation Sequencing

The development of the new technologies such as the next-generation sequencing (NGS) makes more accessible the diagnosis of genetically heterogeneous diseases such as Lynch syndrome (LS). LS is one of the most common hereditary form of colorectal cancer. This autosomal dominant inherited disorder is caused by deleterious germline mutations in one of the mismatch repair (MMR) genes – MLH1, MSH2, MSH6 or PMS2, or the deletion in the EPCAM gene. These mutations eventually result in microsatellite instability (MSI), which can be easily tested in tumor tissue. According to the actual recommendations, all patients with CRC that are suspect to have LS, should be offered the MSI testing. When the MSI is positive, these patients should be recommended to genetic counseling. Here we report a pilot study about the application of NGS in the LS diagnosis in patients considered to have sporadic colorectal cancer. The inclusion criteria for the NGS testing were MSI positivity, BRAF V600E and MHL1 methylation negativity. We have used 5 gene amplicon based massive parallel sequencing on MiSeq platform. In one patient, we have identified a new pathogenic mutation in the exon 4 of the MSH6 gene that was previously not described in ClinVar, Human Gene Mutation Database, Ensembl and InSight databases. This mutation was confirmed by the Sanger method. We have shown that the implementation of new criteria for colorectal patients screening are important in clinical praxis and the NGS gene panel testing is suitable for routine laboratory settings.

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Application of Next Generation Sequencing Approach to Molecular Diagnosis Of Hereditary Colorectal Cancer: Identification Of A Novel Heterozygous Single Nucleotide Germline Deletion In Msh2 Gene Cause Lynch Syndrome

Open Access Journal of Oncology and Medicine ◽

10.32474/oajom.2020.03.000171 ◽

2020 ◽

Vol 3 (5) ◽

Author(s):

Meifang Xiao

Keyword(s):

Colorectal Cancer ◽

Next Generation Sequencing ◽

Lynch Syndrome ◽

Molecular Diagnosis ◽

Hereditary Colorectal Cancer ◽

Next Generation ◽

Msh2 Gene ◽

Single Nucleotide ◽

Generation Sequencing

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Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105698 ◽

2019 ◽

Vol 56 (7) ◽

pp. 462-470 ◽

Cited By ~ 17

Author(s):

Rachel Pearlman ◽

Sigurdis Haraldsdottir ◽

Albert de la Chapelle ◽

Jon G Jonasson ◽

Sandya Liyanarachchi ◽

...

Keyword(s):

Colorectal Cancer ◽

Next Generation Sequencing ◽

Lynch Syndrome ◽

Mismatch Repair ◽

Clinical Characteristics ◽

Population Based ◽

Pathogenic Variants ◽

Age Of Diagnosis ◽

Generation Sequencing ◽

Mmr Proteins

BackgroundPatients with colorectal cancer (CRC) with mismatch repair-deficient (dMMR) tumours without MLH1 methylation or germline MMR pathogenic variants (PV) were previously thought to have Lynch syndrome (LS). It is now appreciated that they can have double somatic (DS) MMR PVs. We explored the clinical characteristics between patients with DS tumours and LS in two population-based cohorts.MethodsWe included patients with CRC from Ohio 2013–2016 and Iceland 2000–2009. All had microsatellite instability testing and/or immunohistochemistry (IHC) of MMR proteins, and MLH1 methylation testing when indicated. Germline next-generation sequencing was performed for all with dMMR tumours; tumour sequencing followed for patients with unexplained dMMR. Clinical characteristics of DS patients and patients with LS were compared.ResultsOf the 232 and 51 patients with non-methylated dMMR tumours in the Ohio and Iceland cohorts, respectively, 57.8% (n=134) and 45.1% (n=23) had LS, 32.8% (n=76) and 31.4% (n=16) had DS PVs, 6% (n=14) and 9.8% (n=5) were unexplained and 4.3% (n=10) and 13.7% (n=7) had incorrect IHC. Age of diagnosis for DS patients was older than patients with LS (p=3.73×10−4) in the two cohorts. Patients with LS were more likely to meet Amsterdam II criteria (OR=15.81, p=8.47×10−6) and have multiple LS-associated tumours (OR=6.67, p=3.31×10−5). Absence of MLH1/PMS2 was predictive of DS PVs; isolated MSH6 and PMS2 absence was predictive of LS in both cohorts.ConclusionsIndividuals with LS are 15× more likely to meet Amsterdam II criteria and >5× more likely to have multiple cancers as compared with those with DS tumours. Furthermore, isolated loss of MSH6 or PMS2 protein predicts LS.

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