Optimization of the diagnosis of inherited colorectal cancer using NGS and capture of exonic and intronic sequences of panel genes

Baert‐Desurmont, Stéphanie; Coutant, Sophie; Charbonnier, Françoise; Macquère, Pierre; Lecoquierre, François; Schwartz, Mathias; Vézain, Myriam; Quenez, Olivier; Bou, Jacqueline; Bouvignies, Emilie; Fourneaux, Steeve; Manase, Sandrine; Vasseur, Stéphanie; Mauillon, Jacques; Gérard, Marion; Marlin, Régine; Bougeard, Gaëlle; Tinat, Julie; Frébourg, Thierry; Tournier, Isabelle

doi:10.1038/s41431-018-0207-2

Cited by 16 publications

(9 citation statements)

References 17 publications

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“…Our mutation detection rate, including class 4 and 5 variants, was 15.5% for EP analysis, which is comparable to similar studies of inherited cancer risk (8 to 15%) 1,6‐9 . Most mutations were identified in genes known to be associated with the personal and familial clinical presentation of patients.…”

Section: Discussionsupporting

confidence: 82%

Feedback of extended panel sequencing in 1530 patients referred for suspicion of hereditary predisposition to adult cancers

et al. 2020

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High-throughput sequencing analysis represented both a medical diagnosis and technological revolution. Gene panel analysis is now routinely performed in the exploration of hereditary predisposition to cancer, which is becoming increasingly heterogeneous, both clinically and molecularly. We present 1530 patients with suspicion of hereditary predisposition to cancer, for which two types of analyses were performed: a) oriented according to the clinical presentation (n = 417), or b) extended to genes involved in hereditary predisposition to adult cancer (n = 1113). Extended panel analysis had a higher detection rate compared to oriented analysis in hereditary predisposition to breast / ovarian cancer (P < .001) and in digestive cancers (P < .094) (respectively 15% vs 5% and 19.3%, vs 12.5%). This higher detection is explained by the inclusion of moderate penetrance genes, as well as the identification of incident mutations and double mutations. Our study underscores the utility of proposing extended gene panel analysis to patients with suspicion of hereditary predisposition to adult cancer.

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Section: Discussionsupporting

confidence: 82%

Feedback of extended panel sequencing in 1530 patients referred for suspicion of hereditary predisposition to adult cancers

et al. 2020

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“…NTHL1 data were obtained through panel testing performed in the 11 participating laboratories (RefSeq NM_002528.6). Analytical strategies varied according to the laboratories but were always based on targeted capture of the whole coding sequence with the flanking intronic consensus splice sites followed by Illumina sequencing and standard mapping and calling procedures 12 . Large rearrangements were only tested in some laboratories and therefore not considered in this study.…”

Section: Methodsmentioning

confidence: 99%

Further delineation of the NTHL1 associated syndrome: A report from the French Oncogenetic Consortium

et al. 2021

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Biallelic pathogenic variants in the NTHL1 (Nth like DNA glycosylase 1) gene cause a recently identified autosomal recessive hereditary cancer syndrome predisposing to adenomatous polyposis and colorectal cancer. Half of biallelic carriers also display multiple colonic or extra‐colonic primary tumors, mainly breast, endometrium, urothelium, and brain tumors. Published data designate NTHL1 as an important contributor to hereditary cancers but also underline the scarcity of available informations. Thanks to the French oncogenetic consortium (Groupe Génétique et Cancer), we collected NTHL1 variants from 7765 patients attending for hereditary colorectal cancer or polyposis (n = 3936) or other hereditary cancers (n = 3829). Here, we describe 10 patients with pathogenic biallelic NTHL1 germline variants, that is, the second largest NTHL1 series. All carriers were from the “colorectal cancer or polyposis” series. All nine biallelic carriers who underwent colonoscopy presented adenomatous polyps. For digestive cancers, average age at diagnosis was 56.2 and we reported colorectal, duodenal, caecal, and pancreatic cancers. Extra‐digestive malignancies included sarcoma, basal cell carcinoma, breast cancer, urothelial carcinoma, and melanoma. Although tumor risks remain to be precisely defined, these novel data support NTHL1 inclusion in diagnostic panel testing. Colonic surveillance should be conducted based on MUTYH recommendations while extra‐colonic surveillance has to be defined.

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“…Panel 1 was set up to focus on genes involved in predisposition to colorectal cancer and digestive polyposis or Li-Fraumeni syndrome (9). This panel was implemented in two successive versions.…”

Section: Gene Panel Sequencingmentioning

confidence: 99%

Detection of copy-number variations from NGS data using read depth information: a diagnostic performance evaluation

Quenez

Cassinari²,

Coutant³

et al. 2020

Eur J Hum Genet

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The detection of Copy Number Variations (CNVs) from NGS data is under-exploited as chip-based or targeted techniques are still commonly used. We assessed the performances of a workflow centered on CANOES, a bioinformatics tool based on read depth information. We applied our workflow to gene panel (GP) and Whole Exome Sequencing (WES) data, and compared CNV calls to Quantitative Multiplex PCR of Short Fluorescent fragments (QMSPF) or array Comparative Genomic Hybridization (aCGH) results. From GP data of 3,776 samples, we reached an overall Positive Predictive Value (PPV) of 87.8%. This dataset included a complete comprehensive QMPSF comparison of 4 genes (60 exons) on which we obtained 100% sensitivity and specificity. From WES data, we first compared 137 samples to aCGH and filtered comparable events (exonic CNVs encompassing enough aCGH probes) and obtained an 87.25% sensitivity. The overall PPV was 86.4% following the targeted confirmation of candidate CNVs from 1,056 additional WES. In addition, our CANOES-centered workflow on WES data allowed the detection of CNVs of any size that were missed by aCGH. Overall, switching to a NGS-only approach should be costeffective as it allows a reduction in overall costs together with likely stable diagnostic yields. Our bioinformatics pipeline is available at : https://gitlab.bioinfo-diag.fr/nc4gpm/canoes-centeredworkflow.

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Optimization of the diagnosis of inherited colorectal cancer using NGS and capture of exonic and intronic sequences of panel genes

Cited by 16 publications

References 17 publications

Feedback of extended panel sequencing in 1530 patients referred for suspicion of hereditary predisposition to adult cancers

Feedback of extended panel sequencing in 1530 patients referred for suspicion of hereditary predisposition to adult cancers

Further delineation of the NTHL1 associated syndrome: A report from the French Oncogenetic Consortium

Detection of copy-number variations from NGS data using read depth information: a diagnostic performance evaluation

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