Rare germline copy number variants in colorectal cancer predisposition characterized by exome sequencing analysis

Franch-Expósito, Sebastià; Esteban-Jurado, Clara; Garré, Pilar; Quintanilla, Isabel; Durán-Sanchón, Saray; Díaz‐Gay, Marcos; Bonjoch, Laia; Cuatrecasas, Míriam; Samper, Esther; Muñoz, Jenifer; Ocaña, Teresa; Carballal, Sabela; López-Cerón, María; Castells, Antoni; Vila-Casadesús, María; Derdak, Sophia; Laurie, Steve; Beltrán, Sergi; Carvajal, Jaime J.; Bujanda, Luís; Ruíz-Ponte, Clara; Camps, Jordi; Gironella, Meritxell; Lozano, Juan José; Balaguer, Francesc; Cubiella, Joaquín; Caldés, Trinidad; Castellví–Bel, Sergi

doi:10.1016/j.jgg.2017.12.001

Cited by 11 publications

(15 citation statements)

References 19 publications

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“…Families were selected based on the following criteria: three or more relatives with CRC, two or more consecutive affected generations and at least one CRC diagnosed before the age of 60. The entire cohort had germline WES data available from previous studies [12,21,31]. The presence of germline alterations in well-known genes related with hereditary CRC syndromes ( APC , MUTYH and the DNA MMR genes) were previously discarded for all probands.…”

Section: Methodsmentioning

confidence: 99%

“…Germline WES data were available from previous studies [12,21,31]. WES was performed in tumor samples of selected patients using the HiSeq2000 platform (Illumina, San Diego, CA, USA) and SureSelectXT Human All Exon v5 kit (Agilent, Santa Clara, CA, USA) for exon enrichment.…”

Section: Methodsmentioning

confidence: 99%

“…Commonly used in recent years for the cost-effective discovery of pathogenic SNVs and indels, whole-exome sequencing (WES) has also marked a turning point for CNV and LOH detection. Despite the challenge of the uneven coverage distribution along the genome, WES approaches have emerged as a solid option for germline CNV calling [11], recently obtaining significant results in CRC predisposition [12]. Regarding tumor LOH detection, classic approaches were based on microsatellite markers around the gene of interest.…”

Section: Introductionmentioning

confidence: 99%

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Integrated Analysis of Germline and Tumor DNA Identifies New Candidate Genes Involved in Familial Colorectal Cancer

Díaz‐Gay

Franch-Expósito

Arnau‐Collell

et al. 2019

Cancers

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Colorectal cancer (CRC) shows aggregation in some families but no alterations in the known hereditary CRC genes. We aimed to identify new candidate genes which are potentially involved in germline predisposition to familial CRC. An integrated analysis of germline and tumor whole-exome sequencing data was performed in 18 unrelated CRC families. Deleterious single nucleotide variants (SNV), short insertions and deletions (indels), copy number variants (CNVs) and loss of heterozygosity (LOH) were assessed as candidates for first germline or second somatic hits. Candidate tumor suppressor genes were selected when alterations were detected in both germline and somatic DNA, fulfilling Knudson’s two-hit hypothesis. Somatic mutational profiling and signature analysis were also performed. A series of germline-somatic variant pairs were detected. In all cases, the first hit was presented as a rare SNV/indel, whereas the second hit was either a different SNV (3 genes) or LOH affecting the same gene (141 genes). BRCA2, BLM, ERCC2, RECQL, REV3L and RIF1 were among the most promising candidate genes for germline CRC predisposition. The identification of new candidate genes involved in familial CRC could be achieved by our integrated analysis. Further functional studies and replication in additional cohorts are required to confirm the selected candidates.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Integrated Analysis of Germline and Tumor DNA Identifies New Candidate Genes Involved in Familial Colorectal Cancer

Díaz‐Gay

Franch-Expósito

Arnau‐Collell

et al. 2019

Cancers

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“…Although the scant available data suggest high penetrance for RSP20 mutations and absence of extracolonic manifestations, data from additional mutation carriers are required to estimate risks and recommend surveillance measures. Many other putative familial CRC genes have been proposed, but most are extremely uncommon and others may only moderately increase the risk of CRC, complicating the assessment of their contribution to predisposition to CRC .…”

Section: Genetic Susceptibility To Colorectal Cancer: Polyposis and Nmentioning

confidence: 99%

Genetic predisposition to colorectal cancer: syndromes, genes, classification of genetic variants and implications for precision medicine

Valle

Vilar

Tavtigian

et al. 2019

The Journal of Pathology

146

102

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This article reviews genes and syndromes associated with predisposition to colorectal cancer (CRC), with an overview of gene variant classification. We include updates on the application of preventive and therapeutic measures, focusing on the use of non-steroidal anti-inflammatory drugs (NSAIDs) and immunotherapy. Germline pathogenic variants in genes conferring high or moderate risk to cancer are detected in 6-10% of all CRCs and 20% of those diagnosed before age 50. CRC syndromes can be subdivided into nonpolyposis and polyposis entities, the most common of which are Lynch syndrome and familial adenomatous polyposis, respectively. In addition to known and novel genes associated with highly penetrant CRC risk, identification of pathogenic germline variants in genes associated with moderate-penetrance cancer risk and/or hereditary cancer syndromes not traditionally linked to CRC may have an impact on genetic testing, counseling, and surveillance. The use of multigene panels in genetic testing has exposed challenges in the classification of variants of uncertain significance. We provide an overview of the main classification systems and strategies for improving these. Finally, we highlight approaches for integrating chemoprevention in the care of individuals with genetic predisposition to CRC and use of targeted agents and immunotherapy for treatment of mismatch repair-deficient and hypermutant tumors.No conflicts of interest were declared. mutations in known high-and moderate-penetrance genes [2][3][4] (one in five of those diagnosed at age less than 50) [5][6][7]. For individuals with certain hereditary cancer syndromes, lifetime risks for CRC may approach IO has become a reality in the treatment of patients with hypermutant cancers in general and also in CRC displaying MSI. The activation of the immune system developed in this type of tumors was noted several decades ago by pathologists who observed extensive Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer.

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“…The strengths of the short-read sequencing technologies lie in the identification of single nucleotide variants (SNV) and small insertion/deletions (indels), while structural variant identification (large duplications, large deletions, translocations and inversions) remains challenging but not impossible. This can be illustrated by the study from Franch-Expósito et al where a 400 kb duplication was identified by whole-exome sequencing analysis ( 142 ). Also, paralogous sequence variant discrimination can be complicated with the current sequencing analyses, e.g.…”

Section: Missed Geneticsmentioning

confidence: 96%

The missing heritability of familial colorectal cancer

et al. 2019

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Abstract Pinpointing heritability factors is fundamental for the prevention and early detection of cancer. Up to one-quarter of colorectal cancers (CRCs) occur in the context of familial aggregation of this disease, suggesting a strong genetic component. Currently, only less than half of the heritability of CRC can be attributed to hereditary syndromes or common risk loci. Part of the missing heritability of this disease may be explained by the inheritance of elusive high-risk variants, polygenic inheritance, somatic mosaicism, as well as shared environmental factors, among others. A great deal of the missing heritability in CRC is expected to be addressed in the coming years with the increased application of cutting-edge next-generation sequencing technologies, routine multigene panel testing and tumour-focussed germline predisposition screening approaches. On the other hand, it will be important to define the contribution of environmental factors to familial aggregation of CRC incidence. This review provides an overview of the known genetic causes of familial CRC and aims at providing clues that explain the missing heritability of this disease.

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Rare germline copy number variants in colorectal cancer predisposition characterized by exome sequencing analysis

Cited by 11 publications

References 19 publications

Integrated Analysis of Germline and Tumor DNA Identifies New Candidate Genes Involved in Familial Colorectal Cancer

Integrated Analysis of Germline and Tumor DNA Identifies New Candidate Genes Involved in Familial Colorectal Cancer

Genetic predisposition to colorectal cancer: syndromes, genes, classification of genetic variants and implications for precision medicine

The missing heritability of familial colorectal cancer

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