Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes

DeRycke, Melissa S.; Gunawardena, Shanaka R.; Balcom, Jessica R.; Pickart, Angela M.; Waltman, Lindsey A.; French, Amy J.; McDonnell, Shannon K.; Riska, Shaun M.; Fogarty, Zachary C.; Larson, Melissa C.; Middha, Sumit; Eckloff, Bruce W.; Asmann, Yan W.; Ferber, Matthew J.; Haile, Robert W.; Gallinger, Steven; Clendenning, Mark; Rosty, Christophe; Win, Aung Ko; Buchanan, Daniel D.; Hopper, John L.; Newcomb, Polly A.; Marchand, Loı̈c Le; Goode, Ellen L.; Lindor, Noralane M.; Thibodeau, Stephen N.

doi:10.1002/mgg3.317

Cited by 37 publications

(34 citation statements)

References 46 publications

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“…The present analyses also identified five patients in group U (3%) with two potential pathogenic variants in different genes. This is consistent with the results of previous studies, which have reported rates of between 0.1 and 3% [7, 16–18] or up to 7.5%, when potentially pathogenic missense mutations were included [19]. These cases may involve digenic inheritance, co-inheritance of genetic modifiers, or clear pathogenic mutations [20, 21].…”

Section: Discussionsupporting

confidence: 92%

Diagnostic yield and clinical utility of a comprehensive gene panel for hereditary tumor syndromes

Henn

Spier

Adam

et al. 2019

Hered Cancer Clin Pract

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BackgroundIn a considerable number of patients with a suspected hereditary tumor syndrome (HTS), no underlying germline mutation is detected in the most likely affected genes. The present study aimed to establish and validate a large gene panel for HTS, and determine its diagnostic yield and clinical utility.MethodsThe study cohort comprised 173 patients with suspected, but unexplained, HTS (group U) and 64 HTS patients with a broad spectrum of known germline mutations (group K). All patients in group U presented with early age at onset, multiple tumors, and/or a familial clustering of various tumor types; no germline mutation had been identified during routine diagnostics. Sequencing of leukocyte DNA was performed for the 94 HTS genes of the Illumina TruSight™Cancer Panel and 54 additional HTS genes.ResultsThe sensitivity of the panel to identify known germline variants was 99.6%. In addition to known mutations, a total of 192 rare, potentially pathogenic germline variants in 86 genes were identified. Neither the proportion of rare variants per patient (group K: 0.9 variants; group U: 0.8 variants) nor the proportion of variants in the most frequently mutated, moderately penetrant genes CHEK2 and ATM showed significant inter-group difference. Four of the five patients from group U with a truncating CHEK2 mutation had thyroid cancer, pointing to a broader tumor spectrum in patients with pathogenic CHEK2 variants. In 22% of patients from group K, a further potential causative variant was identified. Here, the most interesting finding was an NF1 nonsense mutation in a child with a known TP53 frameshift mutation. In 17% of patients from group U, potential causative variants were identified. In three of these patients (2%), mutations in PMS2, PTEN, or POLD1 were considered to be causative. In both groups, incidental findings with presumptive predictive value were generated.ConclusionsThe gene panel identified the genetic cause in some prescreened, unexplained HTS patients and generated incidental findings. Some patients harbored predicted pathogenic mutations in more than one established HTS gene, rendering interpretation of the respective alterations challenging. Established moderate risk genes showed an almost equal distribution among patients with known and unexplained disease.Electronic supplementary materialThe online version of this article (10.1186/s13053-018-0102-4) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Diagnostic yield and clinical utility of a comprehensive gene panel for hereditary tumor syndromes

Henn

Spier

Adam

et al. 2019

Hered Cancer Clin Pract

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“…In conclusion, MMRd rates and prevalences of LS and LLS in our study are similar to the ranges reported in 21 other studies on the incidence of these syndromes in early-onset nonpolyposis CRC (Table 4). [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] Of note, the incidence of LS was higher when the age at CRC diagnosis used as a cutoff to define "early-onset" was lower, when there was a family history of CRC, and when the molecular algorithm for MMRd: tumor MMR deficiency tested by MSI (*), IHC of MMR proteins (**), or both (***).…”

Section: Discussionmentioning

confidence: 99%

Lynch‐like syndrome is as frequent as Lynch syndrome in early‐onset nonfamilial nonpolyposis colorectal cancer

Antelo

Golubicki²,

Roca³

et al. 2019

Intl Journal of Cancer

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Early‐onset (<50 years‐old) nonpolyposis nonfamilial colorectal cancer (EO NP NF CRC) is a common clinical challenge. Although Lynch syndrome (LS) is associated with EO CRC, the frequency of this syndrome in the EO NF cases remains unknown. Besides, mismatch repair deficient (MMRd) CRCs with negative MMR gene testing have recently been described in up to 60% of cases and termed “Lynch‐like syndrome” (LLS). Management and counseling decisions of these patients are complicated because of unconfirmed suspicions of hereditary cancer. To define the prevalence of MMR deficient CRCs, LS and LLS in patients with EO NP NF CRC, we recruited 102 patients with a first diagnosis of NP NF CRC ≤ 50 years old during 2003–2009 who underwent genetic counseling at our institution in Argentina. Tumor immunohistochemical (IHC) MMR for protein expression and microsatellite instability (MSI) status were evaluated, and in those with loss of MLH1 expression by IHC, somatic BRAF V600E mutation and both somatic and germline MLH1 methylation levels were studied. Tumors characterized as MMRd without somatic BRAF mutation nor MLH1 methylation were sent for germline analysis. Twenty one (20.6%) tumors were MMRd. Fourteen of 16 putative LS cases underwent germline testing: 6 pathogenic mutations were identified and 8 cases had no identifiable pathogenic mutations. The prevalence of LS and LLS in this cohort was 5.8% (6/102) and 7.8% (8/102), respectively. As a conclusion we found that 20% of patients with EO NP NF CRC have MMRd tumors, and at least half of these are likely to have LLS.

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“…Contrarily, another meta-analysis suggests that pathogenic variants in BRCA1 increase CRC risk (OR = 1.56) but not in BRCA2 [ 111 ]. Another gene that deserves attention in this section is TP53 , where pathogenic variants have been recurrently found in familial/early onset and unselected CRC patients [ 3 , 4 , 5 , 6 , 28 , 32 , 102 , 112 , 113 , 114 , 115 ]. As occurs with other non-CRC genes, the debate about TP53 ’s causal role in CRC predisposition is open for discussion.…”

Section: Non-crc Hereditary Cancer Genesmentioning

confidence: 99%

“…While estimates indicate that approximately 14% of all colorectal cancer (CRC) patients have at least one first-degree relative affected with the same tumor type [ 1 , 2 ], 4–8% of all CRC patients carry germline pathogenic variants in one of the known high penetrance genes for this tumor [ 3 , 4 , 5 , 6 ], with a relevant proportion of the familial aggregation of CRC remaining unexplained. The identification of a germline pathogenic variant in a colorectal cancer-predisposing gene has important consequences for the patients and their relatives, as they can be counseled and managed based on gene-specific guidelines.…”

Section: Introductionmentioning

confidence: 99%

Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

Terradas

Capellà

Valle

2020

JCM

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In the past two decades, multiple studies have been undertaken to elucidate the genetic cause of the predisposition to mismatch repair (MMR)-proficient nonpolyposis colorectal cancer (CRC). Here, we present the proposed candidate genes according to their involvement in specific pathways considered relevant in hereditary CRC and/or colorectal carcinogenesis. To date, only pathogenic variants in RPS20 may be convincedly linked to hereditary CRC. Nevertheless, accumulated evidence supports the involvement in the CRC predisposition of other genes, including MRE11, BARD1, POT1, BUB1B, POLE2, BRF1, IL12RB1, PTPN12, or the epigenetic alteration of PTPRJ. The contribution of the identified candidate genes to familial/early onset MMR-proficient nonpolyposis CRC, if any, is extremely small, suggesting that other factors, such as the accumulation of low risk CRC alleles, shared environmental exposures, and/or gene–environmental interactions, may explain the missing heritability in CRC.

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Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes

Cited by 37 publications

References 46 publications

Diagnostic yield and clinical utility of a comprehensive gene panel for hereditary tumor syndromes

Diagnostic yield and clinical utility of a comprehensive gene panel for hereditary tumor syndromes

Lynch‐like syndrome is as frequent as Lynch syndrome in early‐onset nonfamilial nonpolyposis colorectal cancer

Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

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