Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

Terradas, Mariona; Capellà, Gabriel; Valle, Laura

doi:10.3390/jcm9061954

Cited by 17 publications

(16 citation statements)

References 125 publications

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“…Thirdly, some patients probably have pathogenic variants in regions that our analysis was not designed to capture, such as deep intronic or regulatory variants in known cancer genes or variants in genes not yet identified or associated with CRC. Many genes have been suggested as candidate colorectal genes, and especially genes such as POLE2, MRE11, and POT1 appear to be interesting genes as well as epigenetic changes in PTPRJ (Venkatachalam et al, 2010;Chubb et al, 2016;Terradas et al, 2020). Another possibility is a non-mendelian predisposition to CRC.…”

Section: Discussionmentioning

confidence: 99%

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

et al. 2020

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A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as APC, POLE, MSH2 or PMS2. The MSH2 variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The POLE variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be de novo. One pathogenic PMS2 variant was novel. We also identified a number of highly interesting variants of unknown significance in APC, BUB1, TP53 and RPS20. The RPS20 variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple in silico tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in RPS20 expands the phenotypic spectrum of RPS20-related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels.

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Section: Discussionmentioning

confidence: 99%

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

et al. 2020

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“…The rapid development of sequencing-based techniques and genome-wide copy number techniques brought hope for the identification of new causal genes for nonpolyposis familial and EOCRC. However, despite the enormous efforts made, which led to the identification of over a hundred candidate genes (reviewed by Terradas et al [ 35 ]), up to date only RPS20 has shown consistent association with hereditary nonpolyposis CRC. Among the other ≈100 candidate genes identified, nine currently show promising evidence to support their involvement in CRC predisposition: MRE11 , BARD1 , POT1 , BUB1B , POLE2 , BRF1 , IL12RB1, and PTPN12 , and the epigenetic alteration of PTPRJ [ 35 ].…”

Section: Inherited Syndromes That Predispose To Eocrcmentioning

confidence: 99%

“…However, despite the enormous efforts made, which led to the identification of over a hundred candidate genes (reviewed by Terradas et al [ 35 ]), up to date only RPS20 has shown consistent association with hereditary nonpolyposis CRC. Among the other ≈100 candidate genes identified, nine currently show promising evidence to support their involvement in CRC predisposition: MRE11 , BARD1 , POT1 , BUB1B , POLE2 , BRF1 , IL12RB1, and PTPN12 , and the epigenetic alteration of PTPRJ [ 35 ]. Additional candidate genes are published on a regular basis that require validation in large cohorts and functional studies that support their involvement in colorectal carcinogenesis.…”

Section: Inherited Syndromes That Predispose To Eocrcmentioning

confidence: 99%

“…While our group found no predicted pathogenic RPS20 variants among 473 familial/EOCRC cases [ 38 ], a recent study identified a splicing variant, c.177 + 1G>A, in a family with four CRC-affected members (ages at diagnosis: 38–61), all of them carriers or obligate carriers of the RPS20 variant [ 39 ]. Although information from additional carriers are required to estimate risks and recommend gene-specific surveillance measures, available data suggests low prevalence (allele frequency in familial/early onset CRC patients: 2/2724; 0.07%) and high penetrance (13/16 (81%) >35-year-old carriers of disruptive or canonical splice-site variants were affected with CRC) for RSP20 pathogenic variants, as well as absence of extracolonic manifestations [ 35 ].…”

Section: Inherited Syndromes That Predispose To Eocrcmentioning

confidence: 99%

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The Inherited and Familial Component of Early-Onset Colorectal Cancer

Daca‐Alvarez

Quintana

Terradas

et al. 2021

Cells

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Early-onset colorectal cancer (EOCRC), defined as that diagnosed before the age of 50, accounts for 10–12% of all new colorectal cancer (CRC) diagnoses. Epidemiological data indicate that EOCRC incidence is increasing, despite the observed heterogeneity among countries. Although the cause for such increase remains obscure, ≈13% (range: 9–26%) of EOCRC patients carry pathogenic germline variants in known cancer predisposition genes, including 2.5% of patients with germline pathogenic variants in hereditary cancer genes traditionally not associated with CRC predisposition. Approximately 28% of EOCRC patients have family history of the disease. This article recapitulates current evidence on the inherited syndromes that predispose to EOCRC and its familial component. The evidence gathered support that all patients diagnosed with an EOCRC should be referred to a specialized genetic counseling service and offered somatic and germline pancancer multigene panel testing. The identification of a germline pathogenic variant in a known hereditary cancer gene has relevant implications for the clinical management of the patient and his/her relatives, and it may guide surgical and therapeutic decisions. The relative high prevalence of hereditary cancer syndromes and familial component among EOCRC patients supports further research that helps understand the genetic background, either monogenic or polygenic, behind this increasingly common disease.

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“…Their clinical management is thus conducted based on their family history. Important efforts have been made to identify new high or moderate penetrance genes that explain the familial aggregation, early ages of onset, or polyposis phenotypes observed in those families or individuals, but the success achieved has been minimal [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants

Mur

Bonifaci

Díez-Villanueva

et al. 2021

Cancers

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A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age ≥50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC.

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Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

Cited by 17 publications

References 125 publications

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

The Inherited and Familial Component of Early-Onset Colorectal Cancer

Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants

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