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Novel Insight in the Etiology of CRC: Genetics, Diagnosis, Management and Risk Assessment

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (20 February 2023) | Viewed by 10979

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Special Issue Editors

Dr. Mev Dominguez Valentin

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Guest Editor

Department of Tumor Biology, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway
Interests: inherited cancer; genetics; cancer risk; biomarkers; datasets
Special Issues, Collections and Topics in MDPI journals

Dr. Pål Moller

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Guest Editor

Department of Tumor Biology, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway
Interests: Lynch syndrome; colorectal cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Colon-rectal cancer (CRC) is the most frequent cancer. Germline variants with high penetrance in the APC and DNA mismatch repair genes may cause up to 5–10% of the cases, while as much as 30–45% CRC cases may have a heritable causative component.

Early onset CRC (EOCRC) is reported to have increasing incidence, and as many as ~18% of patients diagnosed with CRC < age of 50 years (EOCRC) have pathogenic germline variants in genes that are not traditionally associated with CRC, including ATM, CHEK2, BRCA1, BRCA2, CDKN2A and PALB2 genes. The causes for familial clustering of CRC in older ages are less clear. An increase in CRC incidence should be caused by environmental factors, including interaction between genetic and environmental causative factors. Comprehensive testing for multiple genes, both in families and in incident cases, is now generating new knowledge for these topics. Early detection of and screening for cancer may cause overdiagnosis. In addition to treatment of cancer, health care includes knowledge and public education on lifestyle, clean environment, and the inherited cancer syndromes’ medical genetic services. This should cover both high- and low-income areas. The current issue aims to increase knowledge for such aims.

Dr. Mev Dominguez Valentin
Dr. Pål Moller
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

CRC
early-onset CRC
genetics
biomarkers
management
risk prediction
surveillance
prevention
overdiagnosis
early detection
screening
inherited CRC
inherited syndromes

Published Papers (3 papers)

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Research

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13 pages, 1504 KiB

Open AccessArticle

Genetic Characterization in High-Risk Individuals from a Low-Resource City of Peru

by Elizabeth Zavaleta, Nelly Solis, Maria Isabel Palacios, Liz Elva Zevallos-Escobar, Edison Vasquez Corales, Juan Carlos Bazo-Alvarez, Constantino Dominguez-Barrera, Anthony Campos, Patrik Wernhoff, Per Olaf Ekstrøm, Pål Møller, Tina Visnovska, Eivind Hovig, Janina Balazar-Palacios, Karin Alvarez-Valenzuela, Sigve Nakken and Mev Dominguez-Valentin

Cancers 2022, 14(22), 5603; https://doi.org/10.3390/cancers14225603 - 15 Nov 2022

Viewed by 2832

Abstract

Background: Genetic testing for hereditary cancers is inconsistently applied within the healthcare systems in Latin America. In Peru, the prevalence and spectrum of cancer-predisposing germline variants is thus poorly characterized. Purpose: To determine the spectrum and prevalence of cancer-predisposing germline variants and variants of uncertain significance (VUS) in high-risk individuals located in a Peruvian low-resource setting city. Methods: Individuals presenting clinical criteria for hereditary cancer syndromes or being unaffected with familial history of cancer were included in the study. Samples from a total of 84 individuals were subjected to a high-throughput DNA sequencing assay that targeted a panel of 94 cancer predisposition genes. The pathogenicity of detected germline variants was classified according to the established American College of Medical Genetics and Genomics (ACMG) criteria. All pathogenic variants were validated by cycling temperature capillary electrophoresis. Results: We identified a total of eight pathogenic variants, found in 19 out of 84 individuals (23%). Pathogenic variants were identified in 24% (10/42) of unaffected individuals with family history of cancer and in 21% (9/42) of individuals with a cancer diagnosis. Pathogenic variants were identified in eight genes: RET (3), BRCA1 (3), SBDS (2), SBDS/MLH1 (4), MLH1 (4), TP53 (1), FANCD2 (1), DDB2/FANCG (1). In cancer cases, all colon cancer cases were affected by pathogenic variants in MLH1 and SBDS genes, while 20% (2/10) of the thyroid cancer cases by RET c.1900T>C variants were affected. One patient with endometrial cancer (1/3) had a double heterozygous pathogenic variant in DDB2 and FANCG genes, while one breast cancer patient (1/14) had a pathogenic variant in TP53 gene. Overall, each individual presented at least 17 VUS, totaling 1926 VUS for the full study population. Conclusion: We describe the first genetic characterization in a low-resource setting population where genetic testing is not yet implemented. We identified multiple pathogenic germline variants in clinically actionable predisposition genes, that have an impact on providing an appropriate genetic counselling and clinical management for individuals and their relatives who carry these variants. We also reported a high number of VUS, which may indicate variants specific for this population and may require a determination of their clinical significance. Full article

(This article belongs to the Special Issue Novel Insight in the Etiology of CRC: Genetics, Diagnosis, Management and Risk Assessment)

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14 pages, 912 KiB

Open AccessArticle

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

by Pilar Mur, Nuria Bonifaci, Anna Díez-Villanueva, Elisabet Munté, Maria Henar Alonso, Mireia Obón-Santacana, Gemma Aiza, Matilde Navarro, Virginia Piñol, Joan Brunet, Ian Tomlinson, Gabriel Capellá, Victor Moreno and Laura Valle

Cancers 2021, 13(15), 3857; https://doi.org/10.3390/cancers13153857 - 31 Jul 2021

Cited by 6 | Viewed by 2831

Abstract

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. Full article

(This article belongs to the Special Issue Novel Insight in the Etiology of CRC: Genetics, Diagnosis, Management and Risk Assessment)

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Other

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26 pages, 4478 KiB

Open AccessSystematic Review

The Role of Diet and Lifestyle in Early-Onset Colorectal Cancer: A Systematic Review

by Marta Puzzono, Alessandro Mannucci, Simone Grannò, Raffaella Alessia Zuppardo, Andrea Galli, Silvio Danese and Giulia Martina Cavestro

Cancers 2021, 13(23), 5933; https://doi.org/10.3390/cancers13235933 - 25 Nov 2021

Cited by 26 | Viewed by 4487

Abstract

The incidence of early-onset colorectal cancer, defined as colorectal cancer occurring in young adults under the age of 50, is increasing globally. Knowledge of the etiological factors in young adults is far from complete. Questionable eoCRCs’ exogenous factors are represented by processed meat, sugary drinks, alcohol, Western dietary pattern, overweight and obesity, physical inactivity, and smoking, though with heterogeneous results. Therefore, we performed a systematic review to summarize the current evidence on the role of diet and lifestyle as eoCRC risk factors. We systematically searched PubMed, Scopus, and EMBASE up to July 2021, for original studies evaluating diet, alcohol, physical activity, BMI, and smoking in eoCRC and included twenty-six studies. Indeed, the exogenous factors could represent modifiable key factors, whose recognition could establish areas of future interventions through public health strategies for eoCRC primary prevention. Additionally, we discussed the role of additional non-modifiable risk factors, and of epigenetic regulation and microbiota as mediators of the eoCRC triggered by diet and lifestyle. Full article

(This article belongs to the Special Issue Novel Insight in the Etiology of CRC: Genetics, Diagnosis, Management and Risk Assessment)

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