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Cancers
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New Insights into Hereditary Cancer Syndromes
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New Insights into Hereditary Cancer Syndromes

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 15287

Special Issue Editors

Prof. Dr. Melissa Southey

E-Mail Website
Guest Editor
Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria 3800, Australia
Interests: cancer predisposition; precision medicine; precision prevention
Dr. Tu Nguyen-Dumont

E-Mail Website
Co-Guest Editor
Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria 3800, Australia
Interests: cancer genetics; bioinformatics; cancer predisposition
Prof. Ingrid Winship

E-Mail Website
Co-Guest Editor
Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Victoria 3010, Australia
Interests: cancer genetics; clinical genetics; familial cancer

Special Issue Information

Dear Colleagues,

Precision medicine, including genome-wide molecular analytical approaches, have provided new insights into hereditary cancer syndromes. Advances in our understanding of heritable risk factors, their cancer risk spectrum and the functional impacts to specific biological pathways have improved and expanded our understanding of heritable cancer syndromes and enabled precision medicine and precision prevention.

Both the molecular diversity and some core homogeneity of cancers arising in the context of cancer syndromes that are commonly clinically defined have been highlighted in recent research.  This Special Issue will highlight prime examples of how the diagnosis and clinical management of cancer syndromes have been advanced in the precision medicine era and how these advances are also increasing the precision of prevention strategies.

Prof. Dr. Melissa Southey
Dr. Tu Nguyen-Dumont
Prof. Ingrid Winship
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 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

  • cancer syndromes
  • hereditary cancer risk factors
  • cancer predisposition genes
  • clinical genetics
  • precision medicine for cancer syndromes
  • precision prevention for cancer syndromes

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Published Papers (5 papers)

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Research

15 pages, 1988 KiB  
Article
Minigene Splicing Assays Identify 20 Spliceogenic Variants of the Breast/Ovarian Cancer Susceptibility Gene RAD51C
by Lara Sanoguera-Miralles, Elena Bueno-Martínez, Alberto Valenzuela-Palomo, Ada Esteban-Sánchez, Inés Llinares-Burguet, Pedro Pérez-Segura, Alicia García-Álvarez, Miguel de la Hoya and Eladio A. Velasco-Sampedro
Cancers 2022, 14(12), 2960; https://doi.org/10.3390/cancers14122960 - 15 Jun 2022
Cited by 6 | Viewed by 2493
Abstract
RAD51C loss-of-function variants are associated with an increased risk of breast and ovarian cancers. Likewise, splicing disruptions are a frequent mechanism of gene inactivation. Taking advantage of a previous splicing-reporter minigene with exons 2-8 (mgR51C_ex2-8), we proceeded to check its impact on the [...] Read more.
RAD51C loss-of-function variants are associated with an increased risk of breast and ovarian cancers. Likewise, splicing disruptions are a frequent mechanism of gene inactivation. Taking advantage of a previous splicing-reporter minigene with exons 2-8 (mgR51C_ex2-8), we proceeded to check its impact on the splicing of candidate ClinVar variants. A total of 141 RAD51C variants at the intron/exon boundaries were analyzed with MaxEntScan. Twenty variants were selected and genetically engineered into the wild-type minigene. All the variants disrupted splicing, and 18 induced major splicing anomalies without any trace or minimal amounts (<2.4%) of the minigene full-length (FL) transcript. Twenty-seven transcripts (including the wild-type and r.904A FL transcripts) were identified by fluorescent fragment electrophoresis; of these, 14 were predicted to truncate the RAD51C protein, 3 kept the reading frame, and 8 minor isoforms (1.1–4.7% of the overall expression) could not be characterized. Finally, we performed a tentative interpretation of the variants according to an ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme, classifying 16 variants as likely pathogenic. Minigene assays have been proven as valuable tools for the initial characterization of potential spliceogenic variants. Hence, minigene mgR51C_ex2-8 provided useful splicing data for 40 RAD51C variants. Full article
(This article belongs to the Special Issue New Insights into Hereditary Cancer Syndromes)
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25 pages, 1872 KiB  
Article
The Genetic and Molecular Analyses of RAD51C and RAD51D Identifies Rare Variants Implicated in Hereditary Ovarian Cancer from a Genetically Unique Population
by Wejdan M. Alenezi, Larissa Milano, Caitlin T. Fierheller, Corinne Serruya, Timothée Revil, Kathleen K. Oros, Supriya Behl, Suzanna L. Arcand, Porangana Nayar, Dan Spiegelman, Simon Gravel, Anne-Marie Mes-Masson, Diane Provencher, William D. Foulkes, Zaki El Haffaf, Guy Rouleau, Luigi Bouchard, Celia M. T. Greenwood, Jean-Yves Masson, Jiannis Ragoussis and Patricia N. Toninadd Show full author list remove Hide full author list
Cancers 2022, 14(9), 2251; https://doi.org/10.3390/cancers14092251 - 30 Apr 2022
Cited by 5 | Viewed by 3702
Abstract
To identify candidate variants in RAD51C and RAD51D ovarian cancer (OC) predisposing genes by investigating French Canadians (FC) exhibiting unique genetic architecture. Candidates were identified by whole exome sequencing analysis of 17 OC families and 53 early-onset OC cases. Carrier frequencies were determined [...] Read more.
To identify candidate variants in RAD51C and RAD51D ovarian cancer (OC) predisposing genes by investigating French Canadians (FC) exhibiting unique genetic architecture. Candidates were identified by whole exome sequencing analysis of 17 OC families and 53 early-onset OC cases. Carrier frequencies were determined by the genetic analysis of 100 OC or HBOC families, 438 sporadic OC cases and 1025 controls. Variants of unknown function were assayed for their biological impact and/or cellular sensitivity to olaparib. RAD51C c.414G>C;p.Leu138Phe and c.705G>T;p.Lys235Asn and RAD51D c.137C>G;p.Ser46Cys, c.620C>T;p.Ser207Leu and c.694C>T;p.Arg232Ter were identified in 17.6% of families and 11.3% of early-onset cases. The highest carrier frequency was observed in OC families (1/44, 2.3%) and sporadic cases (15/438, 3.4%) harbouring RAD51D c.620C>T versus controls (1/1025, 0.1%). Carriers of c.620C>T (n = 7), c.705G>T (n = 2) and c.137C>G (n = 1) were identified in another 538 FC OC cases. RAD51C c.705G>T affected splicing by skipping exon four, while RAD51D p.Ser46Cys affected protein stability and conferred olaparib sensitivity. Genetic and functional assays implicate RAD51C c.705G>T and RAD51D c.137C>G as likely pathogenic variants in OC. The high carrier frequency of RAD51D c.620C>T in FC OC cases validates previous findings. Our findings further support the role of RAD51C and RAD51D in hereditary OC. Full article
(This article belongs to the Special Issue New Insights into Hereditary Cancer Syndromes)
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15 pages, 1183 KiB  
Article
Potential Involvement of NSD1, KRT24 and ACACA in the Genetic Predisposition to Colorectal Cancer
by Isabel Quintana, Pilar Mur, Mariona Terradas, Sandra García-Mulero, Gemma Aiza, Matilde Navarro, Virginia Piñol, Joan Brunet, Victor Moreno, Rebeca Sanz-Pamplona, Gabriel Capellá and Laura Valle
Cancers 2022, 14(3), 699; https://doi.org/10.3390/cancers14030699 - 29 Jan 2022
Cited by 2 | Viewed by 2239
Abstract
The ALFRED (Allelic Loss Featuring Rare Damaging) in silico method was developed to identify cancer predisposition genes through the identification of somatic second hits. By applying ALFRED to ~10,000 tumor exomes, 49 candidate genes were identified. We aimed to assess the causal association [...] Read more.
The ALFRED (Allelic Loss Featuring Rare Damaging) in silico method was developed to identify cancer predisposition genes through the identification of somatic second hits. By applying ALFRED to ~10,000 tumor exomes, 49 candidate genes were identified. We aimed to assess the causal association of the identified genes with colorectal cancer (CRC) predisposition. Of the 49 genes, NSD1, HDAC10, KRT24, ACACA and TP63 were selected based on specific criteria relevant for hereditary CRC genes. Gene sequencing was performed in 736 patients with familial/early onset CRC or polyposis without germline pathogenic variants in known genes. Twelve (predicted) damaging variants in 18 patients were identified. A gene-based burden test in 1596 familial/early-onset CRC patients, 271 polyposis patients, 543 TCGA CRC patients and >134,000 controls (gnomAD, non-cancer), revealed no clear association with CRC for any of the studied genes. Nevertheless, (non-significant) over-representation of disruptive variants in NSD1, KRT24 and ACACA in CRC patients compared to controls was observed. A somatic second hit was identified in one of 20 tumors tested, corresponding to an NSD1 carrier. In conclusion, most genes identified through the ALFRED in silico method were not relevant for CRC predisposition, although a possible association was detected for NSD1, KRT24 and ACACA. Full article
(This article belongs to the Special Issue New Insights into Hereditary Cancer Syndromes)
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16 pages, 3027 KiB  
Article
Histological and Somatic Mutational Profiles of Mismatch Repair Deficient Endometrial Tumours of Different Aetiologies
by Neil A. J. Ryan, Thomas D. J. Walker, James Bolton, Natalja ter Haar, Tom Van Wezel, Mark A. Glaire, David N. Church, D. Gareth Evans, Tjalling Bosse and Emma J. Crosbie
Cancers 2021, 13(18), 4538; https://doi.org/10.3390/cancers13184538 - 10 Sep 2021
Cited by 9 | Viewed by 2748
Abstract
Background: Mismatch repair deficient (MMRd) tumours may arise from somatic events acquired during carcinogenesis or in the context of Lynch syndrome (LS), an inherited cancer predisposition condition caused by germline MMR pathogenic variants. Our aim was to explore whether sporadic and hereditary MMRd [...] Read more.
Background: Mismatch repair deficient (MMRd) tumours may arise from somatic events acquired during carcinogenesis or in the context of Lynch syndrome (LS), an inherited cancer predisposition condition caused by germline MMR pathogenic variants. Our aim was to explore whether sporadic and hereditary MMRd endometrial cancers (EC) display distinctive tumour biology. Methods: Clinically annotated LS-EC were collected. Histological slide review was performed centrally by two specialist gynaecological pathologists. Mutational analysis was by a bespoke 75- gene next-generation sequencing panel. Comparisons were made with sporadic MMRd EC. Multiple correspondence analysis was used to explore similarities and differences between the cohorts. Results: After exclusions, 135 LS-EC underwent independent histological review, and 64 underwent mutational analysis. Comparisons were made with 59 sporadic MMRd EC. Most tumours were of endometrioid histological subtype (92% LS-EC and 100% sporadic MMRd EC, respectively, p = NS). Sporadic MMRd tumours had significantly fewer tumour infiltrating lymphocytes (p ≤ 0.0001) and showed more squamous/mucinous differentiation than LS-EC (p = 0.04/p = 0.05). PTEN mutations were found in 88% sporadic MMRd and 61% LS-EC, respectively (p < 0.001). Sporadic MMRd tumours had significantly more mutations in PDGFRA, ALK, IDH1, CARD11, CIC, MED12, CCND1, PTPN11, RB1 and KRAS, while LS-EC showed more mutations affecting SMAD4 and ARAF. LS-EC showed a propensity for TGF-β signalling disruption. Cluster analysis found that wild type PTEN associates predominantly with LS-EC, whilst co-occurring mutations in PTEN, PIK3CA and KRAS predict sporadic MMRd EC. Conclusions: Whilst MMRd EC of hereditary and sporadic aetiology may be difficult to distinguish by histology alone, differences in infiltrating immune cell counts and mutational profile may predict heterogenous responses to novel targeted therapies and warrant further study. Full article
(This article belongs to the Special Issue New Insights into Hereditary Cancer Syndromes)
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15 pages, 1353 KiB  
Article
Prevalence of Germline Pathogenic Variants in Cancer Predisposing Genes in Czech and Belgian Pancreatic Cancer Patients
by Greet Wieme, Jan Kral, Toon Rosseel, Petra Zemankova, Bram Parton, Michal Vocka, Mattias Van Heetvelde, Petra Kleiblova, Bettina Blaumeiser, Jana Soukupova, Jenneke van den Ende, Petr Nehasil, Sabine Tejpar, Marianna Borecka, Encarna B. Gómez García, Marinus J. Blok, Marketa Safarikova, Marta Kalousova, Karen Geboes, Robin De Putter, Bruce Poppe, Kim De Leeneer, Zdenek Kleibl, Marketa Janatova and Kathleen B. M. Claesadd Show full author list remove Hide full author list
Cancers 2021, 13(17), 4430; https://doi.org/10.3390/cancers13174430 - 2 Sep 2021
Cited by 14 | Viewed by 2938
Abstract
(1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic [...] Read more.
(1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic variants (PV) in relation to personal/family cancer history were evaluated. PDAC risks were calculated using both gnomAD-NFE and population-matched controls. (3) Results: In 35/298 (11.7%) patients a PV in an established PDAC-predisposition gene was found. BRCA1/2 PV conferred a high risk in both populations, ATM and Lynch genes only in the Belgian subgroup. PV in other known PDAC-predisposition genes were rarer. Interestingly, a high frequency of CHEK2 PV was observed in both patient populations. PV in PDAC-predisposition genes were more frequent in patients with (i) multiple primary cancers (12/38; 32%), (ii) relatives with PDAC (15/56; 27%), (iii) relatives with breast/ovarian/colorectal cancer or melanoma (15/86; 17%) but more rare in sporadic PDAC (5/149; 3.4%). PV in homologous recombination genes were associated with improved overall survival (HR = 0.51; 95% CI 0.34–0.77). (4) Conclusions: Our analysis emphasizes the value of multigene panel testing in PDAC patients, especially in individuals with a positive family cancer history, and underlines the importance of population-matched controls for risk assessment. Full article
(This article belongs to the Special Issue New Insights into Hereditary Cancer Syndromes)
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