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The Study of Cancer Susceptibility Genes (Volume II)

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

Deadline for manuscript submissions: 25 June 2024 | Viewed by 1756

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Prof. Dr. Youri I. Pavlov

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Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska, Omaha, NE, USA
Interests: mechanisms of maintenance of genomic stability during replication; repair; recombination; transcription and editing
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Dear Colleagues,

The collection is the second edition of the previous one on "The Study of Cancer Susceptibility Genes" at https://www.mdpi.com/journal/cancers/special_issues/Susceptibility_Genes.

Cancer is a disease caused by heritable changes that include point mutations, chromosome rearrangements/copy number variation, and epigenetic reprogramming. Several sequential changes are required to produce tumor cells. Aberrant genome maintenance leads to increased mutation rates, fueling tumorigenesis and predisposing to cancer. The examples are genome alterations causing mismatch repair defects, lowering fidelity but increasing endurance of replicative DNA polymerases, and breaking precise control of intrinsic mutagenic factors: error-prone DNA polymerases or editing enzymes of the AID/APOBEC family. The analysis of tumor genomes allows identifying the origins of mutators. The type of factors causing increased cancer incidence influences therapeutic interventions’ outcomes.

Prof. Dr. Youri I. Pavlov
Guest Editor

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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.

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14 pages, 3272 KiB

Open AccessArticle

POLD1 DEDD Motif Mutation Confers Hypermutation in Endometrial Cancer and Durable Response to Pembrolizumab

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Cancers 2023, 15(23), 5674; https://doi.org/10.3390/cancers15235674 - 30 Nov 2023

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Abstract

Background: Mutations in the DNA polymerase delta 1 (POLD1) exonuclease domain cause DNA proofreading defects, hypermutation, hereditary colorectal and endometrial cancer, and are predictive of immunotherapy response. Exonuclease activity is carried out by two magnesium cations, bound to four highly conserved, negatively charged amino acids (AA) consisting of aspartic acid at amino acid position 316 (p.D316), glutamic acid at position 318 (p.E318), p.D402, and p.D515 (termed DEDD motif). Germline polymorphisms resulting in charge-discordant AA substitutions in the DEDD motif are classified as variants of uncertain significance (VUSs) by laboratories and thus would be considered clinically inactionable. We hypothesize this mutation class is clinically pathogenic. Methods: A review of clinical presentation was performed in our index patient with a POLD1(p.D402N) heterozygous proband with endometrial cancer. Implications of this mutation class were evaluated by a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review, in silico analysis with orthogonal biochemical confirmation, and whole-exome and RNA sequencing analysis of the patient’s tumor and engineered cell lines. Results: Our systematic review favored a Mendelian disease mutation class associated with endometrial and colorectal cancers. In silico analysis predicted defective protein function, confirmed by biochemical assay demonstrating loss of nuclease activity. A POLD1-specific mutational signature was found in both the patient’s tumor and POLD1(p.D402N) overexpressing cell. Furthermore, paired whole-exome/transcriptome analysis of endometrial tumor demonstrated hypermutation and T cell-inflamed gene expression profile (GEP), which are joint predictive biomarkers for pembrolizumab. Our patient showed a deep, durable response to immune checkpoint inhibitor (ICI). Conclusion: Charge-discordant AA substitution in the DEDD motif of POLD1 is detrimental to DNA proofreading and should be reclassified as likely pathogenic and possibly predictive of ICI sensitivity. Full article

(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes (Volume II))

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10 pages, 1429 KiB

Open AccessArticle

Only 32.3% of Breast Cancer Families with Pathogenic Variants in Cancer Genes Utilized Cascade Genetic Testing

Cancers 2023, 15(21), 5218; https://doi.org/10.3390/cancers15215218 - 30 Oct 2023

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Abstract

Background: Hereditary cancer predisposition syndromes are responsible for approximately 5–10% of all diagnosed cancer cases. In order to identify individuals at risk in a cost-efficient manner, family members of individuals carrying pathogenic alterations are tested only for the specific variant that was identified in their carrier relative. The purpose of this study was to investigate the clinical use and implementation of cascade family testing (CFT) in families of breast cancer patients with pathogenic/likely pathogenic variants (PVs/LPVs) in cancer-related predisposition genes. Methods: Germline sequencing was carried out with NGS technology using a 52-gene panel, and cascade testing was performed by Sanger sequencing or MLPA. Results: In a cohort of 1785 breast cancer patients (families), 20.3% were found to have PVs/LPVs. Specifically, 52.2%, 25.1%, and 22.7% of patients had positive findings in high-, intermediate-, and low-penetrance breast cancer susceptibility genes, respectively. Although CFT was recommended to all families, only 117 families (32.3%) agreed to proceed with genetic testing. Among the first-degree relatives who underwent CFT, 70.3% were female, and 108 of 121 (89.3%) were cancer free. Additionally, 42.7%, 36.7%, and 20.6% were offspring, siblings, and parents of the subject, respectively. Our data suggest that CFT was mostly undertaken (104/117, 88.8%) in families with positive findings in high-risk genes. Conclusions: Cascade family testing can be a powerful tool for primary cancer prevention by identifying at-risk family members. It is of utmost importance to implement genetic counseling approaches leading to increased awareness and communication of genetic testing results. Full article

(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes (Volume II))

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16 pages, 2385 KiB

Open AccessCommentary

APOBEC Mutagenesis in Cancer Development and Susceptibility

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Cancers 2024, 16(2), 374; https://doi.org/10.3390/cancers16020374 - 15 Jan 2024

Abstract

APOBEC cytosine deaminases are prominent mutators in cancer, mediating mutations in over 50% of cancers. APOBEC mutagenesis has been linked to tumor heterogeneity, persistent cell evolution, and therapy responses. While emerging evidence supports the impact of APOBEC mutagenesis on cancer progression, the understanding of its contribution to cancer susceptibility and malignant transformation is limited. We examine the existing evidence for the role of APOBEC mutagenesis in carcinogenesis on the basis of the reported associations between germline polymorphisms in genes encoding APOBEC enzymes and cancer risk, insights into APOBEC activities from sequencing efforts of both malignant and non-malignant human tissues, and in vivo studies. We discuss key knowledge gaps and highlight possible ways to gain a deeper understanding of the contribution of APOBEC mutagenesis to cancer development. Full article

(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes (Volume II))

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