Novel Genetic Markers for Early Detection of Elevated Breast Cancer Risk in Women

Wu, Bohua; Peng, Yunhui; Eggert, Julie; Alexov, Emil

doi:10.3390/ijms20194828

Cited by 3 publications

(4 citation statements)

References 54 publications

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“…In the current study, we found one patient carrying MSH6 and BRCA1 PVs simultaneously and without any other personal or family history of cancer, while all the other MMR variants identified were VUSs. Since Wu B et al reported two MSH2 variants used to classify VUS are pathogenic mutations 36 . Therefore, these VUS should be investigated further in a large number of patients.…”

Section: Discussionmentioning

confidence: 99%

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What is the appropriate genetic testing criteria for breast cancer in the Chinese population?—Analysis of genetic and clinical features from a single cancer center database

Fang

Yang

et al. 2023

Cancer Medicine

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Background Genetic testing plays an important role in guiding screening, diagnosis, and precision treatment of breast cancer (BC). However, the appropriate genetic testing criteria remain controversial. The current study aims to facilitate the development of suitable strategies by analyzing the germline mutational profiles and clinicopathological features of large‐scale Chinese BC patients. Methods BC patients who had undergone genetic testing at the Sun Yat‐sen University Cancer Center (SYSUCC) from September 2014 to March 2022 were retrospectively reviewed. Different screening criteria were applied and compared in the population cohort. Results A total of 1035 BC patients were enrolled, 237 pathogenic or likely pathogenic variants (P/LPV) were identified in 235 patients, including 41 out of 203 (19.6%) patients tested only for BRCA1/2 genes, and 194 out of 832 (23.3%) received 21 genes panel testing. Among the 235 P/LPV carriers, 222 (94.5%) met the NCCN high‐risk criteria, and 13 (5.5%) did not. While using Desai's criteria of testing, all females diagnosed with BC by 60 years and NCCN criteria for older patients, 234 (99.6%) met the high‐risk standard, and only one did not. The 21 genes panel testing identified 4.9% of non‐BRCA P/LPVs and a significantly high rate of variants of uncertain significance (VUSs) (33.9%). The most common non‐BRCA P/LPVs were PALB2 (11, 1.3%), TP53 (10, 1.2%), PTEN (3, 0.4%), CHEK2 (3, 0.4%), ATM (3, 0.4%), BARD1 (3, 0.4%), and RAD51C (2, 0.2%). Compared with BRCA1/2 P/LPVs, non‐BRCA P/LPVs showed a significantly low incidence of NCCN criteria listed family history, second primary cancer, and different molecular subtypes. Conclusions Desai's criteria might be a more appropriate genetic testing strategy for Chinese BC patients. Panel testing could identify more non‐BRCA P/LPVs than BRCA1/2 testing alone. Compared with BRCA1/2 P/LPVs, non‐BRCA P/LPVs exhibited different personal and family histories of cancer and molecular subtype distributions. The optimal genetic testing strategy for BC still needs to be investigated with larger continuous population studies.

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Section: Discussionmentioning

confidence: 99%

“…Since Wu B et al reported two MSH2 variants used to classify VUS are pathogenic mutations. 36 Therefore, these VUS should be investigated further in a large number of patients. A case of CDH1 PV was found in one female patient diagnosed with ILC at 40 years.…”

Section: Discussionmentioning

confidence: 99%

What is the appropriate genetic testing criteria for breast cancer in the Chinese population?—Analysis of genetic and clinical features from a single cancer center database

Fang

Yang

et al. 2023

Cancer Medicine

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“…DNA MMR Alterations in BrCa Alterations or different variants in DNA MMR genes are correlated with an elevated risk for BrCa development. A study group explored the role of specific MSH2 variants in women without BRCA1/BRCA2 gene mutations (20). They detected a combination of two mutations (p. Ala272Val and p. Met592Val) and designated them as potentially pathogenic in sub-groups of patients.…”

Section: Dna Mismatch Repair System (Dna Mmr): Landscape and Mechanismsmentioning

confidence: 99%

DNA Mismatch Repair System Imbalances in Breast Adenocarcinoma

Metaxas

Tsiambas

Marinopoulos

et al. 2023

CDP

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DNA mismatch repair system (MMR) is considered a leading genetic mechanism in stabilizing DNA structure and maintaining its function. DNA MMR is a highly conserved system in bacteria, prokaryotic, and eukaryotic cells, and provides the highest protection to DNA by repairing micro-structural alterations. DNA MMR proteins are involved in the detection and repair of intra-nucleotide base-to-base errors inside the complementary DNA strand recognizing the recently synthesized strand from the parental template. During DNA replication, a spectrum of errors including base insertion, deletion, and miss-incorporation negatively affect the molecule’s structure and its functional stability. A broad spectrum of genomic alterations such as promoter hyper methylation, mutation, and loss of heterozygosity (LOH) in MMR genes including predominantly hMLH1, hMSH2, hMSH3, hMSH6, hPMS1, and hPMS2 lead to their loss of base-to-base error repairing procedure. Microsatellite instability (MSI) refers to the DNA MMR gene alterations that are observed in a variety of malignancies of different histological origins. In the current review, we present the role of DNA MMR deficiency in breast adenocarcinoma, a leading cancer-based cause of death in females worldwide.

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“…Besides, MSH2 mutations are found in patients with endometrial carcinoma and adenocarcinoma of the colon. Besides, MSH2 mutation carriers have an increased risk of breast cancer (BC) with or without a LS family history 45 . A homozygous G to A transition mutation in the invariant G of the intron 10 splice acceptor of the MSH2 gene is associated with leukemia and multiple cafe´-au-lait spots, a feature of neurofibromatosis type 1 46 .…”

Section: Mmr Gene Polymorphism and Cancermentioning

confidence: 99%

The role of DNA mismatch repair in immunotherapy of human cancer

He¹,

Zhang²,

Zhou³

et al. 2022

Int. J. Biol. Sci.

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DNA mismatch repair (MMR) is an important pathway which helps to maintain genomic stability. Mutations in DNA MMR genes are found to promote cancer initiation and foster tumor progression. Deficiency or inactivation of MMR results in microsatellite instability (MSI) which triggers neoantigen generation and impairs tumor growth. Immunotherapies targeting MMR can increase the burden of neoantigens in tumor cells. While MSI has been regarded as an important predictor of sensitivity and drug resistance for immunotherapy-based strategies. Different approaches targeting genomic instability have been demonstrated to be promising in malignancies derived from different tissues. Underlying MMR deficiency-associated immunogenicity is important for improving the therapeutic efficacy of immunotherapies. In this review we provide an overview of the MMR systems, their role in tumorigenesis, drug resistance, prognostic significance and potential targets for therapeutic treatment in human cancers, especially in hematological malignancies.

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Novel Genetic Markers for Early Detection of Elevated Breast Cancer Risk in Women

Cited by 3 publications

References 54 publications

What is the appropriate genetic testing criteria for breast cancer in the Chinese population?—Analysis of genetic and clinical features from a single cancer center database

What is the appropriate genetic testing criteria for breast cancer in the Chinese population?—Analysis of genetic and clinical features from a single cancer center database

DNA Mismatch Repair System Imbalances in Breast Adenocarcinoma

The role of DNA mismatch repair in immunotherapy of human cancer

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