A Comprehensive Survey of Genomic Mutations in Breast Cancer Reveals Recurrent Neoantigens as Potential Therapeutic Targets

Zhou, Shaomin; Liu, Songming; Zhao, Lijian; Sun, Hai‐Xi

doi:10.3389/fonc.2022.786438

Cited by 9 publications

(16 citation statements)

References 42 publications

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“…Our results showed that SNV is the most abundant variant type with C>T being the most abundant SNV type in both BRCA1 -positive and -negative groups. This corresponds with the study results by Zhou and colleagues in 5991 unspecified breast cancer samples [ 32 ]. Mutational burden represented by total variant counts showed differences between BRCA1 -positive and -negative among all databases with the BRCA1 -positive group harboring more SNVs and indels compared to the BRCA1 -negative group.…”

Section: Discussionsupporting

confidence: 92%

“…TP53 and PIK3CA were found mutated in 30.24–37.39% and 30.08–39.48% of all BRCA1 -negative samples, respectively. These mutational frequencies are similar to the findings in unspecified breast cancer samples ( TP53 37%; PIK3CA 38%) [ 32 , 42 ]. In the BRCA1 -positive group, however, TP53 was found to be the top mutated gene with much higher frequencies of 59.09–75.00% of all BRCA1 -positive samples.…”

Section: Discussionsupporting

confidence: 85%

“…This also correlates with the frequency of PIK3CA mutations in TNBC (16%), which is lower than in the hormonal positive subgroups (HR+/HER2 (42%) and HER2+ (31%)) [ 42 ]. Taken together with the fact that most BRCA1 -mutated samples are TNBC (57–68%) [ 15 , 16 ], and TP53 and PIK3CA mutations are often mutually exclusive [ 32 ], the relationship between hormonal status (TNBC), TP53 , PIK3CA , and BRCA1 mutation status may need to be further explored.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, shared target antigens reported in breast cancer, such as HER2 and MUC1 , are TAAs, not neoantigens [ 28 , 29 , 30 , 31 ]. A study, which recently reported shared neoantigen targets in breast cancer such as PIK3CA H1047R E545K N345K and AKT1 E17K, was conducted on unspecified breast cancer samples [ 32 ]. To the best of our knowledge, shared neoantigen targets for BRCA1 -related breast cancer have not been reported.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Shared Neoantigens in BRCA1-Related Breast Cancer

et al. 2022

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Personalized neoantigen-based cancer vaccines have been shown to be safe and immunogenic in cancer patients; however, the manufacturing process can be costly and bring about delays in treatment. Using off-the-shelf cancer vaccines targeting shared neoantigens may circumvent these problems. Unique mutational signatures and similar phenotypes found among BRCA1-mutated breast cancer make it an ideal candidate for discovering shared neoantigens within the group. We obtained genome sequencing data of breast cancer samples with or without somatic BRCA1 mutations (BRCA1-positive and BRCA1-negative, respectively) from the three public cancer databases; The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Catalogue of Somatic Mutations in Cancer (COSMIC); and from three studies with whole genome/exome sequencing data of samples with germline BRCA1 mutations. Data were analyzed separately within the same database/cohort. We found PIK3CA H1047R, E545K, E542K, and N345K recurrently in BRCA1-negative groups across all databases, whereas recurrent somatic mutations in BRCA1-positive groups were discordant among databases. For germline BRCA1-mutated breast cancer, TP53 R175H was unanimously the most frequent mutation among the three germline cohorts. Our study provides lists of potential shared neoantigens among BRCA1-related breast cancer, which may be used in developing off-the-shelf neoantigen-based vaccines.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of Shared Neoantigens in BRCA1-Related Breast Cancer

et al. 2022

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“…A total of 2 of the 10 predicted peptides stimulated T cells to secrete IFNγ and were cytotoxic to autologous tumor cells, suggesting the presence of neoantigen-specific T cells, which may be suitable vaccine targets. In another study designed to identify a neoantigen signature for breast cancer, Zhou et al integrated mutational data from 8 published cohorts of close to 6000 breast cancer patients [ 20 ]. Interestingly, they found that four mutations (3 from PIK3CA and 1 from AKT1), predicted to be restricted by HLA alleles common in Han Chinese and Americans, were identified in 2.5–14% of the samples.…”

Section: Introductionmentioning

confidence: 99%

Antigens Expressed by Breast Cancer Cells Undergoing EMT Stimulate Cytotoxic CD8+ T Cell Immunity

Camp

Brunetti

Williams

et al. 2022

Cancers

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Antigenic differences formed by alterations in gene expression and alternative splicing are predicted in breast cancer cells undergoing epithelial to mesenchymal transition (EMT) and the reverse plasticity known as MET. How these antigenic differences impact immune interactions and the degree to which they can be exploited to enhance immune responses against mesenchymal cells is not fully understood. We utilized a master microRNA regulator of EMT to alter mesenchymal-like EO771 mammary carcinoma cells to a more epithelial phenotype. A computational approach was used to identify neoantigens derived from the resultant differentially expressed somatic variants (SNV) and alternative splicing events (neojunctions). Using whole cell vaccines and peptide-based vaccines, we find superior cytotoxicity against the more-epithelial cells and explore the potential of neojunction-derived antigens to elicit T cell responses through experiments designed to validate the computationally predicted neoantigens. Overall, results identify EMT-associated splicing factors common to both mouse and human breast cancer cells as well as immunogenic SNV- and neojunction-derived neoantigens in mammary carcinoma cells.

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