Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers

Glodzik, Dominik; Bosch, Ana; Hartman, Johan; Aine, Mattias; Vallon‐Christersson, Johan; Reuterswärd, Christel; Karlsson, Anna; Mitra, Shamik; Niméus, Emma; Holm, Karolina; Häkkinen, Jari; Hegardt, Cecilia; Saal, Lao H.; Larsson, Christer; Malmberg, Martin; Rydén, Lisa; Ehinger, Anna; Loman, Niklas; Kvist, Anders; Ehrencrona, Hans; Nik-Zainal, Serena; Borg, Åke; Staaf, Johan

doi:10.1038/s41467-020-17537-2

Cited by 64 publications

(64 citation statements)

References 68 publications

(152 reference statements)

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“…For patients ≥ 70 years, corresponding values were 2.6% and 7.8%. We have previously shown the genomic equivalency of the phenotypes associated with BRCA1 inactivation by DNA methylation or mutations [ 25 ]. The higher proportion of hypermethylated cases in older patients would suggest that a HRD phenotype brought on by epigenetic silencing represents a more long-tailed process compared to the same phenotype induced by germline alterations.…”

Section: Resultsmentioning

confidence: 99%

“…To further analyze mRNA expression of different immune cell marker genes, we clustered 102 genes related to 23 immune cell types (as previously defined in [ 25 ]) in the 232 SCAN-B cases with gene expression (Fig. 3 b).…”

Section: Resultsmentioning

confidence: 99%

“…BRCA1 -null, BRCA2 -null, and PALB2 -null status was defined as either a somatic or germline loss of function variant with LOH, or a loss of function germline mutation only [ 9 ]. BRCA1 deficiency was defined as either BRCA1 -null or BRCA1 promoter hypermethylation, as these are mutually exclusive and impart an identical genomic phenotype in TNBC [ 25 ]. As estimates of homologous recombination deficiency (HRD), we used the WGS-based HRDetect [ 26 ] and the copy number based HRD score ( genomic scars ) [ 27 ] classifications available from [ 9 ].…”

Section: Methodsmentioning

confidence: 99%

“…Principal component analysis was performed using the R swamp package (ver 1.5.1) and all available refseq genes [ 35 ]. RNAseq-based immune cell deconvolution was obtained for 230 cases using CIBERSORTx [ 36 ] as described [ 25 ].…”

Section: Methodsmentioning

confidence: 99%

“…NeoPredPipe [ 37 ] was used to predict putative neoantigens with substitution mutation calls provided by CaVEMan ( https://cancerit.github.io/CaVEMan/ ) and HLA typing done with Polysolver [ 38 ] as input, as detailed in Glodzik et al [ 25 ].…”

Section: Methodsmentioning

confidence: 99%

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Molecular analyses of triple-negative breast cancer in the young and elderly

et al. 2021

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Background Breast cancer in young adults has been implicated with a worse outcome. Analyses of genomic traits associated with age have been heterogenous, likely because of an incomplete accounting for underlying molecular subtypes. We aimed to resolve whether triple-negative breast cancer (TNBC) in younger versus older patients represent similar or different molecular diseases in the context of genetic and transcriptional subtypes and immune cell infiltration. Patients and methods In total, 237 patients from a reported population-based south Swedish TNBC cohort profiled by RNA sequencing and whole-genome sequencing (WGS) were included. Patients were binned in 10-year intervals. Complimentary PD-L1 and CD20 immunohistochemistry and estimation of tumor-infiltrating lymphocytes (TILs) were performed. Cases were analyzed for differences in patient outcome, genomic, transcriptional, and immune landscape features versus age at diagnosis. Additionally, 560 public WGS breast cancer profiles were used for validation. Results Median age at diagnosis was 62 years (range 26–91). Age was not associated with invasive disease-free survival or overall survival after adjuvant chemotherapy. Among the BRCA1-deficient cases (82/237), 90% were diagnosed before the age of 70 and were predominantly of the basal-like subtype. In the full TNBC cohort, reported associations of patient age with changes in Ki67 expression, PIK3CA mutations, and a luminal androgen receptor subtype were confirmed. Within DNA repair deficiency or gene expression defined molecular subgroups, age-related alterations in, e.g., overall gene expression, immune cell marker gene expression, genetic mutational and rearrangement signatures, amount of copy number alterations, and tumor mutational burden did, however, not appear distinct. Similar non-significant associations for genetic alterations with age were obtained for other breast cancer subgroups in public WGS data. Consistent with age-related immunosenescence, TIL counts decreased linearly with patient age across different genetic TNBC subtypes. Conclusions Age-related alterations in TNBC, as well as breast cancer in general, need to be viewed in the context of underlying genomic phenotypes. Based on this notion, age at diagnosis alone does not appear to provide an additional layer of biological complexity above that of proposed genetic and transcriptional phenotypes of TNBC. Consequently, treatment decisions should be less influenced by age and more driven by tumor biology.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Molecular analyses of triple-negative breast cancer in the young and elderly

et al. 2021

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Constitutional BRCA1 Methylation and Risk of Incident Triple-Negative Breast Cancer and High-grade Serous Ovarian Cancer

et al. 2022

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IMPORTANCE About 25% of all triple-negative breast cancers (TNBCs) and 10% to 20% of high-grade serous ovarian cancers (HGSOCs) harbor BRCA1 promoter methylation. While constitutional BRCA1 promoter methylation has been observed in normal tissues of some individuals, the potential role of normal tissue methylation as a risk factor for incident TNBC or HGSOC is unknown.OBJECTIVE To assess the potential association between white blood cell BRCA1 promoter methylation and subsequent risk of incident TNBC and HGSOC. DESIGN, SETTING, AND PARTICIPANTSThis case-control study included women who were participating in the Women's Health Initiative study who had not received a diagnosis of either breast or ovarian cancer before study entrance. A total of 637 women developing incident TNBC and 511 women developing incident HGSOC were matched with cancer-free controls (1841 and 2982, respectively) in a nested case-control design. Cancers were confirmed after central medical record review. Blood samples, which were collected at entry, were analyzed for BRCA1 promoter methylation by massive parallel sequencing. The study was performed in the Mohn Cancer Research Laboratory (Bergen, Norway) between 2019 and 2022.MAIN OUTCOMES AND MEASURES Associations between BRCA1 methylation and incident TNBC and incident HGSOC were analyzed by Cox proportional hazards regression. RESULTSOf 2478 cases and controls in the TNBC group and 3493 cases and controls in the HGSOC group, respectively, 7 (0.3%) and 3 (0.1%) were American Indian or Alaska Native, 46 (1.9%) and 30 (0.9%) were Asian, 1 (0.04%) and 1 (0.03%) was Native Hawaiian or Pacific Islander, 326 (13.2%) and 125 (3.6%) were Black or African, 56 (2.3%) and 116 (3.3%) were Hispanic, 2046 (82.6%) and 3257 (93.2%) were White, and 35 (1.4%) and 35 (1.0%) were multiracial. Median (range) age at entry was 62 (50-79) years, with a median interval to diagnosis of 9 (TNBC) and 10 (HGSOC) years. Methylated BRCA1 alleles were present in 194 controls (5.5%). Methylation was associated with risk of incident TNBC (12.4% methylated; HR, 2.35; 95% CI, 1.70-3.23; P < .001) and incident HGSOC (9.4% methylated; HR, 1.93; 95% CI, 1.36-2.73; P < .001). Restricting analyses to individuals with more than 5 years between sampling and cancer diagnosis yielded similar results (TNBC: HR, 2.52; 95% CI, 1.75-3.63; P < .001; HGSOC: HR, 1.82; 95% CI, 1.22-2.72; P = .003). Across individuals, methylation was not haplotype-specific, arguing against an underlying cis-acting factor. Within individuals, BRCA1 methylation was observed on the same allele, indicating clonal expansion from a single methylation event. There was no association found between BRCA1 methylation and germline pathogenic variant status. CONCLUSIONS AND RELEVANCEThe results of this case-control suggest that constitutional normal tissue BRCA1 promoter methylation is significantly associated with risk of incident TNBC and HGSOC, with potential implications for prediction of these cancers. These findings warrant further research to determine if constitut...

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PARP Inhibitors for Breast Cancer Treatment

Morganti,

Marra,

De Angelis

et al. 2024

JAMA Oncol

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ImportancePoly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors have revolutionized the treatment of patients with germline BRCA1/2-associated breast cancer, representing the first targeted therapy capable of improving outcomes in patients with hereditary tumors. However, resistance to PARP inhibitors occurs in almost all patients.ObservationsThis narrative review summarizes the biological rationale behind the use of PARP inhibitors in breast cancer, as well as the available evidence, recent progress, and potential future applications of these agents. Recent studies have shown that the benefit of PARP inhibitors extends beyond patients with germline BRCA1/2-associated metastatic breast cancer to patients with somatic BRCA1/2 variants and to those with germline PALB2 alterations. Moreover, these agents proved to be effective both in the metastatic and adjuvant settings. However, patients with metastatic breast cancer usually do not achieve the long-term benefit from PARP inhibitors observed in other tumor types. Mechanisms of resistance have been identified, but how to effectively target them is largely unknown. Ongoing research is investigating both novel therapeutics and new combination strategies to overcome resistance. PARP1-selective inhibitors, by sparing the hematological toxic effects induced by the PARP2 blockade, are promising agents to be combined with chemotherapy, antibody-drug conjugates, and other targeted therapies.Conclusions and RelevanceAlthough the efficacy of PARP inhibitors is well established, many questions persist. Future research should focus on identifying predictive biomarkers and therapeutic strategies to overcome resistance. Integrating well-designed translational efforts into all clinical studies is thereby crucial to laying the groundwork for future insights from ongoing research.

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Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers

Cited by 64 publications

References 68 publications

Molecular analyses of triple-negative breast cancer in the young and elderly

Molecular analyses of triple-negative breast cancer in the young and elderly

Constitutional BRCA1 Methylation and Risk of Incident Triple-Negative Breast Cancer and High-grade Serous Ovarian Cancer

PARP Inhibitors for Breast Cancer Treatment

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