Computational Investigation of Homologous Recombination DNA Repair Deficiency in Sporadic Breast Cancer

Wang, Yue; Ung, Matthew; Cantor, Sharon B.; Cheng, Chao

doi:10.1038/s41598-017-16138-2

Cited by 12 publications

(12 citation statements)

References 71 publications

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“…The "BRCAness" characteristics of the subtypes of breast and HGSOC including BRCA1/2 germline mutation carriers from TCGA database are presented in Tables 1 and 2. The most important aspects of "BRCAness" phenotype chosen from literature were as follows: deficiency in HR, high genomic instability, frequent P53 mutations, but infrequent PI3K mutations in breast and ovarian cancers, in addition to basal like classification and high probability of pathological complete response (pCR) in breast cancers [6,7,28,38,39,41,42]. "BRCAness" is most often found in the BL1 and M subtypes of TNBC.…”

Section: Distribution Of "Brcaness" In Subtypes Of Breast and Ovarianmentioning

confidence: 99%

“…There are interests in expanding the use of PARP inhibitors to sporadic breast and ovarian cancers, some of which express phenotypes similar to hereditary tumors. For example, many sporadic TNBCs show deficiency in HR and demonstrate "BRCAlike" clinicopathological features, often referred to as "BRCAness" [5,6]. "BRCAness" phenotype is also attributed to many hereditary and sporadic HGSOCs.…”

Section: Introductionmentioning

confidence: 99%

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An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers

et al. 2020

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Background: BRCA1/2 germline mutation related cancers are candidates for new immune therapeutic interventions. This study was a hypothesis generating exploration of genomic data collected at diagnosis for 19 patients. The prominent tumor mutation burden (TMB) in hereditary breast and ovarian cancers in this cohort was not correlated with high global immune activity in their microenvironments. More information is needed about the relationship between genomic instability, phenotypes and immune microenvironments of these hereditary tumors in order to find appropriate markers of immune activity and the most effective anticancer immune strategies. Methods: Mining and statistical analyses of the original DNA and RNA sequencing data and The Cancer Genome Atlas data were performed. To interpret the data, we have used published literature and web available resources such as Gene Ontology, The Cancer immunome Atlas and the Cancer Research Institute iAtlas. Results: We found that BRCA1/2 germline related breast and ovarian cancers do not represent a unique phenotypic identity, but they express a range of phenotypes similar to sporadic cancers. All breast and ovarian BRCA1/2 related tumors are characterized by high homologous recombination deficiency (HRD) and low aneuploidy. Interestingly, all sporadic high grade serous ovarian cancers (HGSOC) and most of the subtypes of triple negative breast cancers (TNBC) also express a high degree of HRD. Conclusions: TMB is not associated with the magnitude of the immune response in hereditary BRCA1/2 related breast and ovarian cancers or in sporadic TNBC and sporadic HGSOC. Hereditary tumors express phenotypes as heterogenous as sporadic tumors with various degree of "BRCAness" and various characteristics of the immune microenvironments. The subtyping criteria developed for sporadic tumors can be applied for the classification of hereditary tumors and possibly also characterization of their immune microenvironment. A high HRD score may be a good candidate biomarker for response to platinum, and potentially PARP-inhibition. Trial registration: Phase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients With Recurrent TNBC or HGSOC (NCT01623349), first posted on June 20, 2012. The design and the outcome of the clinical trial is not in the scope of this study.

show abstract

Section: Distribution Of "Brcaness" In Subtypes Of Breast and Ovarianmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The "BRCAness" characteristics of the subtypes of breast and HGSOC including BRCA1/2 germline mutation carriers from TCGA data base are presented in Table 1 and 2. The most important aspects of "BRCAness" phenotype chosen from literature were as follows: deficiency in HR, high genomic instability, frequent P53 mutations, but infrequent PI3K mutations in breast and ovarian cancers, in addition to basal like classification and high probability of pathological complete response (pCR) in breast cancers [6,7,39,40][28] [41,42]. "BRCAness" is most often found in the BL1 and M subtypes of TNBC.…”

Section: Distribution Of "Brcaness" In Subtypes Of Breast and Ovarianmentioning

confidence: 99%

“…There are interests in expanding the use of PARP inhibitors to sporadic breast and ovarian cancers, some of which express phenotypes similar to hereditary tumors. For example, many sporadic TNBCs show deficiency in HR and demonstrate "BRCA-like" clinicopathological features, often referred to as "BRCAness" [5,6]. "BRCAness" phenotype is also attributed to many hereditary and sporadic HGSOCs.…”

Section: Introductionmentioning

confidence: 99%

An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers

Przybytkowski¹,

Davis²,

Hosny³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: BRCA1/2 germline mutation related cancers are candidates for new immune therapeutic interventions. This study was a hypothesis generating exploration of genomic data collected at diagnosis for 19 patients. The prominent tumor mutation burden (TMB) in hereditary breast and ovarian cancers in this cohort was not correlated with high global immune activity in their microenvironments. More information is needed about the relationship between genomic instability, phenotypes and immune microenvironments of these hereditary tumors in order to find appropriate markers of immune activity and the most effective anticancer immune strategies. Methods: Mining and statistical analyses of the original DNA and RNA sequencing data and The Cancer Genome Atlas data were performed. To interpret the data, we have used published literature and web available resources such as Gene Ontology, The Cancer immunome Atlas and the Cancer Research Institute iAtlas. Results: We found that BRCA1/2 germline related breast and ovarian cancers do not represent a unique phenotypic identity, but they express a range of phenotypes similar to sporadic cancers. All breast and ovarian BRCA1/2 related tumors are characterized by high homologous recombination deficiency (HRD) and low aneuploidy. Interestingly, all sporadic high grade serous ovarian cancers (HGSOC) and most of the subtypes of triple negative breast cancers (TNBC) also express a high degree of HRD.Conclusions: TMB is not associated with the magnitude of the immune response in hereditary BRCA1/2 related breast and ovarian cancers or in sporadic TNBC and sporadic HGSOC. Hereditary tumors express phenotypes as heterogenous as sporadic tumors with various degree of “BRCAness” and various characteristics of the immune microenvironments. The subtyping criteria developed for sporadic tumors can be applied for the classification of hereditary tumors and possibly also characterization of their immune microenvironment. A high HRD score may be a good candidate biomarker for response to platinum, and potentially PARP-inhibition.Trial registration: Phase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients With Recurrent TNBC or HGSOC (NCT01623349), first posted on June 20, 2012. The design and the outcome of the clinical trial is not in the scope of this study.

show abstract

“…The "BRCAness" characteristics of the subtypes of breast and HGSOC including BRCA1/2 germline mutation carriers from TCGA data base are presented in Table 1 and 2. The most important aspects of "BRCAness" phenotype chosen from literature were as follows: deficiency in HR, high genomic instability, frequent P53 mutations, but infrequent PI3K mutations in breast and ovarian cancers, in addition to basal like classification and high probability of pathological complete response (pCR) in breast cancers [33][34][35][36][21] [37,38]. "BRCAness" is most often found in the BL1 and M subtypes of TNBC.…”

Section: Distribution Of "Brcaness" In Subtypes Of Breast and Ovarianmentioning

confidence: 99%

An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers

Przybytkowski¹,

Davis²,

Hosny³

et al. 2019

Preprint

View full text Add to dashboard Cite

Background: This study was a hypothesis generating exploration of genomic data collected at diagnosis for patients participating in a clinical trial (#NCT01623349). The cohort consisted of hereditary and sporadic breast and ovarian cancers. Methods: Mining and statistical analyses of the original DNA and RNA sequencing data and data available from The Cancer Genome Atlas (TCGA) were performed using the R computing environment. To interpret the data, we have used published literature and web available resources such as Gene Ontology Tools, The Cancer immunome Atlas (TCIA) and the Cancer Research Institute iAtlas. Results: We found that a prominent tumor mutation burden (TMB) in hereditary breast and ovarian cancers is not correlated with high global immune activity in their microenvironments. We also found that BRCA1/2 germline related breast and ovarian cancers do not represent a unique phenotypic identity, but that they express a range of phenotypes similar to sporadic cancers. Importantly, BRCA2 germline mutation related breast tumors have a different profile of genomic instability compared to those related to BRCA1. However, all breast and ovarian BRCA1/2 related tumors are characterized by high homologous recombination deficiency (HRD) and low aneuploidy. Interestingly, all sporadic high grade serous ovarian cancers (HGSOC) and most of the subtypes of triple negative breast cancers (TNBC), but not other types of breast cancer, also express a high degree of HRD. Conclusions: TMB is not associated with the magnitude of the immune response in hereditary BRCA1/2 related breast and ovarian cancers or in sporadic TNBC and sporadic HGSOC. Hereditary tumors express phenotypes as heterogenous as sporadic tumors with various degree of “BRCAness” and various characteristics of the immune microenvironments. The subtyping criteria developed for sporadic tumors can be applied for the classification of hereditary tumors and possibly also characterization of their immune microenvironment. A high HRD score may be a good candidate biomarker for response to platinum, and potentially PARP-inhibition. Trial registration: Phase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients With Recurrent Triple Negative Breast Cancer or High Grade Serous Ovarian Cancer. ClinicalTrials.gov Identifier: NCT01623349.

show abstract

Computational Investigation of Homologous Recombination DNA Repair Deficiency in Sporadic Breast Cancer

Cited by 12 publications

References 71 publications

An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers

An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers

An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers

An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers

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