Effects of germline and somatic events in candidate BRCA-like genes on breast-tumor signatures

Bodily, Weston R.; Shirts, Brian H.; Walsh, Tom; Gülsüner, Süleyman; King, Mary‐Claire; Parker, Alyssa; Roosan, Moom R.; Piccolo, Stephen R.

doi:10.1371/journal.pone.0239197

Cited by 14 publications

(11 citation statements)

References 100 publications

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“…So far, the differential effects of germline and somatic mutations in BRCA1 or BRCA2 genes on the transcriptome and associated functional processes have not been studied to a great extent as opposed to the clinical effects. A recent transcriptomic study reported similarity between germline and somatic mutations of BRCA1/2 genes in breast cancer [60] in agreement with subtle differences in gene expression observed in this study (Figure 1). However, our functional analysis revealed a series of novel details.…”

Section: Discussionsupporting

confidence: 92%

Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

Arakelyan

Melkonyan

Hakobyan

et al. 2021

IJMS

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Mutations in the BRCA1 and BRCA2 genes are known risk factors and drivers of breast and ovarian cancers. So far, few studies have been focused on understanding the differences in transcriptome and functional landscapes associated with the disease (breast vs. ovarian cancers), gene (BRCA1 vs. BRCA2), and mutation type (germline vs. somatic). In this study, we were aimed at systemic evaluation of the association of BRCA1 and BRCA2 germline and somatic mutations with gene expression, disease clinical features, outcome, and treatment. We performed BRCA1/2 mutation centered RNA-seq data analysis of breast and ovarian cancers from the TCGA repository using transcriptome and phenotype “portrayal” with multi-layer self-organizing maps and functional annotation. The results revealed considerable differences in BRCA1- and BRCA2-dependent transcriptome landscapes in the studied cancers. Furthermore, our data indicated that somatic and germline mutations for both genes are characterized by deregulation of different biological functions and differential associations with phenotype characteristics and poly(ADP-ribose) polymerase (PARP)-inhibitor gene signatures. Overall, this study demonstrates considerable variation in transcriptomic landscapes of breast and ovarian cancers associated with the affected gene (BRCA1 vs. BRCA2), as well as the mutation type (somatic vs. germline). These results warrant further investigations with larger groups of mutation carriers aimed at refining the understanding of molecular mechanisms of breast and ovarian cancers.

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Section: Discussionsupporting

confidence: 92%

Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

Arakelyan

Melkonyan

Hakobyan

et al. 2021

IJMS

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“…Pathogenic or likely pathogenic germline BRCA1 or BRCA2 variants are present in 18% of ovarian cancer cases [29]. In breast cancer, pathogenic or likely pathogenic germline BRCA1 or BRCA2 variants are present in 6.1% of all cases [30][31][32][33][34][35][36], and 10-20% of triple-negative breast cancer cases [37]. Pathogenic or likely pathogenic germline BRCA variants are more often associated with the development of cancer at a younger age and present with more aggressive disease phenotypes with worse prognoses when compared to cancers caused by somatic BRCA mutations [38,39].…”

Section: Homologous Recombination Dna Repair Proficiency (Hrp) and Cancermentioning

confidence: 99%

Homologous recombination proficiency in ovarian and breast cancer patients

et al. 2021

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Homologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2 results in homologous recombination deficiency (HRD) and can be a target for therapeutic strategies including poly (ADP-ribose) polymerase inhibitors (PARPi). However, response is limited in patients who are not HRD, highlighting the need for reliable and robust HRD testing. This manuscript will review BRCA1/2 function and homologous recombination proficiency in respect to breast and ovarian cancer. The current standard testing methods for HRD will be discussed as well as trials leading to approval of PARPi’s. Finally, standard of care treatment and synthetic lethality will be reviewed.

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“…Patient PT8 exhibited a truncal frameshift variant in BRCA1 , while patient PT4 exhibited a truncal variant in a splice region of the gene ZAR1L , which occurs immediately upstream of BRCA2 . The presence of signature S3 in the absence of BRCA mutations is a described phenomenon (43,44). The only case lacking the S3 “BRCA-ness” signature was patient PT2, who instead displayed a strong signature S6 (associated with DNA mismatch repair deficiency).…”

Section: Resultsmentioning

confidence: 99%

Origins and timing of emerging lesions in advanced renal cell carcinoma

Wallace¹,

Porten

Lo³

et al. 2021

Preprint

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Purpose: Renal cell carcinoma (RCC) with venous tumor thrombus (VTT) arising from the primary tumor occurs in 4-10% of cases and is associated with advanced disease. RCC with VTT and distant metastasis represents a unique clinical entity, and provides opportunities to examine the origins and relative timing of tumor lesion emergence and to identify molecular correlates with disease state. Experimental Design: We performed genomic and evolutionary analyses on 16 RCC patients with VTT, with eight also having metastases, using multi-region exome and RNA sequencing. Results: No genomic alterations were specifically associated with the VTT or metastasis lesions; each tumor had multiple hallmark driver alterations, consistent with advanced disease state. We found that 21% (3/14) of clear-cell RCC cases could be assigned a previously defined "evolutionary subtype". Somatic mutation signatures were largely consistent with previously established RCC signatures, and showed low heterogeneity across regions of each tumor. Mismatch repair and homologous recombination ("BRCA-ness") deficiency signatures consistently co-occurred across most tumors, suggesting a pervasive role for intracellular DNA damage in RCC and the potential for related treatment strategies. Phylogenetic timing analysis of metastatic cases suggested that in most tumors, metastases branched from the primary tumor prior to formation of VTT and in some cases before diversification of the primary tumor. Both VTT and the earliest metastases were predicted to emerge many years prior to diagnosis. Transcriptional landscape analysis identified key differences distinguishing each lesion type from primary tumor: VTT upregulated TNF𝛼 signaling and associated inflammatory pathways, whereas metastases upregulated MTOR signaling. Conclusions: Our results provide a map of how RCC tumors can evolve, with metastatic clones typically emerging early in RCC development and taking hold via MTOR signaling, and later formation of VTT via local inflammatory processes.

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Effects of germline and somatic events in candidate BRCA-like genes on breast-tumor signatures

Cited by 14 publications

References 100 publications

Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

Homologous recombination proficiency in ovarian and breast cancer patients

Origins and timing of emerging lesions in advanced renal cell carcinoma

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