Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple-negative breast and serous ovarian cancers

Birkbak, Nicolai J.; Li, Y.; Pathania, Shailja; Greene-Colozzi, April; Dreze, Matija; Bowman-Colin, Christian; Sztupinszki, Zsófia; Krzystanek, Marcin; Dióssy, Miklós; Tung, Nadine; Ryan, Paula D.; Garber, Judy E.; Silver, Daniel P.; Iglehart, J. Dirk; Wang, Z. C.; Szüts, Dávid; Szállási, Zoltán; Richardson, Andrea L.

doi:10.1093/annonc/mdy049

Cited by 50 publications

(43 citation statements)

References 18 publications

(18 reference statements)

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“…3C). In contrast, the expression of BLM, FEN1, and BRCA2 (direct transcriptional targets of BRCA1 that are negatively regulated) was upregulated in HRD tumors 21,22 , as was expression of EXO1, NEIL3, and BRIP 23 . The protein expression of FANC family members was also upregulated.…”

Section: Resultsmentioning

confidence: 97%

Homologous repair deficiency score for identifying breast cancers with defective DNA damage response

Min

Kim

Jeong

et al. 2020

Sci Rep

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Breast cancer (BC) in patients with germline mutations of BRCA1/BRCA2 are associated with benefit from drugs targeting DNA damage response (DDR), but they account for only 5-7% of overall breast cancer. To define the characteristics of these tumors and also to identify tumors without BRCA mutation but with homologous recombination deficiency (HRD) is clinically relevant. To define characteristic features of HRD tumors and analyze the correlations between BRCA1/BRCA2 and BC subtypes, we analyzed 981 breast tumors from the TCGA database using the signature analyzer. The BRCA signature was strongly associated with the HRD score top 10% (score ≥ 57) population. This population showed a high level of mutations in DDR genes, including BRCA1/BRCA2. HRD tumors were associated with high expression levels of BARD1 and BRIP1. Besides, BRCA1/2 mutations were dominantly observed in basal and luminal subtypes, respectively. A comparison of HRD features in BC revealed that BRCA1 exerts a stronger influence inducing HRD features than BRCA2 does. It reveals genetic differences between BRCA1 and BRCA2 and provides a basis for the identification of HRD and other BRCA-associated tumors. Depending on hormone receptor and human epidermal growth factor type II receptor (HER2) oncoprotein expression, breast cancer (BC) is traditionally classified into luminal A or B (i.e., estrogen and/or progesterone receptor-positive), HER2-enriched, or triple-negative BC (TNBC). However, there is high heterogeneity, even within subtypes, making treatment difficult 1,2. To improve treatment, understanding tumor heterogeneity within and across subtypes and proper treatment strategies for each tumor is crucial. One approach is examining the mutations of each tumor and defining distinct molecular signatures for categorization. The Cancer Genome Project (TCGA) serves as an important basis for understanding the genomics of tumor heterogeneity 2. Poly (ADP-ribose) polymerase (PARP) inhibitors are clinically beneficial in patients with BRCA-deficient ovarian, breast, and prostate cancer. In a global phase III trial involving patients with metastatic BC with germline BRCA1 or BRCA2 mutation, olaparib increased progression-free survival (PFS) by 2.8 months 3. In an olaparib maintenance clinical phase II trial of patients with relapsed platinum-sensitive ovarian cancer in addition to BRCA-deficient tumors, one-third of patients with wild-type BRCA showed improvements in PFS 4,5. Based on this, olaparib was additionally approved by the FDA for maintenance treatment in platinum-sensitive patients, regardless of BRCA status. These results suggest that BRCA and other homologous repair deficiency (HRD) markers determine response to PARP inhibitors and that these should be applied to patients with other HRD markers as well. In fact, tumors lacking BRCA mutation but with HRD, similar responses to DNA damaging agents, and similar clinicopathologic features are referred to as having "BRCAness, " and the use of PARP

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Section: Resultsmentioning

confidence: 97%

Homologous repair deficiency score for identifying breast cancers with defective DNA damage response

Min

Kim

Jeong

et al. 2020

Sci Rep

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“…In addition to the DDR pathway gene set, we analyzed tumor protein p53 (TP53), RB transcriptional corepressor 1 (RB1), ERCC excision repair 2, TFIIH core complex helicase subunit (ERCC2), BLM RecQ like helicase (BLM), and DNA topoisomerase I (TOP1) gene, which were previously reported to be related with platinum sensitivity. 2,9,[23][24][25][26][27] Tissue Preparation and Tumor Sequencing All tumor specimens were reviewed by pathologists to determine the percent of viable tumor and adequacy for sequencing. Genomic DNA was extracted from formalin-fixed paraffin-embedded tissue using a Qiagen DNA formalin-fixed paraffin-embedded tissue kit, and from fresh tissue using a QIAamp DNA mini kit (Qiagen, Redwood City, California).…”

Section: Genes and Gene Set Related To Ddr Pathway Selected For The Smentioning

confidence: 99%

DNA Damage Response and Repair Pathway Alteration and Its Association With Tumor Mutation Burden and Platinum-Based Chemotherapy in SCLC

Park

Lee

et al. 2019

Journal of Thoracic Oncology

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Introduction: Impairment in DNA damage response and repair (DDR) pathway is known as a predictive biomarker of platinum sensitivity. Recently, DDR alteration is reemphasized as a predictive biomarker of immune checkpoint inhibitor due to its positive correlation to tumor mutation burden (TMB). Methods: Target gene sequencing (381 genes) was conducted from 100 extensive disease (ED) and 66 limited disease (LD) patients with SCLC. Detected mutations were classified as double-strand breaks (DSB) (n ¼ 82): homologous recombination (n ¼ 54), non-homologous end joining (n ¼ 19), and Fanconi anemia (n ¼ 32); or singlestrand breaks (SSB) (n ¼ 31): mismatch repair (n ¼ 19), base excision repair (n ¼ 7), and nucleotide excision repair (n ¼ 6). Results: Compared to patients with an intact DDR pathway (n ¼ 70), a higher TMB was observed in patients with homologous recombination (p < 0.001), non-homologous end joining (p ¼ 0.002), mismatch repair (p < 0.001), DSB (p < 0.001), and SSB (p < 0.001). Survival analyses based on TMB level showed no predictive or prognostic values in ED patients. In LD patients, prolonged progression-free survival (hazard ratio [HR] ¼ 0.497, p ¼ 0.015), and overall survival (HR ¼ 0.383, p ¼ 0.010) to concurrent chemoradiotherapy were observed in those with TMB above median. Individual DDR pathway alteration showed no survival benefit in ED patients receiving platinum-based chemotherapy. In LD patients, those with mutations in the Fanconi anemia gene set had shorter progression-free survival (HR ¼ 2.048, p ¼ 0.036) to initial treatment. Conclusions: DDR pathway alterations, both DSB and SSB, in SCLC have a positive correlation with high TMB. However, it has shown limited value in prediction of platinum efficacy.

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“…Previous studies showed that overexpression of BLM displaces the localization of RAD51 to the sites of DNA damage 109 , 112 . The loss of RAD51 leads to insufficient HR resulting in genomic instability and DNA damage.…”

Section: Resultsmentioning

confidence: 94%

“…Biochemical studies showed that the deletion of BLM enhances the assembly of RAD51 at the ssDNA break site, while overexpression of BLM disrupts the RAD51 assembly through its helicase activity 108 , 109 . Therefore, BLM works as a ‘anti-recombinase’ at early and late stages of HR by: (i) preventing HR by disrupting the RAD51 assembly on the ssDNA of DSBs to make sure that HR only occurs between sequences with high homology; and (ii) preventing SCEs by separating the repaired DNA from the template DNA strand that arises at the final stages of HR 110 , 111 .…”

Section: Resultsmentioning

confidence: 99%

Investigating the pathogenic SNPs in BLM helicase and their biological consequences by computational approach

Alzahrani

Ahmed

Sharma

et al. 2020

Sci Rep

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The BLM helicase protein plays a vital role in DNA replication and the maintenance of genomic integrity. Variation in the BLM helicase gene resulted in defects in the DNA repair mechanism and was reported to be associated with Bloom syndrome (BS) and cancer. Despite extensive investigation of helicase proteins in humans, no attempt has previously been made to comprehensively analyse the single nucleotide polymorphism (SNPs) of the BLM gene. In this study, a comprehensive analysis of SNPs on the BLM gene was performed to identify, characterize and validate the pathogenic SNPs using computational approaches. We obtained SNP data from the dbSNP database version 150 and mapped these data to the genomic coordinates of the “NM_000057.3” transcript expressing BLM helicase (P54132). There were 607 SNPs mapped to missense, 29 SNPs mapped to nonsense, and 19 SNPs mapped to 3′-UTR regions. Initially, we used many consensus tools of SIFT, PROVEAN, Condel, and PolyPhen-2, which together increased the accuracy of prediction and identified 18 highly pathogenic non-synonymous SNPs (nsSNPs) out of 607 SNPs. Subsequently, these 18 high-confidence pathogenic nsSNPs were analysed for BLM protein stability, structure–function relationships and disease associations using various bioinformatics tools. These 18 mutants of the BLM protein along with the native protein were further investigated using molecular dynamics simulations to examine the structural consequences of the mutations, which might reveal their malfunction and contribution to disease. In addition, 28 SNPs were predicted as “stop gained” nonsense SNPs and one SNP was predicted as “start lost”. Two SNPs in the 3′UTR were found to abolish miRNA binding and thus may enhance the expression of BLM. Interestingly, we found that BLM mRNA overexpression is associated with different types of cancers. Further investigation showed that the dysregulation of BLM is associated with poor overall survival (OS) for lung and gastric cancer patients and hence led to the conclusion that BLM has the potential to be used as an important prognostic marker for the detection of lung and gastric cancer.

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Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple-negative breast and serous ovarian cancers

Cited by 50 publications

References 18 publications

Homologous repair deficiency score for identifying breast cancers with defective DNA damage response

Homologous repair deficiency score for identifying breast cancers with defective DNA damage response

DNA Damage Response and Repair Pathway Alteration and Its Association With Tumor Mutation Burden and Platinum-Based Chemotherapy in SCLC

Investigating the pathogenic SNPs in BLM helicase and their biological consequences by computational approach

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