Bi‐allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer

Mutter, Robert W.; Riaz, Nadeem; Ng, Charlotte K.Y.; Delsite, Robert; Piscuoglio, Salvatore; Edelweiss, Marcia; Martelotto, Luciano G.; Sakr, Rita A.; King, Tari A.; Giri, Dilip; Drobnjak, Maria; Bindra, Ranjit S.; Bernheim, Giana; Lim, Raymond S.; Blecua, Pedro; Higginson, Daniel S.; Towers, Russell; Jiang, Ruomu; Lee, William; Weigelt, Britta; Reis‐Filho, Jorge S.; Powell, Simon N.

doi:10.1002/path.4890

Cited by 46 publications

(48 citation statements)

References 73 publications

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“…In addition to genomic instability assessed by aCGH, various methods have been described to identify BRCAness , including gene expression, specific rearrangement signature, and RAD51 foci analysis by immunostaining . Currently, the concordance of mentioned methods is uncertain, and it is unclear which method most appropriately predicts the therapeutic response.…”

Section: Discussionmentioning

confidence: 99%

“…As RAD51 foci deficiency indicates that the tumor cells have lost the ability to repair DSB, RAD51 could be a good marker to guide treatment with PARP inhibitors. Biallelic alteration of HR genes was significantly associated with RAD51 foci deficiency ( P < .001), indicating that HR gene‐mutated breast tumors lost the ability to repair DSB. However, assay of RAD51 foci requires a primary cancer cell culture treated with radiation and other medications, which is difficult to undertake in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

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Using next‐generation sequencing to redefineBRCAnessin triple‐negative breast cancer

et al. 2020

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This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. AbstractBRCAness is considered a predictive biomarker to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors. However, recent trials showed that its predictive value was limited in triple-negative breast cancer (TNBC) treated with platinum. Moreover, tumors with mutations of DNA damage response (DDR) genes, such as homologous recombination (HR) genes, could be sensitive to platinum and PARP inhibitors. Thus, we aim to explore the relationship between mutation status of DDR genes and BRCAness in TNBC. We sequenced 56 DDR genes in 120 TNBC and identified BRCAness by array comparative genomic hybridization. The sequencing results showed that 13, 14, and 14 patients had BRCA, non-BRCA HR, and non-HR DDR gene mutations, respectively.Array comparative genomic hybridization revealed that BRCA-mutated and HR genemutated TNBC shared similar BRCAness features, both having higher numbers and longer length of large-scale structural aberration (LSA, >10 Mb) and similar altered chromosomal regions of LSA. These suggested non-BRCA HR gene-mutated TNBC shared similar characteristics with BRCA-mutated TNBC, indicating non-BRCA HR gene-mutated TNBC sensitive to platinum and PARP inhibitors. Among tumors with mutation of non-HR DDR genes, 3 PTEN and 1 MSH6 mutation also contained significant LSAs (BRCAness); however, they had different regions of genomic alteration to BRCA and HR gene-mutated tumors, might explain prior findings that PTEN-and MSH6-mutated cancer cells not sensitive to PARP inhibitors. Therefore, we hypothesize that the heterogeneous genomic background of BRCAness indicates different responsiveness to platinum and PARP inhibitors. Direct sequencing DDR genes in TNBC should be applied to predict their sensitivity toward platinum and PARP inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Using next‐generation sequencing to redefineBRCAnessin triple‐negative breast cancer

et al. 2020

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“…Homologous recombination repairs only an estimated 15% of DNA double-strand breaks, and in fact single-allele alterations in BRCA1/2 do not produce the genomic signatures associated with homologous recombination deficiency. 11,87 Correspondingly, emerging clinical data sets find that heterozygous germline BRCA1 and BRCA2 mutations show no increase in radiation toxicity. [17][18][19] Clinical data related to radiation toxicity for other germline heterozygous mutations are more scarce, though a recent study of a small series of patients with BRCA1/2 and non-BRCA1/2 hereditary breast cancer did not reveal an increased risk of radiation toxicity with hypofractionated whole-breast radiation.…”

Section: Brca1/2 Pathogenic Germline Variantsmentioning

confidence: 99%

The Implications of Genetic Testing on Radiation Therapy Decisions: A Guide for Radiation Oncologists

Bergom

West

Higginson

et al. 2019

International Journal of Radiation Oncology*Biology*Physics

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The advent of affordable and rapid next-generation DNA sequencing technology, along with the US Supreme Court ruling invalidating gene patents, has led to a deluge of germline and tumor genetic variant tests that are being rapidly incorporated into clinical cancer decision-making. A major concern for clinicians is whether the presence of germline mutations may increase the risk of radiation toxicity or secondary malignancies. Because scarce clinical data exist to inform decisions at this time, the American Society for Radiation Oncology convened a group of radiation science experts and clinicians to summarize potential issues, review relevant data, and provide guidance for adult patients and their care teams regarding the impact, if any, that genetic testing should have on radiation therapy recommendations. During the American Society for Radiation Oncology workshop, several main points emerged, which are discussed in this manuscript: (1) variants of uncertain significance should be considered nondeleterious until functional genomic data emerge to demonstrate otherwise; (2) possession of germline alterations in a single copy of a gene critical for radiation damage responses does not necessarily equate to increased risk of radiation-induced toxicity; (3) deleterious ataxiatelangiesctasia gene mutations may modestly increase second cancer risk after radiation therapy, and thus follow-up for these patients after indicated radiation therapy should include second cancer screening; (4) conveying to patients the difference between relative and absolute risk is critical to decision-making; and (5) more work is needed to assess the impact of tumor somatic alterations on the probability of response to radiation therapy and the potential for individualization of radiation doses. Data on radiosensitivity related to specific genetic mutations is also briefly discussed.

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“…Despite the success of PARPi monotherapy in gBRCA BC, appropriate biomarkers are still needed for selection of non-gBRCA patients for PARPi therapy (Gelmon et al, 2011;Mutter et al, 2017). Some proposed approaches include the use of mRNA expression signatures, the analysis of genomic scars derived from defective HRR, or the individual analysis of genetic alterations in HRR-related genes (Konstantinopoulos et al, 2010;Abkevich et al, 2012;Wagle et al, 2012;Watkins et al, 2014;Davies et al, 2017;Polak et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

A RAD 51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

Castroviejo-Bermejo¹,

et al. 2018

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Poly(ADP‐ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2‐related cancers. A test to identify additional HRR‐deficient tumors will help to extend their use in new indications. We evaluated the activity of the PARPi olaparib in patient‐derived tumor xenografts (PDXs) from breast cancer (BC) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD51 nuclear foci. In an independent BC PDX panel, the predictive capacity of the RAD51 score and the homologous recombination deficiency (HRD) score were compared. To examine the clinical feasibility of the RAD51 assay, we scored archival breast tumor samples, including PALB2‐related hereditary cancers. The RAD51 score was highly discriminative of PARPi sensitivity versus PARPi resistance in BC PDXs and outperformed the genomic test. In clinical samples, all PALB2‐related tumors were classified as HRR‐deficient by the RAD51 score. The functional biomarker RAD51 enables the identification of PARPi‐sensitive BC and broadens the population who may benefit from this therapy beyond BRCA1/2‐related cancers.

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Bi‐allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer

Cited by 46 publications

References 73 publications

Using next‐generation sequencing to redefineBRCAnessin triple‐negative breast cancer

Using next‐generation sequencing to redefineBRCAnessin triple‐negative breast cancer

The Implications of Genetic Testing on Radiation Therapy Decisions: A Guide for Radiation Oncologists

A RAD 51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

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