Somatic copy number changes in DPYD are associated with lower risk of recurrence in triple-negative breast cancers

Groß, Eva; Meul, Christina; Raab, S.O.; Propping, Corinna; Avril, Stephanie; Aubele, Michaela; Gkazepis, Apostolos; Schuster, Tibor; Grebenchtchikov, Nicolaï; Kiechle, Marion; Meijer, Judith; Vijzelaar, Raymon; Meindl, Alfons; Kuilenburg, André B. P.

doi:10.1038/bjc.2013.621

Cited by 11 publications

(7 citation statements)

References 42 publications

(55 reference statements)

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“…International databases such as the BIC database (Breast Cancer Information core: [ http://www.research.nhgri.nih.gov ]) were searched for these aberrations. BRCA1 copy number variations in mutation carriers were analysed by the MLPA-based P002-C1 test (MRC-Holland, Amsterdam, The Netherlands) as described previously [ 32 ].…”

Section: Methodsmentioning

confidence: 99%

Identification of BRCA1-like triple-negative breast cancers by quantitative multiplex-ligation-dependent probe amplification (MLPA) analysis of BRCA1-associated chromosomal regions: a validation study

Groß

Raab

et al. 2016

BMC Cancer

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BackgroundTriple-negative breast cancer (TNBC) with a BRCA1-like molecular signature has been demonstrated to remarkably respond to platinum-based chemotherapy and might be suited for a future treatment with poly(ADP-ribose)polymerase (PARP) inhibitors. In order to rapidly assess this signature we have previously developed a multiplex-ligation-dependent probe amplification (MLPA)-based assay. Here we present an independent validation of this assay to confirm its important clinical impact.MethodsOne-hundred-forty-four TNBC tumor specimens were analysed by the MLPA-based “BRCA1-like” test. Classification into BRCA1-like vs. non-BRCA1-like samples was performed by our formerly established nearest shrunken centroids classifier. Data were subsequently compared with the BRCA1-mutation/methylation status of the samples. T-lymphocyte infiltration and expression of the main target of PARP inhibitors, PARP1, were assessed on a subset of samples by immunohistochemistry. Data acquisition and interpretation was performed in a blinded manner.ResultsIn the studied TNBC cohort, 63 out of 144 (44 %) tumors were classified into the BRCA1-like category. Among these, the MLPA test correctly predicted 15 out of 18 (83 %) samples with a pathogenic BRCA1-mutation and 20 of 22 (91 %) samples exhibiting BRCA1-promoter methylation. Five false-negative samples were observed. We identified high lymphocyte infiltration as one possible basis for misclassification. However, two falsely classified BRCA1-mutated tumors were also characterized by rather non-BRCA1-associated histopathological features such as borderline ER expression. The BRCA1-like vs. non-BRCA1-like signature was specifically enriched in high-grade (G3) cancers (90 % vs. 58 %, p = 0.0004) and was also frequent in tumors with strong (3+) nuclear PARP1 expression (37 % vs. 16 %; p = 0.087).ConclusionsThis validation study confirmed the good performance of the initial MLPA assay which might thus serve as a valuable tool to select patients for platinum-based chemotherapy regimens. Moreover, frequent PARP1 upregulation in BRCA1-like tumors may also point to susceptibility to treatment with PARP inhibitors. Limitations are the requirement of high tumor content and high-quality DNA.

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Section: Methodsmentioning

confidence: 99%

Identification of BRCA1-like triple-negative breast cancers by quantitative multiplex-ligation-dependent probe amplification (MLPA) analysis of BRCA1-associated chromosomal regions: a validation study

Groß

Raab

et al. 2016

BMC Cancer

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“…Moreover, cancer cell lines may increase expression of drug metabolism genes active against administered therapies [ 26 ]. As a specific example for a commonly administered chemotherapy, the efficacy of 5-florouracil (5-FU) has been shown to be diminished by activation of the gene DPD, which degrades 5-FU [ 27 ], by altered expression levels of export genes [ 28 ], or by inhibited expression of metabolically activating enzymes [ 29 ], while greater efficacy is observed with genomic deletions of DPD [ 30 ]. Thus, the systematic integration of PK knowledge, which we defined as the known relationships between genes and therapies, into the interpretation of individual patient’s tumor genomics may improve IM in oncology.…”

Section: Introductionmentioning

confidence: 99%

The impact of pharmacokinetic gene profiles across human cancers

2018

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BackgroundThe right drug to the right patient at the right time is one of the ideals of Individualized Medicine (IM) and remains one of the most compelling promises of the post-genomic age. The addition of genomic information is expected to increase the precision of an individual patient’s treatment, resulting in improved outcomes. While pilot studies have been encouraging, key aspects of interpreting tumor genomics information, such as somatic activation of drug transport or metabolism, have not been systematically evaluated.MethodsIn this work, we developed a simple rule-based approach to classify the therapies administered to each patient from The Cancer Genome Atlas PanCancer dataset (n = 2858) as effective or ineffective. Our Therapy Efficacy model used each patient’s drug target and pharmacokinetic (PK) gene expression profile; the specific genes considered for each patient depended on the therapies they received. Patients who received predictably ineffective therapies were considered at high-risk of cancer-related mortality and those who did not receive ineffective therapies were considered at low-risk. The utility of our Therapy Efficacy model was assessed using per-cancer and pan-cancer differential survival.ResultsOur simple rule-based Therapy Efficacy model classified 143 (5%) patients as high-risk. High-risk patients had age ranges comparable to low-risk patients of the same cancer type and tended to be later stage and higher grade (odds ratios of 1.6 and 1.4, respectively). A significant pan-cancer association was identified between predictions of our Therapy Efficacy model and poorer overall survival (hazard ratio, HR = 1.47, p = 6.3 × 10− 3). Individually, drug export (HR = 1.49, p = 4.70 × 10− 3) and drug metabolism (HR = 1.73, p = 9.30 × 10− 5) genes demonstrated significant survival associations. Survival associations for target gene expression are mechanism-dependent. Similar results were observed for event-free survival.ConclusionsWhile the resolution of clinical information within the dataset is not ideal, and modeling the relative contribution of each gene to the activity of each therapy remains a challenge, our approach demonstrates that somatic PK alterations should be integrated into the interpretation of somatic transcriptomic profiles as they likely have a significant impact on the survival of specific patients. We believe that this approach will aid the prospective design of personalized therapeutic strategies.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4345-2) contains supplementary material, which is available to authorized users.

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“…This notable response was of particular interest as his cancer was resistant to other standard treatments. In support of the hypothesis that the somatic DPYD loss may contribute to 5-FU response, another study that conducted a retrospective analysis of triple-negative breast cancer patients revealed patients with somatic DPYD copy-number variants (CNVs) demonstrated a trend for a longer time to progression on 5-FU (Gross et al 2013). Unfortunately, the patient relapsed within 3 wk of ending 5-FU therapy and was subsequently reinitiated on oral 5-FU, capecitabine, but did not respond.…”

Section: Discussionmentioning

confidence: 95%

Fluorouracil sensitivity in a head and neck squamous cell carcinoma with a somatic DPYD structural variant

Majounie¹,

Wee²,

Williamson³

et al. 2019

Cold Spring Harb Mol Case Stud

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Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and represents a heterogeneous group of tumors, the majority of which are treated with a combination of surgery, radiation, and chemotherapy. Fluoropyrimidine (5-FU) and its oral prodrug, capecitabine, are commonly prescribed treatments for several solid tumor types including HNSCC. 5-FU-associated toxicity is observed in ∼30% of treated patients and is largely caused by germline polymorphisms in DPYD, which encodes dihydropyrimidine dehydrogenase, a key enzyme of 5-FU catabolism and deactivation. Although the association of germline DPYD alterations with toxicity is well-described, the potential contribution of somatic DPYD alterations to 5-FU sensitivity has not been explored. In a patient with metastatic HNSCC, in-depth genomic and transcriptomic integrative analysis on a biopsy from a metastatic neck lesion revealed alterations in genes that are associated with 5-FU uptake and metabolism. These included a novel somatic structural variant resulting in a partial deletion affecting DPYD, a variant of unknown significance affecting SLC29A1, and homozygous deletion of MTAP. There was no evidence of deleterious germline polymorphisms that have been associated with 5-FU toxicity, indicating a potential vulnerability of the tumor to 5-FU therapy. The discovery of the novel DPYD variant led to the initiation of 5-FU treatment that resulted in a rapid response lasting 17 wk, with subsequent relapse due to unknown resistance mechanisms. This suggests that somatic alterations present in this tumor may serve as markers for tumor sensitivity to 5-FU, aiding in the selection of personalized treatment strategies.

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Somatic copy number changes in DPYD are associated with lower risk of recurrence in triple-negative breast cancers

Cited by 11 publications

References 42 publications

Identification of BRCA1-like triple-negative breast cancers by quantitative multiplex-ligation-dependent probe amplification (MLPA) analysis of BRCA1-associated chromosomal regions: a validation study

Identification of BRCA1-like triple-negative breast cancers by quantitative multiplex-ligation-dependent probe amplification (MLPA) analysis of BRCA1-associated chromosomal regions: a validation study

The impact of pharmacokinetic gene profiles across human cancers

Fluorouracil sensitivity in a head and neck squamous cell carcinoma with a somatic DPYD structural variant

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