Scientific Publications

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14 Results

2018

Comprehensive Profiling of DNA Repair Defects in Breast Cancer Identifies a Novel Class of Endocrine Therapy Resistance Drivers

Anurag M, Punturi N, Hoog J, Bainbridge MN, Ellis MJ, Haricharan S.

Clin Cancer Res. 2018 Oct 1;24(19):4887-4899. doi: 10.1158/1078-0432.CCR-17-3702. Epub 2018 May 23. ABSTRACT Purpose: This study was undertaken to conduct a comprehensive investigation of the role of DNA damage repair (DDR) defects in poor outcome ER+ disease. Experimental Design: Expression and mutational status of DDR genes in ER+ breast tumors were correlated with proliferative response in neoadjuvant aromatase inhibitor therapy trials (discovery dataset), with outcomes in METABRIC, TCGA, and Loi datasets (validation datasets), and in patient-derived xenografts. A causal relationship between candidate DDR genes and endocrine treatment response, and the underlying mechanism, was then tested in ER+ breast cancer cell lines. Results: Correlations between loss of expression of three genes: CETN2 (P < 0.001) and ERCC1 (P = 0.01) from the nucleotide excision repair (NER) and NEIL2 (P = 0.04) from the base excision repair (BER) pathways were associated with endocrine treatment resistance in discovery dataset, and subsequently validated in independent patient cohorts. Complementary mutation analysis supported associations between mutations in NER and BER genes and reduced endocrine treatment response. A causal role for CETN2, NEIL2, and ERCC1 loss in intrinsic endocrine resistance was experimentally validated in ER+ breast cancer cell lines, and in ER+ patient-derived xenograft models. Loss of CETN2, NEIL2, or ERCC1 induced endocrine treatment resistance by dysregulating G1-S transition, and therefore, increased sensitivity to CDK4/6 inhibitors. A combined DDR signature score was developed that predicted poor outcome in multiple patient cohorts. Conclusions: This report identifies DDR defects as a new class of endocrine treatment resistance drivers and indicates new avenues for predicting efficacy of CDK4/6 inhibition in the adjuvant treatment setting. Clin Cancer Res; 24(19); 4887-99. ©2018 AACR. PMID:29793947 | PMC:PMC6822623 | DOI:10.1158/1078-0432.CCR-17-3702

May 26, 2018
Gene Discovery

Syndromic congenital myelofibrosis associated with a loss-of-function variant in RBSN

Magoulas PL, Shchelochkov OA, Bainbridge MN, Ben-Shachar S, Yatsenko S, Potocki L, Lewis RA, Searby C, Marcogliese AN, Elghetany MT, Zapata G, Hernández PP, Gadkari M, Einhaus D, Muzny DM, Gibbs RA, Bertuch AA, Scott DA, Corvera S, Franco LM.

Blood. 2018 Aug 9;132(6):658-662. doi: 10.1182/blood-2017-12-824433. Epub 2018 May 21. ABSTRACT Publisher’s Note: There is a Blood Commentary on this article in this issue. PMID:29784638 | PMC:PMC6085991 | DOI:10.1182/blood-2017-12-824433

May 23, 2018
Gene Discovery

2017

Molecular subtyping of tumors from patients with familial glioma

Ruiz VY, Praska CE, Armstrong G, Kollmeyer TM, Yamada S, Decker PA, Kosel ML, Eckel-Passow JE, Lachance DH, Bainbridge MN, Melin BS, Bondy ML, Jenkins RB; Gliogene Consortium.

Neuro Oncol. 2018 May 18;20(6):810-817. doi: 10.1093/neuonc/nox192. ABSTRACT BACKGROUND: Single-gene mutation syndromes account for some familial glioma (FG); however, they make up only a small fraction of glioma families. Gliomas can be classified into 3 major molecular subtypes based on isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion. We hypothesized that the prevalence of molecular subtypes might differ in familial versus sporadic gliomas and that tumors in the same family should have the same molecular subtype. METHODS: Participants in the FG study (Gliogene) provided samples for germline DNA analysis. Formalin-fixed, paraffin-embedded tumors were obtained from a subset of FG cases, and DNA was extracted. We analyzed tissue from 75 families, including 10 families containing a second affected family member. Copy number variation data were obtained using a first-generation Affymetrix molecular inversion probe (MIP) array. RESULTS: Samples from 62 of 75 (83%) FG cases could be classified into the 3 subtypes. The prevalence of the molecular subtypes was: 30 (48%) IDH-wildtype, 21 (34%) IDH-mutant non-codeleted, and 11 (19%) IDH-mutant and 1p/19q codeleted. This distribution of molecular subtypes was not statistically different from that of sporadic gliomas (P = 0.54). Of 10 paired FG samples, molecular subtypes were concordant for 7 (κ = 0.59): 3 IDH-mutant non-codeleted, 2 IDH-wildtype, and 2 IDH-mutant and 1p/19q codeleted gliomas. CONCLUSIONS: Our data suggest that within individual families, patients develop gliomas of the same molecular subtype. However, we did not observe differences in the prevalence of the molecular subtypes in FG compared with sporadic gliomas. These observations provide further insight into the distribution of molecular subtypes in FG. PMID:29040662 | PMC:PMC5961123 | DOI:10.1093/neuonc/nox192

October 18, 2017
Gene Discovery

Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle. 

Bainbridge MN, Cooney E, Miller M, Kennedy AD, Wulff JE, Donti T, Jhangiani SN, Gibbs RA, Elsea SH, Porter BE, Graham BH.

Mol Genet Metab. 2017 Aug;121(4):314-319. doi: 10.1016/j.ymgme.2017.06.009. Epub 2017 Jun 24. PMID: 28673551; PMCID: PMC7539367. Abstract Objective: To interrogate the metabolic profile of five subjects from three families with rare, nonsense and missense mutations in SLC13A5 and Early Infantile Epileptic Encephalopathies (EIEE) characterized by severe, neonatal onset seizures, psychomotor retardation and global developmental delay. Methods: Mass spectrometry of plasma, CSF and urine was used to identify consistently dysregulated analytes in our subjects. Results: Distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle (TCA) metabolism and may disrupt metabolic compartmentation in the brain. Significance: Our results indicate that analysis of plasma citrate and other TCA analytes in SLC13A5 deficient patients define a diagnostic metabolic signature that can aid in diagnosing children with this disease. PMID: 28673551 | PMCID: PMC7539367 | DOI: 10.1016/j.ymgme.2017.06.009

June 24, 2017
Gene Discovery

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