Robert B Jenkins

Publications (108)801.05 Total impact

• Article: Impact of PTEN Protein Expression on Benefit From Adjuvant Trastuzumab in Early-Stage Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in the North Central Cancer Treatment Group N9831 Trial.

  Edith A Perez, Amylou C Dueck, Ann E McCullough, Beiyun Chen, Xochiquetzal J Geiger, Robert B Jenkins, Wilma L Lingle, Nancy E Davidson, Silvana Martino, Peter A Kaufman, Leila A Kutteh, George W Sledge, Lyndsay N Harris, Julie R Gralow, Monica M Reinholz
  [show abstract] [hide abstract]
  ABSTRACT: PURPOSEIt has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) -positive trial-North Central Cancer Treatment Group (NCCTG) N9831. PATIENTS AND METHODS The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years.ResultsOf 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ(2) P < .001) and nodal positivity (χ(2) P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47). CONCLUSION In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.
  Journal of Clinical Oncology 05/2013; · 18.37 Impact Factor
• Article: RC0639: phase II study of paclitaxel, trastuzumab, and lapatinib as adjuvant therapy for early stage HER2-positive breast cancer.

  Alvaro Moreno-Aspitia, Amylou C Dueck, Ismael Ghanem-Cañete, Tejal Patel, Shaker Dakhil, David Johnson, Sandra Franco, Stephen Kahanic, Gerardo Colon-Otero, Kathleen S Tenner, Richard Rodeheffer, Ann E McCullough, Robert B Jenkins, Frances M Palmieri, Donald Northfelt, Edith A Perez
  [show abstract] [hide abstract]
  ABSTRACT: Lapatinib adds to the efficacy of trastuzumab in preclinical models and also in the neo-adjuvant setting. This study assesses the safety and feasibility of adding lapatinib to paclitaxel and trastuzumab (THL) as part of the adjuvant therapy for HER2-positive breast cancer (HER2+ BC). In this single-arm phase II study, patients with stages I-III HER2+ BC received standard anthracycline-based chemotherapy followed by weekly taxane, with concurrent standard trastuzumab, plus daily lapatinib for a total of 12 months. The primary endpoint was symptomatic congestive heart failure, secondary endpoints included overall safety. A total of 109 eligible patients were enrolled. Median follow-up is 4.3 years. No patients experienced congestive heart failure while on treatment. Mean left ventricular ejection fraction at baseline and at the end of THL were 63.6 % (N = 109, SD = 5.7) and 59.8 % (N = 98, SD = 8.1), respectively [mean change -3.95 % (N = 98, SD = 8.3), p < 0.001]. One hundred and two patients initiated post-AC treatment; of them, 31 % experienced grade 3 (no G4) diarrhea with lapatinib at 750 mg/day. The addition of lapatinib to paclitaxel and trastuzumab following AC does not add cardiac toxicity. Lapatinib dose of 750 mg/day in combination with standard chemotherapy plus trastuzumab has acceptable overall tolerability.
  Breast Cancer Research and Treatment 03/2013; · 4.43 Impact Factor
• Article: Comparison of Fluorescence In Situ Hybridization (FISH) and Dual-ISH (DISH) in the Determination of HER2 Status in Breast Cancer.

  Aaron S Mansfield, William R Sukov, Jeanette E Eckel-Passow, Yuta Sakai, Frank J Walsh, Melissa Lonzo, Anne E Wiktor, Ahmet Dogan, Robert B Jenkins
  [show abstract] [hide abstract]
  ABSTRACT: The determination of HER2 amplification is critical to selecting appropriate patients for HER2 targeted therapy in breast cancer. Dual in situ hybridization (DISH), an alternative to fluorescence in situ hybridization (FISH) and immunohistochemistry, is now available. To compare the FISH and DISH methods, we tested 251 samples enriched for common or difficult-to-assess HER2 anomalies. Seven samples failed DISH testing. There was a 64% (156/244) concordance between FISH and DISH by anomaly (κ = 0.58, 95% confidence interval, 0.51-0.65; P < .0001) and an 83% (203/244) concordance by amplification status (κ = 0.58; 95% confidence interval, 0.47-0.69; P < .0001). DISH resulted in lower estimates of HER2/ centromere 17 ratios than FISH, and many cases that were equivocal with FISH were normal with DISH. DISH did not detect any case with coamplification of HER2 and centromere 17. Using a cohort of difficult specimens, we observed less than 95% concordance between FISH and DISH. DISH may underestimate the HER2/chromosome 17 ratio, or FISH may overestimate this ratio.
  American Journal of Clinical Pathology 02/2013; 139(2):144-50. · 2.60 Impact Factor
• Article: Immunohistochemistry and fluorescence in situ hybridization assessment of HER2 in clinical trials of adjuvant therapy for breast cancer (NCCTG N9831, BCIRG 006, and BCIRG 005).

  Edith A Perez, Michael F Press, Amylou C Dueck, Robert B Jenkins, Chungyeul Kim, Beiyun Chen, Ivonne Villalobos, Soonmyung Paik, Marc Buyse, Anne E Wiktor, Reid Meyer, Melanie Finnigan, Joanne Zujewski, Mona Shing, Howard M Stern, Wilma L Lingle, Monica M Reinholz, Dennis J Slamon
  [show abstract] [hide abstract]
  ABSTRACT: A comprehensive, blinded, pathology evaluation of HER2 testing in HER2-positive/negative breast cancers was performed among three central laboratories. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses were performed on 389 tumor blocks from three large adjuvant trials: N9831, BCIRG-006, and BCIRG-005. In 123 cases, multiple blocks were examined. HER2 status was defined according to FDA-approved guidelines and was independently re-assessed at each site. Discordant cases were adjudicated at an on-site, face-to-face meeting. Results across three independent pathologists were concordant by IHC in 351/381 (92 %) and FISH in 343/373 (92 %) blocks. Upon adjudication, consensus was reached on 16/30 and 18/30 of discordant IHC and FISH cases, respectively, resulting in overall concordance rates of 96 and 97 %. Among 155 HER2-negative blocks, HER2 status was confirmed in 153 (99 %). In the subset of 102 HER2-positive patients from N9831/BCIRG-006, primary blocks from discordant cases were selected, especially those with discordant test between local and central laboratories. HER2 status was confirmed in 73 (72 %) of these cases. Among 118 and 113 cases with IHC and FISH results and >1 block evaluable, block-to-block variability/heterogeneity in HER2 results was seen in 10 and 5 %, respectively. IHC-/FISH- was confirmed for 57/59 (97 %) primary blocks from N9831 (locally positive, but centrally negative); however, 5/22 (23 %) secondary blocks showed HER2 positivity. Among 53 N9831 patients with HER2-normal disease adjudicated as IHC-/FISH-(although locally positive), there was a non-statistically significant improvement in disease-free survival with concurrent trastuzumab compared to chemotherapy alone (adjusted hazard ratio 0.34; 95 % CI, 0.11-1.05; p = 0.06). There were similar agreements for IHC and FISH among pathologists (92 % each). Agreement was improved at adjudication (96 %). HER2 tumor heterogeneity appears to partially explain discordant results in cases initially tested as positive and subsequently called negative.
  Breast Cancer Research and Treatment 02/2013; 138(1):99-108. · 4.43 Impact Factor
• Article: Inherited variant on chromosome 11q23 increases susceptibility to IDH-mutated but not IDH-normal gliomas regardless of grade or histology.

  Terri Rice, Shichun Zheng, Paul A Decker, Kyle M Walsh, Paige Bracci, Yuanyuan Xiao, Lucie S McCoy, Ivan Smirnov, Joseph S Patoka, Helen M Hansen, [......], Matthew L Kosel, Brooke L Fridley, Daniel H Lachance, Jeanette E Eckel-Passow, Hugues Sicotte, Brian Patrick O'Neill, Caterina Giannini, John K Wiencke, Robert B Jenkins, Margaret R Wrensch
  [show abstract] [hide abstract]
  ABSTRACT: IntroductionRecent discoveries of inherited glioma risk loci and acquired IDH mutations are providing new insights into glioma etiology. IDH mutations are common in lower grade gliomas and secondary glioblastomas and uncommon in primary glioblastomas. Because the inherited variant in 11q23 has been associated with risk of lower grade glioma and not with glioblastomas, we hypothesized that this variant increases susceptibility to IDH-mutated gliomas, but not to IDH-wild-type gliomas.Methods We tested this hypothesis in patients with glioma and controls from the San Francisco Adult Glioma Study, the Mayo Clinic, and Illumina controls (1102 total patients, 5299 total controls). Case-control additive associations of 11q23 risk alleles (rs498872, T allele) were calculated using logistic regression, stratified by tumor IDH status (mutated or wild-type) and by histology and grade. We also adjusted for the recently discovered 8q24 glioma risk locus rs55705857 G allele.ResultsThe 11q23 glioma risk locus was associated with increased risk of IDH-mutated gliomas of all histologies and grades (odds ratio [OR] = 1.50; 95% confidence interval [CI] = 1.29-1.74; P = 1.3X10(-7)) but not with IDH-wild-type gliomas of any histology or grade (OR = 0.91; 95% CI = 0.81-1.03; P = 0.14). The associations were independent of the rs55705857 G allele.ConclusionA variant at the 11q23 locus increases risk for IDH-mutated but not IDH-wild-type gliomas, regardless of grade or histology.
  Neuro-Oncology 01/2013; · 5.72 Impact Factor
• Article: Clinical significance and novel mechanism of action of kallikrein 6 in glioblastoma.

  Kristen L Drucker, Alex R Paulsen, Caterina Giannini, Paul A Decker, Sachiko I Blaber, Michael Blaber, Joon H Uhm, Brian P O'Neill, Robert B Jenkins, Isobel A Scarisbrick
  [show abstract] [hide abstract]
  ABSTRACT: Background Kallikreins have prognostic value in specific malignancies, but few studies have addressed their clinical significance to glioblastoma multiforme (GBM). Kallikrein 6 (KLK6) is of potential high relevance to GBM, since it is upregulated at sites of CNS pathology and linked to reactive astrogliosis. Here we examine the clinical value of KLK6 as a prognostic indicator of GBM patient survival and its activity in promoting resistance to cytotoxic agents.Methods The association between patient survival and levels of KLK6 immunoreactivity were investigated in 60 grade IV astrocytoma tumor specimens. Levels of KLK6 RNA were also evaluated in a separate set of GBM patient tumors (n = 23). Recombinant KLK6 or enforced KLK6 overexpression in GBM cell lines was used to evaluate effects on astrocytoma cell survival.ResultsA range of KLK6 expression was observed across grade IV tumors, with higher levels a poor prognostic indicator of patient survival (P = .02) even after adjusting for gender and Eastern Cooperative Oncology Group performance scores (P = .01). KLK6 reduced the sensitivity of GBM cell lines to cytotoxic agents, including staurosporine and cisplatin, and to the current standard of patient care: radiotherapy or temozolomide alone or in combination. The ability of KLK6 to promote resistance to apoptosis was dependent on activation of the thrombin receptor, protease activated receptor 1.Conclusions Taken together, these results indicate that elevated levels of KLK6 in GBM are likely to promote the resistance of tumor cells to cytotoxic agents and are an indicator of reduced patient postsurgical survival times.
  Neuro-Oncology 01/2013; · 5.72 Impact Factor
• Article: Description of selected characteristics of familial glioma patients - Results from the Gliogene Consortium.

  Siegal Sadetzki, Revital Bruchim, Bernice Oberman, Georgina N Armstrong, Ching C Lau, Elizabeth B Claus, Jill S Barnholtz-Sloan, Dora Il'yasova, Joellen Schildkraut, Christoffer Johansen, [......], Robert B Jenkins, Daniel Lachance, Nicholas A Vick, Ryan Merrell, Margaret Wrensch, Faith G Davis, Bridget J McCarthy, Rose Lai, Beatrice S Melin, Melissa L Bondy
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND: While certain inherited syndromes (e.g. Neurofibromatosis or Li-Fraumeni) are associated with an increased risk of glioma, most familial gliomas are non-syndromic. This study describes the demographic and clinical characteristics of the largest series of non-syndromic glioma families ascertained from 14 centres in the United States (US), Europe and Israel as part of the Gliogene Consortium. METHODS: Families with 2 or more verified gliomas were recruited between January 2007 and February 2011. Distributions of demographic characteristics and clinical variables of gliomas in the families were described based on information derived from personal questionnaires. FINDINGS: The study population comprised 841 glioma patients identified in 376 families (9797 individuals). There were more cases of glioma among males, with a male to female ratio of 1.25. In most families (83%), 2 gliomas were reported, with 3 and 4 gliomas in 13% and 3% of the families, respectively. For families with 2 gliomas, 57% were among 1st-degree relatives, and 31.5% among 2nd-degree relatives. Overall, the mean (±standard deviation [SD]) diagnosis age was 49.4 (±18.7) years. In 48% of families with 2 gliomas, at least one was diagnosed at <40y, and in 12% both were diagnosed under 40y of age. Most of these families (76%) had at least one grade IV glioblastoma multiforme (GBM), and in 32% both cases were grade IV gliomas. The most common glioma subtype was GBM (55%), followed by anaplastic astrocytoma (10%) and oligodendroglioma (8%). Individuals with grades I-II were on average 17y younger than those with grades III-IV. INTERPRETATION: Familial glioma cases are similar to sporadic cases in terms of gender distribution, age, morphology and grade. Most familial gliomas appear to comprise clusters of two cases suggesting low penetrance, and that the risk of developing additional gliomas is probably low. These results should be useful in the counselling and clinical management of individuals with a family history of glioma.
  European journal of cancer (Oxford, England: 1990) 01/2013; · 4.12 Impact Factor
• Article: Analysis of 60 Reported Glioma Risk SNPs Replicates Published GWAS Findings but Fails to Replicate Associations From Published Candidate-Gene Studies.

  Kyle M Walsh, Erik Anderson, Helen M Hansen, Paul A Decker, Matt L Kosel, Thomas Kollmeyer, Terri Rice, Shichun Zheng, Yuanyuan Xiao, Jeffrey S Chang, [......], Paige M Bracci, Joe L Wiemels, Alexander R Pico, Ivan Smirnov, Daniel H Lachance, Hugues Sicotte, Jeanette E Eckel-Passow, John K Wiencke, Robert B Jenkins, Margaret R Wrensch
  [show abstract] [hide abstract]
  ABSTRACT: Genomewide association studies (GWAS) and candidate-gene studies have implicated single-nucleotide polymorphisms (SNPs) in at least 45 different genes as putative glioma risk factors. Attempts to validate these associations have yielded variable results and few genetic risk factors have been consistently replicated. We conducted a case-control study of Caucasian glioma cases and controls from the University of California San Francisco (810 cases, 512 controls) and the Mayo Clinic (852 cases, 789 controls) in an attempt to replicate previously reported genetic risk factors for glioma. Sixty SNPs selected from the literature (eight from GWAS and 52 from candidate-gene studies) were successfully genotyped on an Illumina custom genotyping panel. Eight SNPs in/near seven different genes (TERT, EGFR, CCDC26, CDKN2A, PHLDB1, RTEL1, TP53) were significantly associated with glioma risk in the combined dataset (P < 0.05), with all associations in the same direction as in previous reports. Several SNP associations showed considerable differences across histologic subtype. All eight successfully replicated associations were first identified by GWAS, although none of the putative risk SNPs from candidate-gene studies was associated in the full case-control sample (all P values > 0.05). Although several confirmed associations are located near genes long known to be involved in gliomagenesis (e.g., EGFR, CDKN2A, TP53), these associations were first discovered by the GWAS approach and are in noncoding regions. These results highlight that the deficiencies of the candidate-gene approach lay in selecting both appropriate genes and relevant SNPs within these genes.
  Genetic Epidemiology 12/2012; · 3.44 Impact Factor
• Article: Adverse Prognostic Impact of Intratumor Heterogeneous HER2 Gene Amplification in Patients With Esophageal Adenocarcinoma.

  Harry H Yoon, Qian Shi, William R Sukov, Mark A Lewis, Christopher A Sattler, Anne E Wiktor, Tsung-Teh Wu, Robert B Diasio, Robert B Jenkins, Frank A Sinicrope
  [show abstract] [hide abstract]
  ABSTRACT: PURPOSEThere is increasing recognition of the existence of intratumoral heterogeneity of the human epidermal growth factor receptor (HER2), which affects interpretation of HER2 positivity in clinical practice and may have implications for patient prognosis and treatment. We determined the frequency and prognostic impact of heterogeneous HER2 gene amplification and polysomy 17 in patients with esophageal adenocarcinoma (EAC). PATIENTS AND METHODSHER2 amplification (by fluorescence in situ hybridization) was examined in surgical EAC specimens (n = 675). HER2 heterogeneity was defined according to consensus guidelines as gene amplification (HER2/CEP17 ratio ≥ 2.0) in more than 5% but less than 50% of cancer cells. No patient received neoadjuvant or HER2-targeted therapy. Cox models were used to assess disease-specific survival (DSS) and overall survival (OS).ResultsOverall, 117 EACs (17%) demonstrated HER2 amplification, of which 20 (17%) showed HER2 heterogeneity. All HER2-heterogeneous tumors were amplified. Among HER2-amplified tumors, heterogeneous tumors had significantly higher frequency of poor histologic grade and polysomy 17. In multivariable models that included number of metastatic lymph nodes, grade, tumor stage, and polysomy 17, only HER2 heterogeneity and node number were prognostic among HER2-amplified tumors, with heterogeneity showing worse DSS (hazard ratio, 2.04; 95% CI, 1.09 to 3.79; P = .025) and OS (P = .026). Among HER2-nonamplified EACs, polysomy 17 was independently associated with worse DSS (P = .012) and OS (P = .023). CONCLUSION Among HER2-amplified EACs, 17% show HER2 heterogeneity, which independently predicts for worse cancer-specific death. Among HER2-nonamplified EACs, polysomy 17 is independently associated with worse survival. These novel findings demonstrate aggressive subgroups in HER2-amplified and -nonamplified EACs that have important implications for HER2 analysis and determination of benefit from HER2-targeted therapy.
  Journal of Clinical Oncology 09/2012; · 18.37 Impact Factor
• Article: A variable age of onset segregation model for linkage analysis, with correction for ascertainment, applied to glioma.

  Xiangqing Sun, Jaime Vengoechea, Robert Elston, Yanwen Chen, Christopher I Amos, Georgina Armstrong, Jonine L Bernstein, Elizabeth B Claus, Faith Davis, Richard S Houlston, [......], Joellen M Schildkraut, Sanjay S Shete, Robert Yu, Nicholas A Vick, Ryan Merrell, Margaret R Wrensch, Ping Yang, Beatrice Melin, Melissa L Bondy, Jill S Barnholtz-Sloan
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND: We propose a two-step model-based approach, with correction for ascertainment, to linkage analysis of a binary trait with variable age of onset and apply it to a set of multiplex pedigrees segregating for adult glioma. METHODS: First, we fit segregation models by formulating the likelihood for a person to have a bivariate phenotype, affection status and age of onset, along with other covariates, and from these we estimate population trait allele frequencies and penetrance parameters as a function of age (N=281 multiplex glioma pedigrees). Second, the best fitting models are used as trait models in multipoint linkage analysis (N=74 informative multiplex glioma pedigrees). To correct for ascertainment, a prevalence constraint is used in the likelihood of the segregation models for all 281 pedigrees. Then the trait allele frequencies are re-estimated for the pedigree founders of the subset of 74 pedigrees chosen for linkage analysis. RESULTS: Using the best fitting segregation models in model-based multipoint linkage analysis, we identified two separate peaks on chromosome 17; the first agreed with a region identified by Shete et al. (1) who used model-free affected-only linkage analysis, but with a narrowed peak: and the second agreed with a second region they found but had a larger maximum LOD. Conclusions/Impact: Our approach has the advantage of not requiring markers to be in linkage equilibrium unless the minor allele frequency is small (markers which tend to be uninformative for linkage), and of using more of the available information for LOD-based linkage analysis.
  Cancer Epidemiology Biomarkers &amp Prevention 09/2012; · 4.12 Impact Factor
• Article: A low-frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation.

  Robert B Jenkins, Yuanyuan Xiao, Hugues Sicotte, Paul A Decker, Thomas M Kollmeyer, Helen M Hansen, Matthew L Kosel, Shichun Zheng, Kyle M Walsh, Terri Rice, [......], Chandralekha Halder, Amanda L Rynearson, Brooke L Fridley, Jan C Buckner, Brian P O'Neill, Caterina Giannini, Daniel H Lachance, John K Wiencke, Jeanette E Eckel-Passow, Margaret R Wrensch
  [show abstract] [hide abstract]
  ABSTRACT: Variants at 8q24.21 have been shown to be associated with glioma development. By means of tag SNP genotyping and imputation, pooled next-generation sequencing using long-range PCR and subsequent validation SNP genotyping, we identified seven low-frequency SNPs at 8q24.21 that were strongly associated with glioma risk (P = 1 × 10(-25) to 1 × 10(-14)). The most strongly associated SNP, rs55705857, remained highly significant after individual adjustment for the other top six SNPs and two previously published SNPs. After stratifying by histological and tumor genetic subtype, the most significant associations of rs55705857 were with oligodendroglial tumors and gliomas with mutant IDH1 or IDH2 (odds ratio (OR) = 5.1, P = 1.1 × 10(-31) and OR = 4.8, P = 6.6 × 10(-22), respectively). Strong associations were observed for astrocytomas with mutated IDH1 or IDH2 (grades 2-4) (OR = 5.16-6.66, P = 4.7 × 10(-12) to 2.2 × 10(-8)) but not for astrocytomas with wild-type IDH1 and IDH2 (smallest P = 0.26). The conserved sequence block that includes rs55705857 is consistently modeled as a microRNA.
  Nature Genetics 08/2012; 44(10):1122-5. · 35.53 Impact Factor
• Article: p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells.

  Ling Cen, Brett L Carlson, Mark A Schroeder, Jamie L Ostrem, Gaspar J Kitange, Ann C Mladek, Stephanie R Fink, Paul A Decker, Wenting Wu, Jung-Sik Kim, Todd Waldman, Robert B Jenkins, Jann N Sarkaria
  [show abstract] [hide abstract]
  ABSTRACT: Deregulation of the p16(INK4a)-Cdk4/6-Rb pathway is commonly detected in patients with glioblastoma multiforme (GBM) and is a rational therapeutic target. Here, we characterized the p16(INK4a)-Cdk4/6-Rb pathway in the Mayo panel of GBM xenografts, established from primary tissue samples from patients with GBM, and evaluated their response to PD0332991, a specific inhibitor of Cdk4/6. All GBM xenograft lines evaluated in this study had disruptions in the p16(INK4a)-Cdk4/6-Rb pathway. In vitro evaluation using short-term explant cultures from selected GBM xenograft lines showed that PD0332991 effectively arrested cell cycle in G1-phase and inhibited cell proliferation dose-dependently in lines deleted for CDKN2A/B-p16(INK4a) and either single-copy deletion of CDK4 (GBM22), high-level CDK6 amplification (GBM34), or deletion of CDKN2C/p18(INK4c) (GBM43). In contrast, 2 GBM lines with p16(INK4a) expression and either CDK4 amplification (GBM5) or RB mutation (GBM28) were completely resistant to PD0332991. Additional xenograft lines were screened, and GBM63 was identified to have p16(INK4a) expression and CDK4 amplification. Similar to the results with GBM5, GBM63 was resistant to PD0332991 treatment. In an orthotopic survival model, treatment of GBM6 xenografts (CDKN2A/B-deleted and CDK4 wild-type) with PD0332991 significantly suppressed tumor cell proliferation and prolonged survival. Collectively, these data support the concept that GBM tumors lacking p16(INK4a) expression and with nonamplified CDK4 and wild-type RB status may be more susceptible to Cdk4/6 inhibition using PD0332991.
  Neuro-Oncology 06/2012; 14(7):870-81. · 5.72 Impact Factor
• Article: Insight in glioma susceptibility through an analysis of 6p22.3, 12p13.33-12.1, 17q22-23.2 and 18q23 SNP genotypes in familial and non-familial glioma.

  Yanhong Liu, Beatrice S Melin, Preetha Rajaraman, Zhaoming Wang, Martha Linet, Sanjay Shete, Christopher I Amos, Ching C Lau, Michael E Scheurer, Spiridon Tsavachidis, [......], Robert B Jenkins, Daniel LaChance, Nicholas A Vick, Margaret Wrensch, Faith Davis, Bridget J McCarthy, Ulrika Andersson, Patricia A Thompson, Stephen Chanock, Melissa L Bondy
  [show abstract] [hide abstract]
  ABSTRACT: The risk of glioma has consistently been shown to be increased twofold in relatives of patients with primary brain tumors (PBT). A recent genome-wide linkage study of glioma families provided evidence for a disease locus on 17q12-21.32, with the possibility of four additional risk loci at 6p22.3, 12p13.33-12.1, 17q22-23.2, and 18q23. To identify the underlying genetic variants responsible for the linkage signals, we compared the genotype frequencies of 5,122 SNPs mapping to these five regions in 88 glioma cases with and 1,100 cases without a family history of PBT (discovery study). An additional series of 84 familial and 903 non-familial cases were used to replicate associations. In the discovery study, 12 SNPs showed significant associations with family history of PBT (P < 0.001). In the replication study, two of the 12 SNPs were confirmed: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.031) and 17q12-21.32 SPOP rs650461 (P = 0.025). In the combined analysis of discovery and replication studies, the strongest associations were attained at four SNPs: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.0001), SOX5 rs7305773 (P = 0.0001) and STKY1 rs2418087 (P = 0.0003), and 17q12-21.32 SPOP rs6504618 (P = 0.0006). Further, a significant gene-dosage effect was found for increased risk of family history of PBT with these four SNPs in the combined data set (P(trend) <1.0 × 10(-8)). The results support the linkage finding that some loci in the 12p13.33-12.1 and 17q12-q21.32 may contribute to gliomagenesis and suggest potential target genes underscoring linkage signals.
  Human Genetics 06/2012; 131(9):1507-17. · 5.07 Impact Factor
• Article: A cytogenetic analysis of 2 cases of phosphaturic mesenchymal tumor of mixed connective tissue type.

  Rondell P Graham, Jennelle C Hodge, Andrew L Folpe, Andre M Oliveira, Kevin J Meyer, Robert B Jenkins, Franklin H Sim, William R Sukov
  [show abstract] [hide abstract]
  ABSTRACT: Phosphaturic mesenchymal tumor of mixed connective tissue type is a rare, histologically distinctive mesenchymal neoplasm associated with tumor-induced osteomalacia resulting from production of the phosphaturic hormone fibroblast growth factor 23. Because of its rarity, specific genetic alterations that contribute to the pathogenesis of these tumors have yet to be elucidated. Herein, we report the abnormal karyotypes from 2 cases of confirmed phosphaturic mesenchymal tumor of mixed connective tissue type. G-banded analysis demonstrated the first tumor to have a karyotype of 46,Y,t(X;3;14)(q13;p25;q21)[15]/46XY[5], and the second tumor to have a karyotype of 46, XY,add(2)(q31),add(4)(q31.1)[2]/92,slx2[3]/46,sl,der(2)t(2;4)(q14.2;p14),der(4)t(2;4)(q14.2;p14),add(4)(q31.1)[10]/46,sdl,add(13)(q34)[4]/92,sdl2x2[1]. These represent what is, to our knowledge, the first examples of abnormal karyotypes obtained from phosphaturic mesenchymal tumor of mixed connective tissue type.
  Human pathology 04/2012; 43(8):1334-8. · 3.03 Impact Factor
• Article: SSBP2 variants are associated with survival in glioblastoma patients.

  Yuanyuan Xiao, Paul A Decker, Terri Rice, Lucie S McCoy, Ivan Smirnov, Joseph S Patoka, Helen M Hansen, Joe L Wiemels, Tarik Tihan, Michael D Prados, [......], Reid C Thompson, Louis Burt Nabors, Jeffrey J Olson, Steve Brem, Melissa H Madden, James E Browning, John K Wiencke, Kathleen M Egan, Robert B Jenkins, Margaret R Wrensch
  [show abstract] [hide abstract]
  ABSTRACT: Glioblastoma is a devastating, incurable disease with few known prognostic factors. Here, we present the first genome-wide survival and validation study for glioblastoma. Cox regressions for survival with 314,635 inherited autosomal single-nucleotide polymorphisms (SNP) among 315 San Francisco Adult Glioma Study patients for discovery and three independent validation data sets [87 Mayo Clinic, 232 glioma patients recruited from several medical centers in Southeastern United States (GliomaSE), and 115 The Cancer Genome Atlas patients] were used to identify SNPs associated with overall survival for Caucasian glioblastoma patients treated with the current standard of care, resection, radiation, and temozolomide (total n = 749). Tumor expression of the gene that contained the identified prognostic SNP was examined in three separate data sets (total n = 619). Genotype imputation was used to estimate hazard ratios (HR) for SNPs that had not been directly genotyped. From the discovery and validation analyses, we identified a variant in single-stranded DNA-binding protein 2 (SSBP2) on 5q14.1 associated with overall survival in combined analyses (HR, 1.64; P = 1.3 × 10(-6)). Expression of SSBP2 in tumors from three independent data sets also was significantly related to patient survival (P = 5.3 × 10(-4)). Using genotype imputation, the SSBP2 SNP rs17296479 had the strongest statistically significant genome-wide association with poorer overall patient survival (HR, 1.79; 95% CI, 1.45-2.22; P = 1.0 × 10(-7)). The minor allele of SSBP2 SNP rs17296479 and the increased tumor expression of SSBP2 were statistically significantly associated with poorer overall survival among glioblastoma patients. With further confirmation, previously unrecognized inherited variations influencing survival may warrant inclusion in clinical trials to improve randomization. Unaccounted for genetic influence on survival could produce unwanted bias in such studies.
  Clinical Cancer Research 04/2012; 18(11):3154-62. · 7.74 Impact Factor
• Article: Association of HER2/ErbB2 expression and gene amplification with pathologic features and prognosis in esophageal adenocarcinomas.

  Harry H Yoon, Qian Shi, William R Sukov, Anne E Wiktor, Maliha Khan, Christopher A Sattler, Axel Grothey, Tsung-Teh Wu, Robert B Diasio, Robert B Jenkins, Frank A Sinicrope
  [show abstract] [hide abstract]
  ABSTRACT: We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression and gene amplification in patients with curatively resected esophageal adenocarcinoma (EAC). HER2 expression was analyzed by immunohistochemistry (IHC) in surgical EAC specimens (n = 713). Gene amplification was examined by FISH in a large subset (n = 344). Most tumors were T3-4 (66%) or node positive (72%); 95% were located in the esophagus or gastroesophageal junction. No patient received neoadjuvant therapy. Cox models were used. Overall, 17% of EACs were HER2 positive (i.e., IHC3(+) or IHC2(+) with amplification), with strong agreement between HER2 amplification (HER2/CEP17 ratio ≥2) and expression (κ = 0.83). HER2 positivity was significantly associated with lower tumor grade, less invasiveness, fewer malignant nodes, and the presence of adjacent Barrett's esophagus (BE). EACs with BE had higher odds of HER2 positivity than EACs without BE, independent of pathologic features [OR = 1.8 (95% CI: 1.1-2.8), P = 0.014]. Among all cases, HER2 positivity was significantly associated with disease-specific survival (DSS) in a manner that differed by the presence or absence of BE (P(interaction) = 0.0047). In EACs with BE, HER2 positivity was significantly associated with improved DSS [HR = 0.54 (95% CI: 0.35-0.84), P = 0.0065] and overall survival (P = 0.0022) independent of pathologic features, but was not prognostic among EACs without BE. HER2 positivity was shown in 17% of resected EACs and associated with reduced tumor aggressiveness. EACs with BE had nearly twice the odds of being HER2 positive and, within this subgroup, HER2 positivity was independently associated with improved survival.
  Clinical Cancer Research 01/2012; 18(2):546-54. · 7.74 Impact Factor
• Article: Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium.

  Sanjay Shete, Ching C Lau, Richard S Houlston, Elizabeth B Claus, Jill Barnholtz-Sloan, Rose Lai, Dora Il'yasova, Joellen Schildkraut, Siegal Sadetzki, Christoffer Johansen, [......], Eastwood Hon-chiu Leung, Caleb Davis, Rita Cheng, Fay J Hosking, Georgina N Armstrong, Yanhong Liu, Robert K Yu, Roger Henriksson, Beatrice S Melin, Melissa L Bondy
  [show abstract] [hide abstract]
  ABSTRACT: Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma.
  Cancer Research 12/2011; 71(24):7568-75. · 7.86 Impact Factor
• Source

  Available from: PubMed Central

  Article: Meta-analysis of 8q24 for seven cancers reveals a locus between NOV and ENPP2 associated with cancer development.

  Abra G Brisbin, Yan W Asmann, Honglin Song, Ya-Yu Tsai, Jeremiah A Aakre, Ping Yang, Robert B Jenkins, Paul Pharoah, Fredrick Schumacher, David V Conti, David J Duggan, Mark Jenkins, John Hopper, Steven Gallinger, Polly Newcomb, Graham Casey, Thomas A Sellers, Brooke L Fridley
  [show abstract] [hide abstract]
  ABSTRACT: Human chromosomal region 8q24 contains several genes which could be functionally related to cancer, including the proto-oncogene c-MYC. However, the abundance of associations around 128 Mb on chromosome 8 could mask the appearance of a weaker, but important, association elsewhere on 8q24. In this study, we completed a meta-analysis of results from nine genome-wide association studies for seven types of solid-tumor cancers (breast, prostate, pancreatic, lung, ovarian, colon, and glioma) to identify additional associations that were not apparent in any individual study. Fifteen SNPs in the 8q24 region had meta-analysis p-values < 1E-04. In particular, the region consisting of 120,576,000-120,627,000 bp contained 7 SNPs with p-values < 1.0E-4, including rs6993464 (p = 1.25E-07). This association lies in the region between two genes, NOV and ENPP2, which have been shown to play a role in tumor development and motility. An additional region consisting of 5 markers from 128,478,000 bp - 128,524,000 (around gene POU5F1B) had p-values < 1E-04, including rs6983267, which had the smallest p-value (p = 6.34E-08). This result replicates previous reports of association between rs6983267 and prostate and colon cancer. Further research in this area is warranted as these results demonstrate that the chromosomal region 8q24 may contain a locus that influences general cancer susceptibility between 120,576 and 120,630 kb.
  BMC Medical Genetics 12/2011; 12:156. · 2.33 Impact Factor
• Article: Predictability of adjuvant trastuzumab benefit in N9831 patients using the ASCO/CAP HER2-positivity criteria.

  Edith A Perez, Amylou C Dueck, Ann E McCullough, Monica M Reinholz, Kathleen S Tenner, Nancy E Davidson, Julie Gralow, Lyndsay N Harris, Leila A Kutteh, David W Hillman, Robert B Jenkins, Beiyun Chen
  [show abstract] [hide abstract]
  ABSTRACT: The 2007 American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) joint guidelines defined criteria for HER2 positivity of tumors that modified those of the US Food and Drug Administration (FDA), causing some confusion and uncertainty among clinicians. Using data from the HER2-positive breast cancer adjuvant trial N9831, we compared eligibility for patients who met both criteria, and disease-free survival (DFS) was assessed by Cox proportional hazards regression. The number of patients in the N9831 trial retrospectively eligible for trastuzumab therapy was decreased when ASCO/CAP criteria vs FDA criteria were applied to immunohistochemistry and/or fluorescence in situ hybridization results (107 [3.7%] of 2904 patients with immunohistochemistry results, 37 [1.3%] of 2809 patients with fluorescence in situ hybridization results, and 47 [1.7%] of 2809 patients with both results). Improvement in DFS was similar among patients treated with trastuzumab under either set of criteria (concurrent trastuzumab and chemotherapy compared with chemotherapy alone: by ASCO/CAP criteria, hazard ratio of DFS = 0.59, 95% confidence interval = 0.48 to 0.73; by FDA criteria but not ASCO/CAP criteria, hazard ratio = 0.60, 95% confidence interval = 0.12 to 3.13; number needed to treat to prevent one additional DFS event at 5 years: 10 and 11.2 patients, respectively). Following the 2007 ASCO/CAP criteria for HER2 positivity would negate the option of potentially life-saving trastuzumab therapy for a small but meaningful group of patients. We recommend using FDA-approved HER2 criteria for therapeutic decision making.
  CancerSpectrum Knowledge Environment 12/2011; 104(2):159-62. · 14.07 Impact Factor
• Article: Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer.

  Edith A Perez, Vera J Suman, Nancy E Davidson, Julie R Gralow, Peter A Kaufman, Daniel W Visscher, Beiyun Chen, James N Ingle, Shaker R Dakhil, Joanne Zujewski, Alvaro Moreno-Aspitia, Thomas M Pisansky, Robert B Jenkins
  [show abstract] [hide abstract]
  ABSTRACT: NCCTG (North Central Cancer Treatment Group) N9831 is the only randomized phase III trial evaluating trastuzumab added sequentially or used concurrently with chemotherapy in resected stages I to III invasive human epidermal growth factor receptor 2-positive breast cancer. Patients received doxorubicin and cyclophosphamide every 3 weeks for four cycles, followed by paclitaxel weekly for 12 weeks (arm A), paclitaxel plus sequential trastuzumab weekly for 52 weeks (arm B), or paclitaxel plus concurrent trastuzumab for 12 weeks followed by trastuzumab for 40 weeks (arm C). The primary end point was disease-free survival (DFS). Comparison of arm A (n = 1,087) and arm B (n = 1,097), with 6-year median follow-up and 390 events, revealed 5-year DFS rates of 71.8% and 80.1%, respectively. DFS was significantly increased with trastuzumab added sequentially to paclitaxel (log-rank P < .001; arm B/arm A hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.85). Comparison of arm B (n = 954) and arm C (n = 949), with 6-year median follow-up and 313 events, revealed 5-year DFS rates of 80.1% and 84.4%, respectively. There was an increase in DFS with concurrent trastuzumab and paclitaxel relative to sequential administration (arm C/arm B HR, 0.77; 99.9% CI, 0.53 to 1.11), but the P value (.02) did not cross the prespecified O'Brien-Fleming boundary (.00116) for the interim analysis. DFS was significantly improved with 52 weeks of trastuzumab added to adjuvant chemotherapy. On the basis of a positive risk-benefit ratio, we recommend that trastuzumab be incorporated into a concurrent regimen with taxane chemotherapy as an important standard-of-care treatment alternative to a sequential regimen.
  Journal of Clinical Oncology 12/2011; 29(34):4491-7. · 18.37 Impact Factor