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Jeannine Meinrath, Anja Haak, Nesrin Igci, Priya Dalvi, Christoph Arolt, Sonja Meemboor, Udo Siebolts, Hannah Eischeidt-Scholz, Claudia Wickenhauser, Inga Grünewald, et al.
Published: 10 November 2020
Oncotarget, Volume 11, pp 4123-4137; doi:10.18632/oncotarget.27797

Abstract:
Introduction: The underlying molecular mechanisms of parotid gland carcinomas (PGC) are still unknown. Knowledge about the tumor-driving signaling pathways is necessary either for diagnostics or developing new therapeutic options in this heterogeneous and rare entity.
, , Antonio Marra, Said Afqir
Illuminating Colorectal Cancer Genomics by Next-Generation Sequencing pp 29-71; doi:10.1007/978-3-030-53821-7_2

The publisher has not yet granted permission to display this abstract.
Amir-Hassan Zarnani, Davood Jafari, Mahmood Bozorgmehr, Mahdi Shabani, Leila Barzegar-Yarmohammadi, Fatemeh Ghaemimanesh,
Cancer Immunology pp 273-312; doi:10.1007/978-3-030-50287-4_15

The publisher has not yet granted permission to display this abstract.
Maren T. Scheuner, Shweta U. Dhar
Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics pp 265-282; doi:10.1016/b978-0-12-812536-6.00009-2

Alissa Greenbaum, Charles Wiggins, Angela Lw Meisner, Manuel Rojo, ,
Published: 1 November 2017
Heliyon, Volume 3; doi:10.1016/j.heliyon.2017.e00448

Abstract:
IntroductionAmerican Society of Clinical Oncology (ASCO) guidelines recommend that all patients with metastatic colorectal cancer (mCRC) receive KRAS testing to guide anti-EGFR monoclonal antibody treatment. The aim of this study was to assess for disparities in KRAS testing and mutational status.MethodsThe New Mexico Tumor Registry (NMTR), a population-based cancer registry participating in the National Cancer Institute's Surveillance, Epidemiology and End Results program, was queried to identify all incident cases of CRC diagnosed among New Mexico residents from 2010 to 2013.ResultsSix hundred thirty-seven patients were diagnosed with mCRC from 2010–2013. As expected, KRAS testing in Stage 4 patients presented the highest frequency (38.4%), though testing in stage 3 (8.5%), stage 2 (3.4%) and stage 1 (1.2%) was also observed. In those with metastatic disease, younger patients (≤ 64 years) were more likely to have had testing than patients 65 years and older (p < 0.0001). Patients residing in urban areas received KRAS testing more often than patients living in rural areas (p = 0.019). No significant racial/ethnic disparities were observed (p = 0.66). No significant differences were seen by year of testing.ConclusionAge and geographic disparities exist in the rates of KRAS testing, while sex, race/ethnicity and the year tested were not significantly associated with testing. Further study is required to assess the reasons for these disparities and continued suboptimal adherence to current ASCO KRAS testing guidelines.
Emilie M. J. Van Brummelen, Anthonius De Boer, Jos H. Beijnen,
Published: 2 June 2017
by Wiley
The Oncologist, Volume 22, pp 864-872; doi:10.1634/theoncologist.2017-0031

Abstract:
Recently, the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) recommended that patients with epidermal growth factor receptor (EGFR)‐expressing metastatic colorectal cancer could be treated with anti‐EGFR monoclonal antibodies (mAbs) cetuximab and panitumumab only in absence of Rat‐Sarcoma (RAS) mutations. In addition to the previously established biomarker Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2, cumulative evidence also shows that patients whose tumors harbor KRAS exons 3 or 4 and neuroblastoma rat‐sarcoma viral oncogene homolog (NRAS) exons 2, 3, and 4 mutations are found unlikely to benefit from anti‐EGFR treatment. In line with the resistance of RAS mutated (mt) tumors, treatment response in BRAFmt tumors may also be altered given their important role in the EGFR signaling pathway. However, BRAF is not recommended as predictive biomarker yet because the evidence for the impact of BRAF mutations on treatment outcome is considered insufficient. This article summarizes the evidence for the impact of BRAF mutations on treatment outcome of anti‐EGFR mAbs. Based on a review of literature, eight meta‐analyses were included that consistently show that patients with BRAF mutations have a lack of treatment benefit of anti‐EGFR mAbs. After discussing the quality and quantity of available evidence, we conclude that evidence is stronger than suggested by ESMO and ASCO. Additionally, we highlight that the quality of evidence for BRAF is even higher than for extended RAS as a biomarker. We therefore advise ESMO and ASCO to reconsider BRAF status as a predictive biomarker for response. Implications for Practice. In metastatic colorectal cancer (mCRC), therapy with anti‐epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab is indicated in absence of RAS mutations. Cumulative evidence shows that patients with BRAF mutations, who comprise 10% of the mCRC population, do not benefit from anti‐EGFR‐antibody treatment. Although guidelines state that evidence for BRAF as a predictive marker is insufficient, we highlight that the quality and quantity of evidence is higher than suggested. We therefore encourage the use of BRAF as a predictive marker in order to exclude patients from therapy for whom limited treatment benefit is expected.
Antonia R. Sepulveda, Stanley R. Hamilton, Carmen J. Allegra, Wayne Grody, Allison M. Cushman-Vokoun, William K. Funkhouser, , Christopher Lieu, Noralane M. Lindor, Bruce D. Minsky, et al.
Journal of Clinical Oncology, Volume 35, pp 1453-1486; doi:10.1200/jco.2016.71.9807

The publisher has not yet granted permission to display this abstract.
Junjie Peng, Dan Huang, Graeme Poston, Xiaoji Ma, Renjie Wang, Weiqi Sheng, Xiaoyan Zhou, Xiaoli Zhu, Sanjun Cai
Published: 14 March 2017
Oncotarget, Volume 8, pp 49076-49083; doi:10.18632/oncotarget.16176

Abstract:
// Junjie Peng 1, 2, * , Dan Huang 2, 3, * , Graeme Poston 4 , Xiaoji Ma 1, 2 , Renjie Wang 1, 2 , Weiqi Sheng 2, 3 , Xiaoyan Zhou 2, 3 , Xiaoli Zhu 2, 3 and Sanjun Cai 1, 2 1 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China 3 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China 4 Department of Surgery, Aintree University Hospital, Liverpool L9 7AL, UK * These authors have contributed equally to this work Correspondence to: Junjie Peng, email: [email protected] Keywords: colorectal cancer, RAS, BRAF, mutation, heterogeneity Received: August 31, 2016 Accepted: November 22, 2016 Published: March 14, 2017 ABSTRACT Purpose: To assess the biological variability of clinical meaningful molecular markers and their clinical correlations in Chinese patients with colorectal cancer (CRC). Materials and methods: In this prospective observational study, frequencies and clinico-pathological features of RAS and BRAFV600E mutations, deficiency of DNA mismatch repair (dMMR) were evaluated in patients with colorectal cancer staged I-IV. The molecular heterogeneity between right-sided and left-sided colorectal cancers was studied in our series by classifying patients with different mutations and dMMR status. Results: Among 400 evaluable patients, mutations in KRAS exon 2, exon 3 or 4, NRAS and BRAFV600E were detected in 36%, 7.5%, 3.5% and 2.5%, respectively. RAS mutations were significantly higher in metastatic CRCs (56.4% vs. 43.1%, p=0.015) and right-sided CRCs (62.5% vs 41.7%, p=0.003). In 212 RAS wild-type patients, V600E mutation was higher in older patients (9.5% vs. 2.2%, p=0.017), women (9.2% vs. 2.2%, p=0.021) and right-sided CRCs (10.5% vs. 3.4%, p=0.06). dMMR was detected in 7.75% of all stages of CRCs, with the highest dMMR rate of 40% in stage II right-sided colon cancer. Conclusions: By assessing the mutations and clinical correlations of RAS and BRAF genes, and dMMR status, similar RAS mutation, dMMR frequency and lower BRAF mutation was observed in Chinese patients compared to western patients. A distinct molecular heterogeneity was found between patients with right-sided and left-sided CRCs. Junjie Peng1,2,*, Dan Huang2,3,*, Graeme Poston4, Xiaoji Ma1,2, Renjie Wang1,2, Weiqi Sheng2,3, Xiaoyan Zhou2,3, Xiaoli Zhu2,3, Sanjun Cai1,2 1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China 3Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China 4Department of Surgery, Aintree University Hospital, Liverpool L9 7AL, UK *These authors have contributed equally to this work Correspondence to: Junjie Peng, email: [email protected] Keywords: colorectal cancer, RAS, BRAF, mutation, heterogeneity Received: August 31, 2016 Accepted: November 22, 2016 Published: March 14, 2017 ABSTRACT Purpose: To assess the biological variability of clinical meaningful molecular markers and their clinical correlations in Chinese patients with colorectal cancer (CRC). Materials and methods: In this prospective observational study, frequencies and clinico-pathological features of RAS and BRAFV600E mutations, deficiency of DNA mismatch repair (dMMR) were evaluated in patients with colorectal cancer staged I-IV. The molecular heterogeneity between right-sided and left-sided colorectal cancers was studied in our series by classifying patients with different mutations and dMMR status. Results: Among 400 evaluable patients, mutations in KRAS exon 2, exon 3 or 4, NRAS and BRAFV600E were detected in 36%, 7.5%, 3.5% and 2.5%, respectively. RAS mutations were significantly higher in metastatic CRCs (56.4% vs. 43.1%, p=0.015) and right-sided CRCs (62.5% vs 41.7%, p=0.003). In 212 RAS wild-type patients, V600E mutation was higher in older patients (9.5% vs. 2.2%, p=0.017), women (9.2% vs. 2.2%, p=0.021) and right-sided CRCs (10.5% vs. 3.4%, p=0.06). dMMR was detected in 7.75% of all stages of CRCs, with the highest dMMR rate of 40% in stage II right-sided colon cancer. Conclusions: By assessing the mutations and clinical correlations of RAS and BRAF genes, and dMMR status, similar RAS mutation, dMMR frequency and lower BRAF mutation was observed in Chinese patients compared to western patients. A distinct molecular heterogeneity was found between patients with right-sided and left-sided CRCs.
, Stanley R. Hamilton, Carmen J. Allegra, Wayne Grody, Allison M. Cushman-Vokoun, William K. Funkhouser, , Christopher Lieu, Noralane M. Lindor, Bruce D. Minsky, et al.
The Journal of Molecular Diagnostics, Volume 19, pp 187-225; doi:10.1016/j.jmoldx.2016.11.001

Abstract:
Objectives: To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens. Methods: The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted. Results: Twenty-one guideline statements were established. Conclusions: Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented. Key Words: Molecular diagnostics; Gastrointestinal; Histology; Genetics; Oncology.
Antonia R. Sepulveda, Stanley R. Hamilton, Carmen J. Allegra, Wayne Grody, Allison M. Cushman-Vokoun, William K. Funkhouser, , Christopher Lieu, Noralane M. Lindor, Bruce D. Minsky, et al.
Archives of Pathology & Laboratory Medicine, Volume 141, pp 625-657; doi:10.5858/arpa.2016-0554-cp

The publisher has not yet granted permission to display this abstract.
Antonia R. Sepulveda, Stanley R. Hamilton, Carmen J. Allegra, Wayne Grody, Allison M. Cushman-Vokoun, William K. Funkhouser, , Christopher Lieu, Noralane M. Lindor, Bruce D. Minsky, et al.
American Journal of Clinical Pathology, Volume 147, pp 221-260; doi:10.1093/ajcp/aqw209

Abstract:
Objectives: To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens. Methods: The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted. Results: Twenty-one guideline statements were established. Conclusions: Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented.
J. Merhautová, P. Vychytilová-Faltejsková, R. Demlová,
Physiological Research, Volume 65; doi:10.33549/physiolres.933546

The publisher has not yet granted permission to display this abstract.
Abderrahim El Guerrab, Mahchid Bamdad, , Frédérique Penault-Llorca,
Published: 19 November 2016
by Wiley
Molecular Carcinogenesis, Volume 56, pp 1383-1394; doi:10.1002/mc.22596

The publisher has not yet granted permission to display this abstract.
Susan D Richman, Jennifer Fairley, Rachel Butler,
Published: 28 September 2016
by BMJ
Journal of Clinical Pathology, Volume 70, pp 58-62; doi:10.1136/jclinpath-2016-203822

Abstract:
AimsSince 2008, KRAS mutation status in exon 2 has been used to predict response to anti-EGFR therapies. Recent evidence has demonstrated that NRAS status is also predictive of response. Several retrospective ‘extended RAS’ analyses have been performed on clinical trial material. Despite this, are we really moving towards such extended screening practice in reality?MethodsData were analysed from four consecutive UK National External Quality Assessment Service for Molecular Genetics Colorectal cancer External Quality Assessment schemes (during the period 2014–2016), with up to 110 laboratories (worldwide) participating in each scheme. Testing of four or five tumour samples is required per scheme. Laboratories provided information on which codons were routinely screened, and provided genotyping and interpretation results for each sample.ResultsAt least 85% of laboratories routinely tested KRAS codons 12, 13 and 61. Over the four schemes, an increasing number of laboratories routinely tested KRAS codons 59, 117 and 146. Furthermore, more laboratories were introducing next generation sequencing technologies. The pattern of ‘extended testing’ was reassuringly similar for NRAS, although fewer laboratories currently test for mutations in this gene. Alarmingly, still only 36.1% and 24.1% of participating laboratories met the ACP Molecular Pathology and Diagnostics Group and American Society of Clinical Oncology guidelines, respectively, for extended RAS testing in the latest assessment.ConclusionsDespite recommendations in the UK and USA on extended RAS testing, there has clearly been, based on these results, a delay in implementation. Inadequate testing results in patients being subjected to harmful treatment regimens, which would not be the case, were routine practice altered, in line with evidence-based guidelines.
Abderrahim El Guerrab, Mahchid Bamdad, Fabrice Kwiatkowski, , Frédérique Penault-Llorca,
Published: 15 September 2016
Oncotarget, Volume 7, pp 73618-73637; doi:10.18632/oncotarget.12037

Abstract:
// Abderrahim El Guerrab 1, 2 , Mahchid Bamdad 2, 3 , Fabrice Kwiatkowski 1 , Yves-Jean Bignon 1, 2, * , Frédérique Penault-Llorca 1, 2, * , Corinne Aubel 1, 2 1 Centre Jean Perrin - ERTICa-EA4677, BP392, 63011 Clermont-Ferrand Cedex, France 2 Clermont Université - Université d’Auvergne - ERTICa-EA4677, Faculté de Médecine, BP38, 63001 Clermont-Ferrand Cedex, France 3 Clermont Université - Université d’Auvergne - ERTICa-EA4677, Institut Universitaire de Technologie, Département Génie Biologique, Ensemble Universitaire des Cézeaux, BP86, 63172 Aubière Cedex, France * These authors have contributed equally to this work Correspondence to: Yves-Jean Bignon, email: [email protected] Keywords: triple-negative breast cancer, epidermal growth factor receptor, anti-EGFR targeted therapy, cytotoxicity, cell cycle Received: November 09, 2015 Accepted: August 22, 2016 Published: September 15, 2016 ABSTRACT Triple-negative breast cancer (TNBC) is characterized by overexpression of epidermal growth factor receptor (EGFR) and activation of its downstream signaling pathways. Dual targeting of EGFR using one monoclonal antibody (mAb; cetuximab or panitumumab) and one tyrosine kinase inhibitor (EGFR-TKI; gefitinib or erlotinib) is a potential therapeutic approach. We investigated the effect of these therapies in EGFR-expressing TNBC cell lines that do or do not harbor the main activating mutations of EGFR pathways. Cell lines were sensitive to EGFR-TKIs, whereas mAbs were active only in MDA-MB-468 ( EGFR amplification) and SUM-1315 ( KRAS and PTEN wild-type) cells. MDA-MB-231 ( KRAS mutated) and HCC-1937 ( PTEN deletion) cells were resistant to mAbs. The combined treatment resulted in a synergistic effect on cell proliferation and superior inhibition of the RAS/MAPK signaling pathway in mAb-sensitive cells. The anti-proliferative effect was associated with G1 cell cycle arrest followed by apoptosis. Sensitivity to therapies was characterized by induction of positive regulators and inactivation of negative regulators of cell cycle. These results suggest that dual EGFR inhibition might result in an enhanced antitumor effect in a subgroup of TNBC. The status of EGFR , KRAS and PTEN could be used as a molecular marker for predicting the response to this therapeutic strategy. Abderrahim El Guerrab1,2, Mahchid Bamdad2,3, Fabrice Kwiatkowski1, Yves-Jean Bignon1,2,*, Frédérique Penault-Llorca1,2,*, Corinne Aubel1,2 1Centre Jean Perrin - ERTICa-EA4677, BP392, 63011 Clermont-Ferrand Cedex, France 2Clermont Université - Université d’Auvergne - ERTICa-EA4677, Faculté de Médecine, BP38, 63001 Clermont-Ferrand Cedex, France 3Clermont Université - Université d’Auvergne - ERTICa-EA4677, Institut Universitaire de Technologie, Département Génie Biologique, Ensemble Universitaire des Cézeaux, BP86, 63172 Aubière Cedex, France *These authors have contributed equally to this work Correspondence to: Yves-Jean Bignon, email: [email protected] Keywords: triple-negative breast cancer, epidermal growth factor receptor, anti-EGFR targeted therapy, cytotoxicity, cell cycle Received: November 09, 2015 Accepted: August 22, 2016 Published: September 15, 2016 ABSTRACT Triple-negative breast cancer (TNBC) is characterized by overexpression of epidermal growth factor receptor (EGFR) and activation of its downstream signaling pathways. Dual targeting of EGFR using one monoclonal antibody (mAb; cetuximab or panitumumab) and one tyrosine kinase inhibitor (EGFR-TKI; gefitinib or erlotinib) is a potential therapeutic approach. We investigated the effect of these therapies in EGFR-expressing TNBC cell lines that do or do not harbor the main activating mutations of EGFR pathways. Cell lines were sensitive to EGFR-TKIs, whereas mAbs were active only in MDA-MB-468 (EGFR amplification) and SUM-1315 (KRAS and PTEN wild-type) cells. MDA-MB-231 (KRAS mutated) and HCC-1937 (PTEN deletion) cells were resistant to mAbs. The combined treatment resulted in a synergistic effect on cell proliferation and superior inhibition of the RAS/MAPK signaling pathway in mAbsensitive cells. The anti-proliferative effect was associated with G1 cell cycle arrest followed by apoptosis. Sensitivity to therapies was characterized by induction of positive regulators and inactivation of negative regulators of cell cycle. These results suggest that dual EGFR inhibition might result in an enhanced antitumor effect in a subgroup of TNBC. The status of EGFR, KRAS and PTEN could be used as a molecular marker for predicting the response to this therapeutic strategy.
, , , Antonio Pazzola, Giovanni Baldino, Mario Scartozzi, Maria Teresa Ionta, Salvatore Ortu, Francesca Capelli, Annamaria Lanzillo, et al.
Published: 29 June 2016
Oncology Letters, Volume 12, pp 1415-1421; doi:10.3892/ol.2016.4798

Abstract:
The presence of mutations in the KRAS gene is a predictor of a poor clinical response to EGFR-targeted agents in patients affected by colorectal cancer (CRC), but its significance as a global prognostic factor remains unclear. The aim of the present study was to evaluate the impact of the KRAS mutational status on time to first metastasis (TTM) and overall survival (OS) in a cohort of Sardinian CRC patients. A total of 551 patients with metastatic CRC at the time of enrolment were included. Clinical and pathological features of the disease, including follow-up information, were obtained from medical records and cancer registry data. For mutational analysis formalin-fixed paraffin-embedded tissue samples were processed using a standard protocol. The coding sequence and splice junctions of exons 2 and 3 of the KRAS gene were screened for mutations by direct automated sequencing. Overall, 186 KRAS mutations were detected in 183/551 (33%) patients: 125 (67%) were located in codon 12, 36 (19%) in codon 13, and 18 (10%) in codon 61. The remaining mutations (7; 4%) were detected in uncommonly-affected codons. No significant correlation between KRAS mutations and gender, age, anatomical location and stage of the disease at the time of diagnosis was identified. Furthermore, no prognostic value of KRAS mutations was found considering either TTM or OS. When patients were stratified by KRAS mutational status and gender, males were significantly associated with a longer TTM. The results of the present study indicate that KRAS mutation correlated with a slower metastatic progression in males with CRC from Sardinia, irrespective of the age at diagnosis and the codon of the mutation.
Carmen J. Allegra, R. Bryan Rumble, Stanley R. Hamilton, Pamela B. Mangu, Nancy Roach, Alexander Hantel, Richard L. Schilsky
Journal of Clinical Oncology, Volume 34, pp 179-185; doi:10.1200/jco.2015.63.9674

The publisher has not yet granted permission to display this abstract.
Inga Grünewald, Claudia Vollbrecht, Jeannine Meinrath, Moritz F. Meyer, , Uta Drebber, Alexander Quaas, Dirk Beutner, Karl-Bernd Hüttenbrink, Eva Wardelmann, et al.
Published: 25 May 2015
Oncotarget, Volume 6, pp 18224-18237; doi:10.18632/oncotarget.4015

Abstract:
// Inga Grünewald 1, 2 , Claudia Vollbrecht 1 , Jeannine Meinrath 1 , Moritz F. Meyer 3 , Lukas C. Heukamp 1 , Uta Drebber 1 , Alexander Quaas 1 , Dirk Beutner 3 , Karl-Bernd Hüttenbrink 3 , Eva Wardelmann 2 , Wolfgang Hartmann 1, 2 , Reinhard Büttner 1, 4 , Margarete Odenthal 1, 4, * , Markus Stenner 3, 5, * 1 Institute of Pathology, University Hospital of Cologne, Cologne, Germany 2 Department of Pathology, University Hospital of Muenster, Muenster, Germany 3 Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Cologne, Cologne, Germany 4 Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany 5 Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Muenster, Muenster, Germany * These authors have contributed equally to this work Correspondence to: Inga Grünewald, e-mail: [email protected] Keywords: salivary gland cancer, individualized therapy, PIK3CA, HRAS, carcinogenesis Received: January 21, 2015 Accepted: May 14, 2015 Published: May 25, 2015 ABSTRACT Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations. Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes. Mutations were identified in 22 different genes. The most frequent alterations affected TP53 , followed by RAS genes, PIK3CA , SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK , HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4 . In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts. Inga Grünewald1,2, Claudia Vollbrecht1, Jeannine Meinrath1, Moritz F. Meyer3, Lukas C. Heukamp1, Uta Drebber1, Alexander Quaas1, Dirk Beutner3, Karl-Bernd Hüttenbrink3, Eva Wardelmann2, Wolfgang Hartmann1,2, Reinhard Büttner1,4, Margarete Odenthal1,4,*, Markus Stenner3,5,* 1Institute of Pathology, University Hospital of Cologne, Cologne, Germany 2Department of Pathology, University Hospital of Muenster, Muenster, Germany 3Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Cologne, Cologne, Germany 4Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany 5Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Muenster, Muenster, Germany *These authors have contributed equally to this work Correspondence to: Inga Grünewald, e-mail: [email protected] Keywords: salivary gland cancer, individualized therapy, PIK3CA, HRAS, carcinogenesis Received: January 21, 2015 Accepted: May 14, 2015 Published: May 25, 2015 ABSTRACT Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations. Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes. Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4. In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts.
, Paul J. Limburg, John A. Baron, Andrea N. Burnett-Hartman, Daniel J. Weisenberger, Peter W. Laird, Frank A. Sinicrope, Christophe Rosty, Daniel D. Buchanan, , et al.
Published: 1 January 2015
Gastroenterology, Volume 148, pp 77-87.e2; doi:10.1053/j.gastro.2014.09.038

Abstract:
Background and Aims Colorectal cancer (CRC) is a heterogeneous disease that can develop via several pathways. Different CRC subtypes, identified based on tumor markers, have been proposed to reflect these pathways. We evaluated the significance of these previously proposed classifications to survival. Methods Participants in the population-based Seattle Colon Cancer Family Registry were diagnosed with invasive CRC from 1998 through 2007 in western Washington State (N = 2706), and followed for survival through 2012. Tumor samples were collected from 2050 participants and classified into 5 subtypes based on combinations of tumor markers: type 1 (microsatellite instability [MSI]–high, CpG island methylator phenotype [CIMP] –positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMP-positive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS). Multiple imputation was used to impute tumor markers for those missing data on 1–3 markers. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of subtypes with disease-specific and overall mortality, adjusting for age, sex, body mass, diagnosis year, and smoking history. Results Compared with participants with type 4 tumors (the most predominant), participants with type 2 tumors had the highest disease-specific mortality (HR = 2.20, 95% CI: 1.47–3.31); subjects with type 3 tumors also had higher disease-specific mortality (HR = 1.32, 95% CI: 1.07–1.63). Subjects with type 5 tumors had the lowest disease-specific mortality (HR = 0.30, 95% CI: 0.14–0.66). Associations with overall mortality were similar to those with disease-specific mortality. Conclusions Based on a large, population-based study, CRC subtypes, defined by proposed etiologic pathways, are associated with marked differences in survival. These findings indicate the clinical importance of studies into the molecular heterogeneity of CRC.
, Scott Berry, Yoo-Joung Ko, Kelvin K W Chan
Expert Review of Pharmacoeconomics & Outcomes Research, Volume 15, pp 81-100; doi:10.1586/14737167.2015.982100

The publisher has not yet granted permission to display this abstract.
, Mirjam A. G. Sprangers, Jeff A. Sloan, Donald L. Patrick, Ping Yang, Cornelis J. F. Van Noorden
Quality of Life Research, Volume 24, pp 1163-1177; doi:10.1007/s11136-014-0844-z

The publisher has not yet granted permission to display this abstract.
M. (Marie) Westwood, Thea Van Asselt, , Penny Whiting, M.A. (Manuela) Joore, N. (Nigel) Armstrong, Caro Noake, , J.L. (Hans) Severens, J. (Jos) Kleijnen
Health Technology Assessment, Volume 18, pp 1-132; doi:10.3310/hta18620

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Eva Serup-Hansen, Dorte Linnemann, , Poul Flemming Geertsen, Hanne Havsteen
Published: 22 September 2014
by Wiley
APMIS, Volume 123, pp 53-59; doi:10.1111/apm.12306

The publisher has not yet granted permission to display this abstract.
Naouel Ailane, Cã©Line Greco, Yingying Zhu, Monica Sala-Valdã©S, Martine Billard, Ibrahim Casal, Olivia Bawa, Paule Opolon, Eric Rubinstein,
Published: 19 September 2014
Frontiers in Physiology, Volume 5; doi:10.3389/fphys.2014.00364

Abstract:
New therapeutic agents are needed in digestive tract tumours. Co-029/tspan8 is a tetraspanin frequently expressed on human colorectal tumours, In this work, we report the effects of the monoclonal antibody Ts29.2, targeting Co-029/tspan8, on colorectal tumor cells in vitro and after implantation in nude mice. HT29, Isreco1 and SW480 colorectal tumor cell lines were used for this study. HT29 has a strong endogenous expression of Co-029/tspan8, whereas Isreco1 cells don’t express Co-029/tspan8 and SW480 has only a weak expression. Isreco1 and SW480 were transduced to express Co-029/tspan8 at the same level as HT29. In order to check the specificity of the effect of monoclonal antibody Ts29.2, low Co029/tspan8 expressing SW480 cells were injected simultaneously with transduced cells in the back, on the left and right sides of the mice. With an early treatment, Ts29.2 mAb inhibited growth of tumors expressing Co-029/tspan8 up to 70%, whereas a delayed treatment was less efficient. No effect of the antibody on cell proliferation or apoptosis induction was detected in vitro. No increase of activated caspase 3 labeling was observed in vivo and areas occupied by vessels were not significantly different between treated mice and controls. This suggests that the action of Ts29.2 is linked neither to cellular toxicity nor to the inhibition of the previously reported angiogenic properties of Co-029/tspan8. An inhibition of cell proliferation in vivo is demonstrated by a reduction of the mitotic index in HT29 tumors of Ts29.2 treated mice. The discrepancy between in vitro and in vivo data on cell proliferation suggests that the binding of Ts29.2 to tumour cells may modify their response to signals issued from the microenvironment. Given the restricted pattern of tissue expression of the tetraspanin Co-029/tspan8, these preliminary results put forth for consideration the antibody targeting of this tetraspanin in further investigations for therapeutic applications.
, , Tzu-Chen Lin, , Shung-Haur Yang, , , , Muh-Hwa Yang,
Published: 25 June 2014
by Wiley
Journal of Surgical Oncology, Volume 110, pp 451-457; doi:10.1002/jso.23675

The publisher has not yet granted permission to display this abstract.
, Brock C. Christensen
Published: 2 June 2014
by Wiley
Cancer Medicine, Volume 3, pp 1385-1395; doi:10.1002/cam4.279

Abstract:
There is a small but growing body of literature regarding the predictive utility of a Let‐7 microRNA‐binding‐site polymorphism in the 3′‐untranslated region (UTR) of KRAS (KRAS‐LCS6) for colorectal cancer outcome, although the results are conflicting. We performed a review and meta‐analysis in an attempt to better clarify this relationship. A PubMed search was conducted to identify all studies reporting on KRAS let‐7 microRNA‐binding site polymorphism (LCS6; rs61764370) and colorectal cancer outcome. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were extracted or estimated from each manuscript. Log HRs and log CIs were combined across studies using the inverse‐variance weight to calculate fixed‐ and random‐effects summary estimates and corresponding 95% CIs for overall and progression‐free survival. We did not observe any significant association between overall or progression‐free survival, neither when considering all colorectal cancer patients nor for subgroup analyses (metastatic, anti‐EGFR [epidermal growth factor receptor] treatment, or KRAS wild type). There was substantial heterogeneity across studies, overall and among subgroups analyzed. We have found no clear evidence to support an association between the KRAS‐LCS6 genotype and overall or progression‐free survival among colorectal cancer patients, even after conducting subgroup analyses by stage and anti‐EGFR treatment status. This information helps to clarify the confusing body of literature regarding the clinical implications of the KRAS‐LCS6 genetic variant on colorectal cancer outcomes, indicating that it should not be used at the present time to personalize therapeutic strategies (PROSPERO registration number: CRD42013005325).
, Annika Loft, , , , Eric V. Benzon, Nils Brünner, I. J. Christensen, Susanne H. Hansson, Niels H. Holländer, et al.
Published: 21 January 2014
by Wiley
The Oncologist, Volume 19, pp 164-172; doi:10.1634/theoncologist.2013-0229

Abstract:
Background. Treatment options for metastatic colon cancer (mCC) are widening. We prospectively evaluated serial 2-deoxy-2-[18F]fluoro-d-glucose positron-emission tomography/computed tomography (PET/CT) and measurements of tissue inhibitor of metalloproteinases-1 (TIMP-1), carcinoembryonic antigen (CEA), and liberated domain I of urokinase plasminogen activator receptor (uPAR(I)) for early assessment of treatment response in mCC patients. Methods. Thirty-three mCC patients scheduled for first-line chemotherapy with capecitabine and oxaliplatin (CAPOX) and bevacizumab participated; 27 were evaluated by PET/CT before treatment, after one and four treatment series. Morphological and metabolic response was independently assessed according to Response Evaluation Criteria in Solid Tumors and European Organization for Research and Treatment of Cancer PET criteria. Plasma TIMP-1, plasma uPAR(I), and serum CEA were determined. Results. Metabolic response after one treatment course predicted the ability of CAPOX and bevacizumab to induce morphological response after four treatment series with a sensitivity of 80%, specificity of 69%, and odds ratio of 13.9 (95% confidence interval [CI] 1.9; 182). Early metabolically stable or progressive disease was associated with shorter progression-free survival (hazard ratio [HR] = 3.2 [CI 1.3; 7.8]). Biomarker levels at early evaluation were associated with shorter OS (TIMP-1 per unit increase on a log-2-transformed ng/mL scale: HR = 2.6 [CI 1.4; 4.9]; uPAR(I) per 25 fmol/mL increase: HR = 1.5 [CI 1.1; 2.1]). Conclusion. This monocentric study demonstrated predictive value of early metabolic PET response and prognostic value of TIMP-1 and uPAR(I) levels in mCC treated with CAPOX and bevacizumab. Results support investigation of PET/CT, TIMP-1, and uPAR(I) guided early treatment adaptation in mCC.
, Laurent Azoulay, Eric Van Cutsem, , Salvatore Siena, Michael Wolf
Targeted Oncology, Volume 8, pp 127-136; doi:10.1007/s11523-013-0271-z

Abstract:
Panitumumab is a fully human monoclonal antibody that targets the epidermal growth factor receptor. Results from the primary analysis of a phase 3, randomized, controlled study showed a statistically significant improvement in progression-free survival for patients receiving panitumumab; however, overall survival was confounded by best supportive care (BSC) patients that crossed over to panitumumab therapy after disease progression. Three post hoc analyses are presented that approximate the panitumumab overall survival treatment effect in both the all-randomized and wild-type (WT) KRAS populations by using the BSC patients with mutant (MT) KRAS as the comparator group to discount the effect of crossover from BSC to panitumumab. The primary post hoc analysis showed a median overall survival of 6.4 months for all KRAS-evaluable patients randomized to panitumumab versus 4.4 months for patients with MT KRAS tumors randomized to BSC, yielding an adjusted hazard ratio (95 % CI) of 0.764 (0.598-0.977). Similar results were observed for the two secondary post hoc analyses. These analyses suggest a positive treatment effect of panitumumab in both the overall and WT KRAS patient populations consistent with an improvement in overall survival relative to BSC.
, Yu Han, Hongwei Zhang, Qingchuan Zhao, ,
Genetic Testing and Molecular Biomarkers, Volume 17, pp 348-351; doi:10.1089/gtmb.2012.0421

The publisher has not yet granted permission to display this abstract.
, , K W Makar, , J A Baron, N M Lindor, , P A Newcomb
British Journal of Cancer, Volume 108, pp 1757-1764; doi:10.1038/bjc.2013.118

Abstract:
Mutations in the Kirsten Ras (KRAS) oncogene are common in colorectal cancer (CRC). The role of KRAS-mutation status as a prognostic factor, however, is unclear. We evaluated the relationship between KRAS-mutation status and CRC survival, considering heterogeneity in this association by tumour and patient characteristics. The population-based study included individuals diagnosed with CRC between 1998–2007 in Western Washington State. Tumour specimens were tested for KRAS exon 2 mutations, the BRAF p.V600E mutation, and microsatellite instability (MSI). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between KRAS-mutation status and disease-specific and overall survival. Stratified analyses were conducted by age, sex, tumour site, stage, and MSI. We conducted additional analyses combining KRAS-mutation, BRAF-mutation, and MSI status. Among 1989 cases, 31% had KRAS-mutated CRC. Kirsten Ras (KRAS)-mutated CRC was associated with poorer disease-specific survival (HR=1.37, 95% CI: 1.13–1.66). This association was not evident in cases who presented with distant-stage CRC. Cases with KRAS-wild-type/BRAF-wild-type/MSI-high CRC had the most favourable prognosis; those with CRC exhibiting a KRAS- or BRAF-mutation and no MSI had the poorest prognosis. Patterns were similar for overall survival. Kirsten Ras (KRAS)-mutated CRC was associated with statistically significantly poorer survival after diagnosis than KRAS-wild-type CRC.
, Caterina Fontanella, Alessandro Follador, Gianpiero Fasola, Giuseppe Aprile
Critical Reviews in Oncology/Hematology, Volume 85, pp 32-44; doi:10.1016/j.critrevonc.2012.04.001

Maren T. Scheuner, Shannon Rhodes
Emery and Rimoin's Principles and Practice of Medical Genetics pp 1-13; doi:10.1016/b978-0-12-383834-6.00027-6

Hilary S. Serracino, Wilbur A. Franklin,
Published: 1 December 2012
Surgical Pathology Clinics, Volume 5, pp 903-918; doi:10.1016/j.path.2012.08.006

The publisher has not yet granted permission to display this abstract.
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