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Conference Paper: The mutational landscape of LN metastasis and recurrence in HNSCC

TitleThe mutational landscape of LN metastasis and recurrence in HNSCC
Authors
KeywordsMedical sciences
Oncology
Issue Date2014
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
The 2014 Annual Meeting of the American Association for Cancer research (AACR 2014), San Diego, CA., 5-9 April 2014. In Cancer Research, 2014, v. 74 n. 19 suppl., abstract no. 985 How to Cite?
AbstractRecent whole exome sequencing (WES) studies have reported the mutations that characterize primary head and neck squamous cell carcinomas (HNSCC). While exposure to tobacco, alcohol and HPV infection are known to contribute to HNSCC development and prognosis, the largest obstacle to long term survival is recurrent and metastatic disease. Approximately 50% of patients present with synchronous lymph node metastases (SLNM), where 5-year adjusted survival is ≈85% for patients without SLNM compared with 30-60% in patients with SLNM. 20-30% of patients cured of their primary HNSCC go on to develop recurrent disease, which is usually refractory to standard therapies. Here, we report the first WES study of paired primary tumor and SLNM from 14 HNSCC patients, and paired primary tumor and metachronous loco-regional metastases (MLRM) from 11 HNSCC patients. Primary tumors averaged 67 nonsynonymous mutations per tumor (n=21), SLNM averaged 89.3 (n=12), and MLRM averaged 41.7 (n=9). TP53 was the only gene mutated in a majority (57%) of primary tumors in our cohort. We observed similar rates of mutation in several of the TCGA-defined “HNSCC signature” genes in our primary cohort, including FAT1 (14.3%) and CASP8 (4.8%), among others. While the size of our cohort does not allow for appropriately powered statistical analyses; 206 and 204 genes, were mutated in metastatic tumors, but not the respective paired primary tumors, in the SLNM and MLRM cohorts, respectively. AP2B1 and ITPR3 mutations were enriched in SLNM, as newly acquired mutations were seen in multiple (2 and 2/12) SLNM samples. GLUL and DDR2 mutations were enriched in MLRM, as newly acquired mutations were seen in multiple (2 and 2/9) MLRM samples. All 4 genes have previously been implicated in the metastatic process in other cancers. The potential enrichment of DDR2 mutations in HNSCC metastases is especially intriguing, as mutations in this gene have been shown to confer sensitivity to the SRC-family kinase inhibitor, dasatinib, in lung and breast cancer. Here we report exquisite sensitivity to dasatinib in our HNSCC preclinical models harboring DDR2 mutations, suggesting further investigation of this drug is warranted in recurrent HNSCC. ©2014 American Association for Cancer Research.
DescriptionMeeting Theme: Harnessing Breakthroughs - Targeting Cures
Session - Molecular and Cellular Biology: Proffered Oral Presentations - Molecular Profiling to Elucidate Tumor Heterogeneity and Clonal Evolution: abstract no. 985
This journal suppl. entitled: Proceedings: AACR Annual Meeting 2014
Persistent Identifierhttp://hdl.handle.net/10722/213528
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372

 

DC FieldValueLanguage
dc.contributor.authorHedberg, ML-
dc.contributor.authorGoh, G-
dc.contributor.authorFreilino, M-
dc.contributor.authorZeng, Y-
dc.contributor.authorLui, VW-
dc.contributor.authorHerbst, RS-
dc.contributor.authorLifton, RP-
dc.contributor.authorGrandis, JR-
dc.date.accessioned2015-08-05T01:33:25Z-
dc.date.available2015-08-05T01:33:25Z-
dc.date.issued2014-
dc.identifier.citationThe 2014 Annual Meeting of the American Association for Cancer research (AACR 2014), San Diego, CA., 5-9 April 2014. In Cancer Research, 2014, v. 74 n. 19 suppl., abstract no. 985-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/213528-
dc.descriptionMeeting Theme: Harnessing Breakthroughs - Targeting Cures-
dc.descriptionSession - Molecular and Cellular Biology: Proffered Oral Presentations - Molecular Profiling to Elucidate Tumor Heterogeneity and Clonal Evolution: abstract no. 985-
dc.descriptionThis journal suppl. entitled: Proceedings: AACR Annual Meeting 2014-
dc.description.abstractRecent whole exome sequencing (WES) studies have reported the mutations that characterize primary head and neck squamous cell carcinomas (HNSCC). While exposure to tobacco, alcohol and HPV infection are known to contribute to HNSCC development and prognosis, the largest obstacle to long term survival is recurrent and metastatic disease. Approximately 50% of patients present with synchronous lymph node metastases (SLNM), where 5-year adjusted survival is ≈85% for patients without SLNM compared with 30-60% in patients with SLNM. 20-30% of patients cured of their primary HNSCC go on to develop recurrent disease, which is usually refractory to standard therapies. Here, we report the first WES study of paired primary tumor and SLNM from 14 HNSCC patients, and paired primary tumor and metachronous loco-regional metastases (MLRM) from 11 HNSCC patients. Primary tumors averaged 67 nonsynonymous mutations per tumor (n=21), SLNM averaged 89.3 (n=12), and MLRM averaged 41.7 (n=9). TP53 was the only gene mutated in a majority (57%) of primary tumors in our cohort. We observed similar rates of mutation in several of the TCGA-defined “HNSCC signature” genes in our primary cohort, including FAT1 (14.3%) and CASP8 (4.8%), among others. While the size of our cohort does not allow for appropriately powered statistical analyses; 206 and 204 genes, were mutated in metastatic tumors, but not the respective paired primary tumors, in the SLNM and MLRM cohorts, respectively. AP2B1 and ITPR3 mutations were enriched in SLNM, as newly acquired mutations were seen in multiple (2 and 2/12) SLNM samples. GLUL and DDR2 mutations were enriched in MLRM, as newly acquired mutations were seen in multiple (2 and 2/9) MLRM samples. All 4 genes have previously been implicated in the metastatic process in other cancers. The potential enrichment of DDR2 mutations in HNSCC metastases is especially intriguing, as mutations in this gene have been shown to confer sensitivity to the SRC-family kinase inhibitor, dasatinib, in lung and breast cancer. Here we report exquisite sensitivity to dasatinib in our HNSCC preclinical models harboring DDR2 mutations, suggesting further investigation of this drug is warranted in recurrent HNSCC. ©2014 American Association for Cancer Research.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/-
dc.relation.ispartofCancer Research-
dc.subjectMedical sciences-
dc.subjectOncology-
dc.titleThe mutational landscape of LN metastasis and recurrence in HNSCC-
dc.typeConference_Paper-
dc.identifier.emailLui, VW: vlui002@hku.hk-
dc.identifier.authorityLui, VW=rp01876-
dc.identifier.doi10.1158/1538-7445.AM2014-985-
dc.identifier.hkuros246505-
dc.identifier.volume74-
dc.identifier.issue19 suppl.-
dc.publisher.placeUnited States-

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