Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy
About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. Howev...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-03-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/11/4/445 |
| _version_ | 1797727721949757440 |
|---|---|
| author | David M. Vossen Caroline V.M. Verhagen Martijn van der Heijden Paul B.M. Essers Harry Bartelink Marcel Verheij Lodewyk F.A. Wessels Michiel W.M. van den Brekel Conchita Vens |
| author_facet | David M. Vossen Caroline V.M. Verhagen Martijn van der Heijden Paul B.M. Essers Harry Bartelink Marcel Verheij Lodewyk F.A. Wessels Michiel W.M. van den Brekel Conchita Vens |
| author_sort | David M. Vossen |
| collection | DOAJ |
| description | About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance in patient outcome prognosis remains to be assessed in patients that receive standard-of-care chemoradiotherapy. We therefore tested whether frequent genetic alterations were associated with progression free survival (PFS) in advanced stage HNSCC patients who were uniformly treated with definitive platinum-based chemoradiotherapy. To this end, we performed targeted DNA sequencing on frozen pre-treatment tumor biopsy material from 77 patients with advanced stage oro- and hypopharyngeal carcinoma. This provided somatic point mutation and copy number aberration data of 556 genes. The most frequently mutated genes, <i>TP53</i> (62%), <i>CCND1</i> (51%), <i>CDKN2A</i> (30%) and <i>PIK3CA</i> (21%), were not associated with PFS. However, co-occurring <i>CCND1</i> and <i>CDKN2A</i> mutations were associated with short PFS (HR 2.24, <i>p</i> = 0.028) in HPV-negative tumors. Furthermore, tumor mutational burden (sum of somatic point mutations) showed a trend towards decreased PFS (HR 1.9, <i>p</i> = 0.089), and chromosomal instability (CIN) was associated with shorter PFS (HR 2.3, <i>p</i> = 0.023), independent of HPV status. Our results show that tumor mutational burden, CIN markers, and co-occurring <i>CCND1</i> and <i>CDKN2A</i> mutations are associated with chemoradiotherapy outcomes in advanced stage oro- and hypopharyngeal HNSCC patients, thereby highlighting their prognostic potential. Given their poor prognosis association and link to biological targets, they may also identify patients for novel targeted therapies and immunotherapies. |
| first_indexed | 2024-03-12T11:03:51Z |
| format | Article |
| id | doaj.art-d2aa0268742f41e5945d3912f4b8d5a6 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T11:03:51Z |
| publishDate | 2019-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d2aa0268742f41e5945d3912f4b8d5a62023-09-02T04:29:45ZengMDPI AGCancers2072-66942019-03-0111444510.3390/cancers11040445cancers11040445Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive ChemoradiotherapyDavid M. Vossen0Caroline V.M. Verhagen1Martijn van der Heijden2Paul B.M. Essers3Harry Bartelink4Marcel Verheij5Lodewyk F.A. Wessels6Michiel W.M. van den Brekel7Conchita Vens8Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The NetherlandsDivision of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The NetherlandsDivision of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The NetherlandsDepartment of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, 1066 CX Amsterdam, The NetherlandsDepartment of Radiation Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The NetherlandsDivision of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The NetherlandsDivision of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The NetherlandsDepartment of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, 1066 CX Amsterdam, The NetherlandsDivision of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The NetherlandsAbout half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance in patient outcome prognosis remains to be assessed in patients that receive standard-of-care chemoradiotherapy. We therefore tested whether frequent genetic alterations were associated with progression free survival (PFS) in advanced stage HNSCC patients who were uniformly treated with definitive platinum-based chemoradiotherapy. To this end, we performed targeted DNA sequencing on frozen pre-treatment tumor biopsy material from 77 patients with advanced stage oro- and hypopharyngeal carcinoma. This provided somatic point mutation and copy number aberration data of 556 genes. The most frequently mutated genes, <i>TP53</i> (62%), <i>CCND1</i> (51%), <i>CDKN2A</i> (30%) and <i>PIK3CA</i> (21%), were not associated with PFS. However, co-occurring <i>CCND1</i> and <i>CDKN2A</i> mutations were associated with short PFS (HR 2.24, <i>p</i> = 0.028) in HPV-negative tumors. Furthermore, tumor mutational burden (sum of somatic point mutations) showed a trend towards decreased PFS (HR 1.9, <i>p</i> = 0.089), and chromosomal instability (CIN) was associated with shorter PFS (HR 2.3, <i>p</i> = 0.023), independent of HPV status. Our results show that tumor mutational burden, CIN markers, and co-occurring <i>CCND1</i> and <i>CDKN2A</i> mutations are associated with chemoradiotherapy outcomes in advanced stage oro- and hypopharyngeal HNSCC patients, thereby highlighting their prognostic potential. Given their poor prognosis association and link to biological targets, they may also identify patients for novel targeted therapies and immunotherapies.https://www.mdpi.com/2072-6694/11/4/445head and neck squamous cell carcinomapharyngeal neoplasmsgenomicsDNA sequence analysismutationchemoradiotherapyprognosis |
| spellingShingle | David M. Vossen Caroline V.M. Verhagen Martijn van der Heijden Paul B.M. Essers Harry Bartelink Marcel Verheij Lodewyk F.A. Wessels Michiel W.M. van den Brekel Conchita Vens Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy Cancers head and neck squamous cell carcinoma pharyngeal neoplasms genomics DNA sequence analysis mutation chemoradiotherapy prognosis |
| title | Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy |
| title_full | Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy |
| title_fullStr | Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy |
| title_full_unstemmed | Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy |
| title_short | Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy |
| title_sort | genetic factors associated with a poor outcome in head and neck cancer patients receiving definitive chemoradiotherapy |
| topic | head and neck squamous cell carcinoma pharyngeal neoplasms genomics DNA sequence analysis mutation chemoradiotherapy prognosis |
| url | https://www.mdpi.com/2072-6694/11/4/445 |
| work_keys_str_mv | AT davidmvossen geneticfactorsassociatedwithapooroutcomeinheadandneckcancerpatientsreceivingdefinitivechemoradiotherapy AT carolinevmverhagen geneticfactorsassociatedwithapooroutcomeinheadandneckcancerpatientsreceivingdefinitivechemoradiotherapy AT martijnvanderheijden geneticfactorsassociatedwithapooroutcomeinheadandneckcancerpatientsreceivingdefinitivechemoradiotherapy AT paulbmessers geneticfactorsassociatedwithapooroutcomeinheadandneckcancerpatientsreceivingdefinitivechemoradiotherapy AT harrybartelink geneticfactorsassociatedwithapooroutcomeinheadandneckcancerpatientsreceivingdefinitivechemoradiotherapy AT marcelverheij geneticfactorsassociatedwithapooroutcomeinheadandneckcancerpatientsreceivingdefinitivechemoradiotherapy AT lodewykfawessels geneticfactorsassociatedwithapooroutcomeinheadandneckcancerpatientsreceivingdefinitivechemoradiotherapy AT michielwmvandenbrekel geneticfactorsassociatedwithapooroutcomeinheadandneckcancerpatientsreceivingdefinitivechemoradiotherapy AT conchitavens geneticfactorsassociatedwithapooroutcomeinheadandneckcancerpatientsreceivingdefinitivechemoradiotherapy |