Analysis of clinically relevant somatic mutations in high-risk head and neck cutaneous squamous cell carcinoma

Zilberg, Catherine; Lee, Matthew Weicai; Yu, Bing; Ashford, Bruce; Kraitsek, Spiridoula; Ranson, Marie; Shannon, Kerwin F.; Cowley, Mark J.; Iyer, N. Gopalakrishna; Palme, Carsten E.; Ch’ng, Sydney; Low, Tsu-Hui Hubert; O’Toole, Sandra A.; Clark, Jonathan; Gupta, Ruta

doi:10.1038/modpathol.2017.128

Cited by 45 publications

(35 citation statements)

References 53 publications

(57 reference statements)

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“…While whole genome and whole exome studies produce significantly larger amounts of data, use of a clinically relevant gene panel that encompasses the current therapeutic armamentarium ensures reproducibility, cost effectivity and rapid translation. This study expands on previous work by Zilberg et al 3 and assesses genetic alterations in high risk HNcSCC present at variant allele frequencies (VAFs) >1% for suitability of targeted therapies in light of the current literature demonstrating response, as well resistance, to targeted therapies at VAFs<5% of the implicated mutation 4…”

Section: Introductionsupporting

confidence: 55%

“…Patient selection and sample preparation were performed as per Zilberg et al 3. High-risk characteristics were defined as per the seventh edition of the American Joint Committee on Cancer Staging (AJCC) Manual 6.…”

Section: Methodsmentioning

confidence: 99%

“…Semiquantitatively assessed tumour cellularity (table 1) was used to calculate true VAF. Unlike in our previous study,3 all mutations with a VAF >1% were included in analysis. Those with a read depth of <50 were deemed likely artefacts and were filtered out.…”

Section: Methodsmentioning

confidence: 99%

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Is high-risk cutaneous squamous cell carcinoma of the head and neck a suitable candidate for current targeted therapies?

et al. 2019

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ObjectiveCutaneous squamous cell carcinoma (cSCC) is the second most common malignancy, most frequently affecting the head and neck. Treatment often requires surgery and can have significant functional morbidity. Research into disease pathogenesis and second line medical management of cSCC is limited. We assess genetic mutations in high-risk, primary head and neck cutaneous squamous cell carcinomas (HNcSCC) that may hinder or be beneficial for use of targeted therapy in disease management.MethodsGenetic alterations and variant allele frequencies (VAFs) were analysed using a clinically relevant 48 gene panel in 10 primary high-risk non-metastatic treatment-naïve HNcSCC to evaluate applicability of targeted therapeutics. Variants present at all VAFs were evaluated for pathogenicity. Somatic mutation patterns of individual tumours were analysed.ResultsHigh-risk HNcSCC showed a high proportion (82%) of C to T transitions in keeping with ultraviolet-mediated damage. There was significant intratumour genetic heterogeneity in this cohort (MATH scores 20–89) with the two patients <45 years of age showing highest intratumour heterogeneity. TP53 was altered at VAF >22% in all cases, and mutations with highest VAF were observed in tumour suppressor genes in 80%. 70% of cases demonstrated at least one mutation associated with treatment resistance (KIT S821F, KIT T670I, RAS mutations at codons 12 and 13).ConclusionWe demonstrate high proportion tumour suppressor loss of function mutations, high intratumour genetic heterogeneity, and presence of well recognised resistance mutations in treatment naïve primary HNcSCC. These factors pose challenges for successful utilisation of targeted therapies.

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Section: Introductionsupporting

confidence: 55%

Section: Methodsmentioning

confidence: 99%

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Is high-risk cutaneous squamous cell carcinoma of the head and neck a suitable candidate for current targeted therapies?

et al. 2019

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“…4,5 We have recently identified alterations in MLH1 genes in two young (<45 years of age) cSCC patients using Illumina TruSeq 48 gene panel. 6 Meira et al 7 have demonstrated MSH2-null mice to have an increased predisposition to UVB induced tumors with onset of tumors at lower dosage of UVB and more aggressive progression. MSI and MMR alterations are well described in sebaceous neoplasms in Muir-Torre syndrome.…”

Section: Introductionmentioning

confidence: 99%

Mismatch repair protein loss in cutaneous head and neck squamous cell carcinoma

Vasan

Anand

Satgunaseelan

et al. 2020

Journal of Surgical Oncology

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Background The treatment of advanced cutaneous head and neck cutaneous squamous cell carcinomas (HNcSCC) results in significant morbidity. Recently, immune checkpoint inhibitor treatment has been approved for DNA mismatch repair (MMR) deficient patients in a histology‐agnostic manner. This study aims to evaluate the incidence of MMR deficiency in advanced HNcSCC and its association with clinicopathologic factors. Methods The cohort included 176 consecutive HNcSCC cases treated with curative intent. Immunohistochemistry for MMR proteins (hMLH1, hMSH2, hMSH6, and hPMS2) was performed. Clinicopathological and survival data was collected prospectively. Results The incidence of MMR protein deficiency was 9.1%. There was no association between age, incidence of metachronous malignancies, clinicopathological factors, or survival outcomes. Conclusion A higher incidence of MMR deficiency was observed in this cohort of advanced HNcSCC. The lack of association with young age at onset or increased incidence of metachronous malignancies suggests that MMR deficiency is likely to be sporadic in HNcSCC.

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“…Furthermore, compared with NTRK-wt group, APC and PTPRD mutations were more common in NTRK-GA group. APC and PTPRD have been reported to associated with inferior outcome of HNSCC [42,43]. The potential interactions between these two genes and NTRK aberrations need further study.…”

Section: Discussionmentioning

confidence: 98%

The Genomic Profiling in Chinese Head and Neck Cancer and Incidence of NTRK Fusion

Xu¹,

R²,

Wang³

et al. 2020

Preprint

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Background Head and neck cancers are aggressive epithelial tumors and well recognized as a particularly challenging class of tumors to treat. Comprehensive molecular profiling is leading to the development of “personalized” or “precision” medicine. Here we report the genomic profiling of Chinese head and neck cancers and the incidence of NTRK aberrations. Methods We retrospectively analyzed the genetic aberrations in 127 patients of Chinese head and neck cancer. All the patients were detected by 1021-gene panel (including NTRK1, NTRK2, NTRK3) of hybridization capture-based next-generation sequencing with tumor tissue and matched peripheral blood control samples. Results This studied was inspired by the outcome benefit of a parotid cancer patient harboring ETV6-NTRK3 fusion, who received crizotinib treatment and achieved a 2-year progression-free survival (PFS). Then, we reviewed 127 cases of head and neck cancer in our database. The most common histology type was HNSCC (79.5%). The genomic profiling indicated that both in our Chinese cohort and TCGA database, TP53 is the most frequently mutated gene in head and neck cancer. The incidence of NTRK genetic aberrations was 7.9% (10/127) including NTRK fusion (n = 4, 3.1%) and NTRK mutation (n = 6, 4.7%). The most common fusion was ETV6-NTRK3 (n = 3, 2.4%). Compared to NTRK-wt group, NTRK aberration group had more APC and PTPRD aberrations (p < 0.05). The association of genetic aberrations with tumor mutation burden (TMB) had been analyzed. NTRK fusion-group had a lower TMB compared to the NTRK-wt group (p = 0.034). TP53 and LRP1B showed significant association with higher TMB (both p < 0.01), which may be potential markers of immunotherapy in head and neck cancer patients. Conclusions Our data is the first study to report the genomic profiling in Chinese head and neck cancers and the incidence of NTRK fusion. About 3% of Chinese head and neck patients may benefit from targeted therapy of NTRK inhibitors. An ETV6-NTRK3 fusion patient reached a long-term response with crizotinib treatment,indicating crizotinib might be an alternative treatment option for patients with NTRK fusions.

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Analysis of clinically relevant somatic mutations in high-risk head and neck cutaneous squamous cell carcinoma

Cited by 45 publications

References 53 publications

Is high-risk cutaneous squamous cell carcinoma of the head and neck a suitable candidate for current targeted therapies?

Is high-risk cutaneous squamous cell carcinoma of the head and neck a suitable candidate for current targeted therapies?

Mismatch repair protein loss in cutaneous head and neck squamous cell carcinoma

The Genomic Profiling in Chinese Head and Neck Cancer and Incidence of NTRK Fusion

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