Dataset Information

Genomic analysis of metastatic cutaneous squamous cell carcinoma.

ABSTRACT:

Purpose

A rare 5% of cutaneous squamous cell carcinomas (cSCC) metastasize, lack FDA-approved therapies, and carry a poor prognosis. Our aim was to identify recurrent genomic alterations in this little-studied population of metastatic cSCCs.

Experimental design

We performed targeted sequencing of 504 cancer-associated genes on lymph node metastases in 29 patients with cSCC and identified mutations and somatic copy-number alterations associated with metastatic cSCC. We determined significantly mutated, deleted, and amplified genes and associated genomic alterations with clinical variables.

Results

The cSCC genome is heterogeneous with widely varying numbers of genomic alterations and does not appear to be associated with human papillomavirus. We found previously identified recurrently altered genes (TP53, CDKN2A, NOTCH1/2) but also a wide spectrum of oncogenic mutations affecting RAS/RTK/PI3K, squamous differentiation, cell cycle, and chromatin remodeling pathway genes. Specific mutations in known oncogenic drivers and pathways were correlated with inferior patient outcomes. Our results suggest potential therapeutic targets in metastatic cSCC, including PIK3CA, FGFR3, BRAF, and EGFR, similar to those reported in SCCs of the lung and head and neck, suggesting that clinical trials could be developed to accrue patients with SCCs from multiple sites of origin.

Conclusions

We have genomically characterized a rare cohort of 29 metastatic cSCCs and identified a diverse array of oncogenic alterations that can guide future studies of this disease.

SUBMITTER: Li YY

PROVIDER: S-EPMC4359951 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Publications

Genomic analysis of metastatic cutaneous squamous cell carcinoma.

Li Yvonne Y YY Hanna Glenn J GJ Laga Alvaro C AC Haddad Robert I RI Lorch Jochen H JH Hammerman Peter S PS

Clinical cancer research : an official journal of the American Association for Cancer Research 20150114 6

<h4>Purpose</h4>A rare 5% of cutaneous squamous cell carcinomas (cSCC) metastasize, lack FDA-approved therapies, and carry a poor prognosis. Our aim was to identify recurrent genomic alterations in this little-studied population of metastatic cSCCs.<h4>Experimental design</h4>We performed targeted sequencing of 504 cancer-associated genes on lymph node metastases in 29 patients with cSCC and identified mutations and somatic copy-number alterations associated with metastatic cSCC. We determined s ...[more]

PMID: 25589618

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Project description:Metastatic cutaneous squamous cell carcinoma (CSCC) is a highly morbid disease requiring radical surgery and adjuvant therapy, which is associated with a poor prognosis. Yet, compared to other advanced malignancies, relatively little is known of the genomic landscape of metastatic CSCC. We have previously reported the mutational signatures and mutational patterns of CCCTC-binding factor (CTCF) regions in metastatic CSCC. However, many other genomic components (indel signatures, non-coding drivers, and structural variants) of metastatic CSCC have not been reported. To this end, we performed whole genome sequencing on lymph node metastases and blood DNA from 25 CSCC patients with regional metastases of the head and neck. We designed a multifaceted computational analysis at the whole genome level to provide a more comprehensive perspective of the genomic landscape of metastatic CSCC. In the non-coding genome, 3' untranslated region (3'UTR) regions of EVC (48% of specimens), PPP1R1A (48% of specimens), and ABCA4 (20% of specimens) along with the tumor-suppressing long non-coding RNA (lncRNA) LINC01003 (64% of specimens) were significantly functionally altered (Q-value < 0.05) and represent potential non-coding biomarkers of CSCC. Recurrent copy number loss in the tumor suppressor gene PTPRD was observed. Gene amplification was much less frequent, and few genes were recurrently amplified. Single nucleotide variants driver analyses from three tools confirmed TP53 and CDKN2A as recurrently mutated genes but also identified C9 as a potential novel driver in this disease. Furthermore, indel signature analysis highlighted the dominance of ID signature 13 (ID13) followed by ID8 and ID9. ID9 has previously been shown to have no association with skin melanoma, unlike ID13 and ID8, suggesting a novel pattern of indel variation in metastatic CSCC. The enrichment analysis of various genetically altered candidates shows enrichment of "TGF-beta regulation of extracellular matrix" and "cell cycle G1 to S check points." These enriched terms are associated with genetic instability, cell proliferation, and migration as mechanisms of genomic drivers of metastatic CSCC.

Project description:ImportanceCutaneous squamous cell carcinoma (cSCC) is the most common skin cancer with metastatic potential, but epidemiologic data are poor. Changes to the National Cancer Registration and Analysis Service (NCRAS) in England have allowed more accurate data analysis of primary and metastatic cSCC since 2013.ObjectiveTo assess the national incidence of cSCC and metastatic cSCC (mcSCC) in England from 2013 through 2015.Design, setting, and participantsThis national population-based study identified a cohort of patients with cSCC and mcSCC in England from January 1, 2013, through December 31, 2015. Patients were identified using diagnostic codes derived from pathology reports in the NCRAS. Data were analyzed from March 1, 2017, through March 1, 2018.Main outcomes and measuresIncidence rates across sex and risk factors for cSCC were derived from the NCRAS data. Risk of occurrence of mcSCC among the population with cSCC was assessed with Cox proportional hazards regression analysis to determine indicators of mcSCC.ResultsAmong the 76 977 patients with first primary cSCC in 2013 through 2015 (62.7% male; median age, 80 years [interquartile range, 72-86 years]), the age-standardized rates for the first registered cSCC in England from 2013 through 2015 were 77.3 per 100 000 person-years (PY) (95% CI, 76.6-78.0) in male patients and 34.1 per 100 000 PY (95% CI, 33.7-34.5) in female patients. Increased primary cSCC tumor count was observed in older, white male patients in lower deprivation quintiles. After a maximum follow-up of 36 months, cumulative incidence of mcSCC developed in 1.1% of women and 2.4% of men with a primary cSCC. Significant increases in the risk of metastasis with adjusted hazard rates of approximately 2.00 were observed in patients who were aged 80 to 89 years (hazard ratio [HR], 1.23; 95% CI, 1.07-1.43), 90 years or older (HR, 1.35; 95% CI, 1.09-1.66), male (HR, 1.79; 95% CI, 1.52-2.10), immunosuppressed (HR, 1.99; 95% CI, 1.64-2.42), and in higher deprivation quintiles (HR for highest quintile, 1.64; 95% CI, 1.35-2.00). Primary cSCC located on the ear (HR, 1.70; 95% CI, 1.42-2.03) and lip (HR, 1.85; 95% CI, 1.29-2.63) were at highest risk of metastasis.Conclusions and relevanceThis study presents the first national study of the incidence of mcSCC. With limited health care resources and an aging population, accurate epidemiologic data are essential for informing future health care planning, identifying high-risk patients, and evaluating skin cancer prevention policies.

Project description:IntroductionAdjuvant radiotherapy is an established component in the management of metastatic cutaneous squamous cell carcinoma (SCC) involving the parotid gland. Radiotherapy technique, dose and volumes are seldom described sufficiently to allow close examination. We report our treatment outcomes and focus on treatment-related factors that affect outcomes in this cohort.MethodsWe performed a retrospective review of patients with metastatic cutaneous SCCs who underwent parotidectomy with or without ipsilateral neck dissection. All patients received adjuvant radiotherapy. Demographics, clinical data and treatment details were collected from an intuitional electronic database. Individual patient-level radiotherapy technique, volumes and doses were reviewed.ResultsBetween July 2008 and July 2018, 60 patients met our inclusion criteria. Median follow-up duration was 32.7 months. The mean age was 66.4 years. The majority of patients (49 patients) received full neck irradiation. The 2-year and 5-year loco-regional failure-free survival was 87% (95% confidence interval (CI): 0.74-0.93) and 71% (95% CI: 0.52, 0.83), respectively. The 2-year and 5-year overall survival was 76% (95% CI: 0.62, 0.85) and 60% (95% CI: 0.45, 0.72), respectively. There were 15 cases of loco-regional failures, with 6 cases with dermal involvement. Lymphovascular invasion (LVI) was associated with higher loco-regional failure (hazard ratio: 8.43, 95% CI: 1.85-38.39, P = 0.005) and cancer-specific mortality (hazard ratio: 5.40, 95% CI: 1.40-20.87, P = 0.015). Treatment technique, intensity-modulated radiation therapy (IMRT) vs 3D conformal radiotherapy (3D CRT), bolus use, perineural invasion (PNI) and surgical margins were not significantly associated with loco-regional failure.ConclusionWe demonstrated high loco-regional control rates with routine use of comprehensive adjuvant radiotherapy. The presence of LVI was identified as a strong predictor for recurrence. Further analysis will help to define optimal radiation dose and techniques.

Dataset Information

Genomic analysis of metastatic cutaneous squamous cell carcinoma.

Purpose

Experimental design

Results

Conclusions

Publications

Genomic analysis of metastatic cutaneous squamous cell carcinoma.

Similar Datasets

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