Genetic Changes in Squamous Cell Lung Cancer A Review

Department of Hematology Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer (Impact Factor: 5.28). 05/2012; 7(5):924-33. DOI: 10.1097/JTO.0b013e31824cc334
Source: PubMed


Identifying specific somatic mutations that drive tumor growth has transformed the treatment of lung cancer. For example, cancers with sensitizing epidermal growth factor receptor mutations and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase translocations can have remarkable responses to epidermal growth factor receptor and ALK inhibitors respectively, leading to significant clinical benefit. However, effective molecularly targeted therapies have disproportionately impacted adenocarcinomas compared to squamous cell carcinomas, and never or light smokers compared to heavy smokers. Further progress in non-small-cell lung cancer will require the identification and effective targeting of molecular alterations in all subtypes of lung cancer. Here, we review the current knowledge about the molecular alterations found in squamous cell carcinoma of the lung. First, we will discuss the ongoing efforts to comprehensively assess the squamous cell carcinoma genome. We will then discuss the evidence supporting the role of specific genes in driving squamous cell carcinomas. By describing the landscape of somatic targets in squamous cell lung cancer, we hope to crystallize the current understanding of potential targets, spur development of therapies that can have clinical impact, and underscore the importance of new discoveries in this field.

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    • "Additionally, SCC is highly immunogenic, thus susceptible to immunotherapeutic approaches. Both characteristics are related to cigarette smoking, which is commonly associated with SCC and with lack of driver mutations in non-SCC [1] [2]. Interestingly, the last few months have seen a partial inversion of the general trend favoring non-SCC. "
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    ABSTRACT: Squamous non-small cell lung cancer (NSCLC) has always been characterized by a limited number of therapeutic options and by the lack of actionable biomarkers compared to its non-squamous counterpart. Recent clinical trials have led to the approval of new anti-neoplastic drugs available to both non-squamous and squamous NSCLC, consisting in a vascular-disrupting agent and two immune check-point inhibitors; additionally, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) is currently under evaluation by the Food and Drug Administration (FDA). While predictive molecular biomarkers have not been identified with consistency and are still highly demanded, these agents proved themselves noteworthy and can be considered a powerful addition to the available treatments for squamous NSCLC.
    Expert Review of Anti-infective Therapy 11/2015; DOI:10.1586/14737140.2016.1121112 · 2.25 Impact Factor
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    • "Squamous cell carcinoma (SQ) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases and is closely associated with long term tobacco exposure while adenocarcinoma (AD) is the most common form of NSCLC, even more so in never or light smokers [10]. AD tumors often present in the periphery and are the most prevalent histology detected by CT [11-13]. "
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    ABSTRACT: Background CT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations. Results Blood-based proteomic profiles were generated with SOMAscan technology, which measured 1033 proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation. Conclusions Selecting biomarkers resistant to sample processing variation led to robust lung cancer biomarkers that performed consistently in independent validations. They form a sensitive signature for detection of lung cancer, especially squamous cell histology. This non-invasive test could be used to improve the positive predictive value of CT screening, with the potential to avoid invasive evaluation of nonmalignant pulmonary nodules.
    Clinical Proteomics 08/2014; 11(1):32. DOI:10.1186/1559-0275-11-32
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    • "Mutations in KRAS and BRAF are present at the low frequencies of 6 and 2%, respectively, in LSCC, mostly occurring in current or former smokers (2–5). It has been reported that BRAF and KRAS mutations do not occur concomitantly within the same tumor, as simultaneous mutation in the same RAS/RAF/MEK/ERK signal pathway are redundant for the tumor cells (3,5). The present study describes the case of a treatment-naïve LSCC patient with coexisting BRAF V600E and oncogenic KRAS G12A mutations in the primary lung lesion and the peritoneum metastases, and with prominent manifestations of peritoneal carcinomatosis and an eosinophilic leukemoid reaction. "
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    ABSTRACT: Peritoneal carcinomatosis from lung cancer is rare, particularly from lung squamous cell carcinoma (LSCC). Concurrent somatic BRAF and KRAS mutations within the same tumor specimen have not been reported. The present study describes the case of a treatment-naïve LSCC patient with coexisting BRAF V600E and oncogenic KRAS G12A mutations in the primary lung lesion and the peritoneal metastases. The patient presented with prominent peritoneal carcinomatosis and an eosinophilic leukemoid reaction, but no respiratory symptoms. The patient succumbed 8 days after the onset of the condition due to rapid aggravation of the peritoneal carcinomatosis. To the best of our knowledge, this is the first study concerning the coexistence of BRAF and KRAS mutations in LSCC. Intensive activation of ERK was also observed in the primary lung lesion and the peritoneal metastases. Although the exact pathogenesis was unclear, the observations indicated that in the present study, the BRAF V600E and KRAS G12A mutations may have cooperate in inducing the malignant phenotype of LSCC. This case also highlighted the potential aggressive course and unusual pattern of spread of this specific dual-mutated tumor.
    Oncology letters 08/2014; 8(2):589-593. DOI:10.3892/ol.2014.2169 · 1.55 Impact Factor
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