ABSTRACT
BACKGROUND: A germline mutation in the 3'-untranslated region of KRAS (rs61764370, KRAS-variant: TG/GG) has previously been associated with altered patient outcome and drug resistance/sensitivity in various cancers. We examined the prognostic and predictive significance of this variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: We conducted a retrospective study of 103 HNSCCs collected from three completed clinical trials. KRAS-variant genotyping was conducted for these samples and 8 HNSCC cell lines. p16 expression was determined in a subset of 26 oropharynx tumors by immunohistochemistry. Microarray analysis was also utilized to elucidate differentially expressed genes between KRAS-variant and non-variant tumors. Drug sensitivity in cell lines was evaluated to confirm clinical findings. RESULTS: KRAS-variant status was determined in 95/103 (92%) of the HNSCC tumor samples and the allelic frequency of TG/GG was 32% (30/95). Three of the HNSCC cell lines (3/8) studied had the KRAS-variant. No association between KRAS-variant status and p16 expression was observed in the oropharynx subset (Fisher's exact test, P = 1.0). With respect to patient outcome, patients with the KRAS-variant had poor progression-free survival when treated with cisplatin (log-rank P = 0.002). Conversely, KRAS-variant patients appeared to experience some improvement in disease control when cetuximab was added to their platinum-based regimen (log-rank P = 0.04). CONCLUSIONS: The TG/GG rs61764370 KRAS-variant is a potential predictive biomarker for poor platinum response in R/M HNSCC patients. CLINICAL TRIAL REGISTRATION NUMBERS: NCT00503997, NCT00425750, NCT00003809.
Subject(s)
Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/genetics , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/genetics , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Proto-Oncogene Proteins/genetics , ras Proteins/genetics , 3' Untranslated Regions/genetics , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized , Carcinoma, Squamous Cell/pathology , Cetuximab , Cisplatin/administration & dosage , Cisplatin/adverse effects , Cyclin-Dependent Kinase Inhibitor p16/biosynthesis , Disease-Free Survival , Drug Resistance, Neoplasm/genetics , Female , Gene Expression Regulation, Neoplastic , Genotype , Head and Neck Neoplasms/pathology , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local/pathology , Prognosis , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogene Proteins p21(ras) , Squamous Cell Carcinoma of Head and Neck , ras Proteins/biosynthesisABSTRACT
Stable nitrogen isotopes (delta(15)N) in bioindicators are increasingly employed to identify nitrogen sources in many ecosystems and biological characteristics of the eastern oyster (Crassostrea virginica) make it an appropriate species for this purpose. To assess nitrogen isotopic fractionation associated with assimilation and baseline variations in oyster mantle, gill, and muscle tissue delta(15)N, manipulative fieldwork in Chesapeake Bay and corresponding modeling exercises were conducted. This study (1) determined that five individuals represented an optimal sample size; (2) verified that delta(15)N in oysters from two locations converged after shared deployment to a new location reflecting a change in nitrogen sources; (3) identified required exposure time and temporal integration (four months for muscle, two to three months for gill and mantle); and (4) demonstrated seasonal delta(15)N increases in seston (summer) and oysters (winter). As bioindicators, oysters can be deployed for spatial interpolation of nitrogen sources, even in areas lacking extant populations.
