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Summary Background The frequent recurrence of early-stage non-small-cell lung cancer (NSCLC) is generally attributable to metastatic disease undetected at complete resection. Management of such patients depends on prognostic staging to identify the individuals most likely to have occult disease. We aimed to develop and validate a practical, reliable assay that improves risk stratification compared with conventional staging. Methods A 14-gene expression assay that uses quantitative PCR, runs on formalin-fixed paraffin-embedded tissue samples, and differentiates patients with heterogeneous statistical prognoses was developed in a cohort of 361 patients with non-squamous NSCLC resected at the University of California, San Francisco. The assay was then independently validated by the Kaiser Permanente Division of Research in a masked cohort of 433 patients with stage I non-squamous NSCLC resected at Kaiser Permanente Northern California hospitals, and on a cohort of 1006 patients with stage I–III non-squamous NSCLC resected in several leading Chinese cancer centres that are part of the China Clinical Trials Consortium (CCTC). Findings Kaplan-Meier analysis of the Kaiser validation cohort showed 5 year overall survival of 71·4% (95% CI 60·5–80·0) in low-risk, 58·3% (48·9–66·6) in intermediate-risk, and 49·2% (42·2–55·8) in high-risk patients (ptrend=0·0003). Similar analysis of the CCTC cohort indicated 5 year overall survivals of 74·1% (66·0–80·6) in low-risk, 57·4% (48·3–65·5) in intermediate-risk, and 44·6% (40·2–48·9) in high-risk patients (ptrend<0·0001). Multivariate analysis in both cohorts indicated that no standard clinical risk factors could account for, or provide, the prognostic information derived from tumour gene expression. The assay improved prognostic accuracy beyond National Comprehensive Cancer Network criteria for stage I high-risk tumours (p<0·0001), and differentiated low-risk, intermediate-risk, and high-risk patients within all disease stages. Interpretation Our practical, quantitative-PCR-based assay reliably identified patients with early-stage non-squamous NSCLC at high risk for mortality after surgical resection. Funding UCSF Thoracic Oncology Laboratory and Pinpoint Genomics.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer rare throughout most of the world but common in certain geographic areas, such as southern Asia. While environmental factors and genetic susceptibility play important roles in NPC pathogenesis, the Epstein-Barr virus in particular has been implicated in the molecular abnormalities leading to NPC. There is upregulation of cellular proliferation pathways such as the Akt pathway, mitogen-activated protein kinases, and the Wnt pathway. Cell adhesion is compromised due to abnormal E-cadherin and β-catenin function. Aberrations in cell cycle are due to dysregulation of factors such as p16, cyclin D1, and cyclin E. Anti-apoptotic mechanisms are also upregulated. There are multiple abnormalities unique to NPC that are potential targets for novel treatments. Keywordsnasopharyngeal carcinoma (NPC); Epstein; Barr virus (EBV); LMP1; tumorigenesis; review Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma that usually develops around the ostium of the Eustachian tube in the lateral wall of the nasopharynx. 1 Though rare among whites, NPC is particularly common in the southern Chinese population of Guangdong, Inuits of Alaska, and native Greenlanders. 2,3 Chinese emigrants continue to have a high incidence of the disease, but the rate of NPC among ethnic Chinese born in North America is considerably lower than those born in China. 4 This epidemiologic evidence implies that both environmental factors and genetic susceptibility play roles in the development of NPC. The environmental factors may include exposure to nitrosamines in salted and pickled foods. 5 Certain human leukocyte antigen subtypes have been associated with NPC, as they have various genetic polymorphisms. 6 The World Health Organization classifies NPC based on histology. 7 Type 1, keratinizing squamous carcinoma, is characterized by well-differentiated cells that produce keratin. Type 2, nonkeratinizing squamous carcinoma, varies in cell differentiation but does not produce keratin. Type 3 is also nonkeratinizing, but is less differentiated, with highly variable cell types (clear cell, spindle cell, anaplastic). Types 2 and 3 NPC are Epstein-Barr virus (EBV) Correspondence to: D. M. Jablons, jablonsd@surgery.ucsf.edu. Standard treatment for NPC is radiotherapy, but concurrent adjuvant chemotherapy improves survival rates. 10 As with other cancers, the prognosis of NPC depends upon tumor size, lymph node involvement, and distant metastasis (TMN staging). 11 But NPC, in contrast to other head and neck malignancies, is highly sensitive to radiation and chemotherapy. 12,13 High survival rates are reported for stage 1 and 2 diseases, but the prognosis for metastatic disease remains poor even with combined radiation and chemotherapy treatment, with disease relapse rates as high as 82%. 14,15 Unfortunately, the majority of NPC is diagnosed at an advanced stage because of non-specific presenting symptoms (cervical nodal enlargement, headache, nasal and aural dysfunction), delay in seeking treat...