A B S T R A C T PurposeRecent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking. Patients and MethodsHPV status was determined for all 271 oropharyngeal cancers collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses. ResultsHPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay (P trend Ͻ .05). For example, HPV prevalence by Inno-LiPA increased from 16.3% during 1984 to 1989 to 71.7% during 2000 to 2004. Median survival was significantly longer for HPV-positive than for HPV-negative patients (131 v 20 months; log-rank P Ͻ .001; adjusted hazard ratio, 0.31; 95% CI, 0.21 to 0.46). Survival significantly increased across calendar periods for HPV-positive (P ϭ .003) but not for HPV-negative patients (P ϭ .18). Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000). If recent incidence trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020. ConclusionIncreases in the population-level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection.

SUMMARY Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA-sequencing in primary human hepatocytes activated with synthetic dsRNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a novel, transiently induced region that harbors dinucleotide variant ss469415590 (TT/ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590-ΔG is a frame-shift variant that creates a novel primate-specific gene, designated interferon lambda 4 (IFNL4), which encodes a protein of moderate similarity with IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, whereas it provides comparable information in Europeans and Asians. Transient over-expression of IFNL4 in a hepatoma cell line induced STAT1/STAT2 phosphorylation and expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.

Context Solid organ transplant recipients have elevated cancer risk due to immunosuppression and oncogenic viral infections. Since most prior research has concerned kidney recipients, large studies that include recipients of differing organs can inform cancer etiology. Objective Describe the overall pattern of cancer among solid organ transplant recipients. Design Cohort study using linked data from the U.S. Scientific Registry of Transplant Recipients (1987–2008) and 13 state/regional cancer registries. Participants and Setting Solid organ transplant recipients in the U.S. Main Outcome Measure Standardized incidence ratios (SIRs) and excess absolute risks (EARs) assessing relative and absolute cancer risk in transplant recipients compared to the general population. Results Registry linkages yielded data on 175,732 solid organ transplants (58.4% kidney, 21.6% liver, 10.0% heart, 4.0% lung). Overall cancer risk was elevated (N=10,656 cases, incidence 1374.7 per 100,000 person-years; SIR 2.10, 95%CI 2.06–2.14; EAR 719.3, 95%CI 693.3–745.6, per 100,000 person-years). Risk was increased (p<0.001) for 32 different malignancies, some related to known infections (e.g., anal cancer, Kaposi sarcoma) and others unrelated (e.g., melanoma, thyroid and lip cancers). The most common malignancies with elevated risk were non-Hodgkin lymphoma (N=1504, incidence 194.0; SIR 7.54, 95%CI 7.17–7.93; EAR 168.3, 95%CI 158.6–178.4) and cancers of the lung (N=1344, incidence 173.4; SIR 1.97, 95%CI 1.86–2.08; EAR 85.3, 95%CI 76.2–94.8), liver (N=930, incidence 120.0; SIR 11.56, 95%CI 10.83–12.33; EAR 109.6, 95%CI 102.0–117.6), and kidney (N=752, incidence 97.0; SIR 4.65, 95%CI 4.32–4.99; EAR 76.1, 95%CI 69.3–83.3). Lung cancer risk was most elevated in lung recipients (SIR 6.13, 95%CI 5.18–7.21) but also increased among other recipients (SIR 1.46, 95%CI 1.34–1.59 for kidney; 1.95, 1.74–2.19 for liver; 2.67, 2.40–2.95 for heart). Liver cancer was elevated only among liver recipients (SIR 43.83, 95%CI 40.90–46.91), who manifested exceptional risk in the first 6 months (SIR 508.97, 95%CI 474.16–545.66) and continuing two-fold excess for 10–15 years (SIR 2.22, 95%CI 1.57–3.04). Among kidney recipients, kidney cancer was elevated (SIR 6.66, 95%CI 6.12–7.23) and bimodal in onset. Kidney cancer was also increased in liver and heart recipients (SIR 1.80, 95%CI 1.40–2.29, and 2.90, 2.32–3.59, respectively). Conclusions Recipients of a kidney, liver, heart, or lung transplant have an increased risk for diverse infection-related and unrelated cancers, compared with the general population.

A complete compilation of results and R code for simulations and analyses are available in Molinaro et al. (2005) (http://linus.nci.nih.gov/brb/TechReport.htm).

Monoclonal gammopathy of undetermined significance (MGUS) is a premalig-

Dramatic declines in KS and NHL were temporally related to improving therapies, especially introduction of HAART, but those with AIDS remain at marked risk. Among non-AIDS-related cancers, a recent increase in Hodgkin lymphoma was observed.

Over a 15-year period (1991-2005), increases in non-AIDS-defining cancers were mainly driven by growth and aging of the AIDS population. This growing burden requires targeted cancer prevention and treatment strategies.

Background & Aims Epstein-Barr virus (EBV) has been causally associated with cancer; some gastric carcinomas have a monoclonal EBV genome in every cancer cell, indicating that they arose from a single infected progenitor cell. However, the proportion of EBV-positive gastric carcinomas is uncertain and the etiological significance is unknown. Methods We conducted a meta-analysis of 70 studies including 15,952 cases of gastric cancer assessed by in situ hybridization for EBV-encoded small RNA. Results The pooled prevalence estimate of EBV-positivity was 8.7% (95% CI: 7.5, 10.0) overall, with a two-fold difference by sex: 11.1% (95% CI: 8.7, 14.1) of gastric cancer cases in males vs. 5.2% (95% CI: 3.6, 7.4) of cases in females. Tumors arising in the gastric cardia (13.6%) or corpus (13.1%) were more than twice as likely to be EBV-positive as those in the antrum (5.2%; p<0.01 for both comparisons). EBV-prevalence was four times higher (35.1%) for tumors in post-surgical gastric stump/remnants. Over 90% of lymphoepithelioma-like carcinomas were EBV-positive but only 15 studies reported any cases of this type; prevalence did not significantly differ between the more common diffuse (7.6%) and intestinal (9.5%) histologies. EBV-prevalence was similar in cases from Asia (8.3%), Europe (9.2%), and the Americas (9.9%). Conclusions EBV-positive gastric cancers greatly differ from other gastric carcinomas based on sex, anatomic subsite, and surgically disrupted anatomy, indicating that it is a distinct etiologic entity. Epidemiologic studies comparing EBV-positive and -negative gastric cancers are warranted to investigate EBV’s role in gastric carcinogenesis.