Gene network modeling via TopNet reveals functional dependencies between diverse tumor-critical mediator genes.

Malignant cell transformation and the underlying reprogramming of gene expression require the cooperation of multiple oncogenic mutations. This cooperation is reflected in the synergistic regulation of non-mutant downstream genes, so-called cooperation response genes (CRGs). CRGs affect diverse hallmark features of cancer cells and are not known to be functionally connected. However, they act as critical mediators of the cancer phenotype at an unexpectedly high frequency >50%, as indicated by genetic perturbations. Here, we demonstrate that CRGs function within a network of strong genetic interdependencies that are critical to the malignant state. Our network modeling methodology, TopNet, takes the approach of incorporating uncertainty in the underlying gene perturbation data and can identify non-linear gene interactions. In the dense space of gene connectivity, TopNet reveals a sparse topological gene network architecture, effectively pinpointing functionally relevant gene interactions. Thus, among diverse potential applications, TopNet has utility for identification of non-mutant targets for cancer intervention.

Genomic Landscape of Primary and Recurrent Anal Squamous Cell Carcinomas in Relation to HPV Integration, Copy-Number Variation, and DNA Damage Response Genes.

The incidence of anal squamous cell carcinoma (ASCC) has been increasing, particularly in populations with HIV. Human papillomavirus (HPV) is the causal factor in 85% to 90% of ASCCs, but few studies evaluated HPV genotypes and integrations in relation to genomic alterations in ASCC. Using whole-exome sequence data for primary (n = 56) and recurrent (n = 31) ASCC from 72 patients, we detected HPV DNA in 87.5% of ASCC, of which HPV-16, HPV-18, and HPV-6 were detected in 56%, 22%, and 33% of HIV-positive (n = 9) compared with 83%, 3.2%, and 1.6% of HIV-negative cases (n = 63), respectively. Recurrent copy-number variations (CNV) involving genes with documented roles in cancer included amplification of PI3KCA and deletion of APC in primary and recurrent tumors; amplifications of CCND1, MYC, and NOTCH1 and deletions of BRCA2 and RB1 in primary tumors; and deletions of ATR, FANCD2, and FHIT in recurrent tumors. DNA damage response genes were enriched among recurrently deleted genes in recurrent ASCCs (P = 0.001). HPV integrations were detected in 29 of 76 (38%) ASCCs and were more frequent in stage III-IV versus stage I-II tumors. HPV integrations were detected near MYC and CCND1 amplifications and recurrent targets included NFI and MUC genes. These results suggest HPV genotypes in ASCC differ by HIV status, HPV integration is associated with ASCC progression, and DNA damage response genes are commonly disrupted in recurrent ASCCs. IMPLICATIONS: These data provide the largest whole-exome sequencing study of the ASCC genomic landscape to date and identify HPV genotypes, integrations, and recurrent CNVs in primary or recurrent ASCCs.

Increased risk of anal squamous cell carcinoma in HIV-positive men with prior hepatitis B virus infection.

OBJECTIVE(S): HIV-positive individuals have elevated rates of anal squamous cell carcinoma (SCC), and sexually transmitted infections with its causative agent, high-risk human papillomavirus, and other oncoviruses including hepatitis B virus (HBV). HBV infection can cause liver cancer, and has been associated with increased risk of some extra-hepatic cancers including biliary tract cancer, pancreatic cancer, and non-Hodgkin lymphoma. Whether HBV is associated with anal SCC risk is unknown. DESIGN: Prospective study of anal SCC risk in HIV-positive and HIV-negative MSM in the Multicenter AIDS Cohort Study from 1984 to 2014. METHODS: Poisson regression models were used to examine the association between past or current HBV infection (positive tests for HBV core antibodies, surface antigen, and/or DNA) and anal SCC risk. RESULTS: We observed 53 cases of anal SCC among 5298 participants with 79 334 person-years follow-up. Among HIV-positive men, past or current HBV infection was associated with anal SCC risk in models adjusted for age, CD4+ cell counts, HAART use, and other risk factors [incidence rate ratio (IRR), 95% confidence interval 3.15, 1.27-7.82]. Additional risk factors included immunological parameters 1 and 6 years prior to diagnosis (IRR, 95% confidence interval 2.45, 1.31-4.58 and 2.44, 1.3-4.59 for CD4+ cell counts <500 cells/µl; 2.43, 1.34-4.42 and 2.77, 1.5-5.11 for CD4+ : CD8+ ratios <0.5, respectively). Among HIV-negative men, IRR for prior HBV and anal SCC risk was similar, but NS due to small number of cases. CONCLUSION: HIV-positive MSM with prior HBV infection have increased anal SCC risk. This population may benefit from screening.