Wu, Szu‐Yuan

Abstract Squamous cell carcinoma (SCC) development in mammals is thought to require months or years from the time that initial changes occur. We show that SCCs induced by the mouse papillomavirus MmuPV1, which are generally diagnosed 4-6 months post infection, can be found as soon as 2 weeks post infection. SCCs developed within 2 weeks in immune-competent, adult FVB (FVB/NTac) mice at sites prone to human papillomavirus (HPV)-induced tumors and cancers in human patients: the base of the tongue, the anus, and the skin. The anterior tongue, less susceptible than the base of the tongue to HPV-induced cancer in humans, was resistant to rapid-onset cancer. The presence of invasive cancer in histological tissue sections was verified by multiple pathologists. These diagnoses were corroborated by the results of a classic test of malignancy: skin tumors obtained two weeks post infection grew ectopically as subcutaneous grafts in immune-deficient hosts. Preventative treatment with a novel BRD4 inhibitor dramatically reduced the frequency of ear skin SCCs present 2 weeks post infection and significantly reduced overall disease severity. Like many human papillomaviruses, MmuPV1 lacks an E5 gene. Expression of HPV16 E5 driven by the Keratin 14 promoter in FVB mice (FVB/NTac-Tg(KRT14-HPV16E5*)33Plam/Plam) significantly increased the frequency of rapid-onset invasive cancers caused by MmuPV1 at the base of the tongue and in the anus. In an E5-transgenic mouse with a persistent MmuPV1-induced ear skin lesion, we detected a lymph node metastasis at 38 weeks - further demonstrating a cancer phenotype. Cancers and less severe dysplasia induced by infection at the base of the tongue or the anus spontaneously regressed within 4 to 8 weeks of infection; however, ear lesions persisted. When CD4+ and CD8+ T cells were depleted, lesions at the base of the tongue and anus also persisted, indicating that spontaneous regression involves a T cell-mediated immune response. These results indicate that papillomavirus infection alone is sufficient to induce rapid onset of invasive cancer, and that persistence of disease depends on the tissue-specific immune microenvironment. Citation Format: Andrea Bilger, Ella T. Ward-Shaw, Denis L. Lee, Renee E. King, Shwu-Yuan Wu, Michael A. Newton, Cheng-Ming Chiang, Darya Buehler, Kristina Matkowskyj, John P. Sundberg, Rong Hu, Paul F. Lambert. Rapid-onset squamous cell carcinoma and spontaneous regression following papillomavirus infection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7237.

Abstract Multiple myeloma (MM) is 2-3 times more common among African-Americans compared to non-Hispanic whites. The 2-3-fold increased risk among family members of cases suggests a genetic contribution to risk. Genome-wide association studies (GWAS) in populations of European ancestry have identified seven novel risk loci at 2p23.3 (rs6746082), 3q26.2 (rs10936599), 3p22.1 (rs1052501), 6p21.32 (rs2285803), 7p15.3 (rs4487645), 17p11.2 (rs4273077) and 22q13.1 (rs877529) (Broderick, et al. Nat Genet, 2011, Chubb, et al. Nat Genet, 2013), three of which were replicated in another European series (Martino et al., Br J Haematol, 2012). Here we examined the index signals and conducted fine-mapping for each locus in a case-control study of 1,049 multiple myeloma cases and 7,084 controls of African ancestry to identify better markers of risk and novel independent loci in seven previously reported regions in this high risk population. Incident cases were recruited from 10 clinical centers and SEER cancer registries from 2011 to 2013 and genotyped using the Illumina HumanCore GWAS array. Control data were obtained from previous genome-wide studies of breast and prostate cancer, genotyped using the Illumina 1M-Duo in 4425 male controls from the African Ancestry Prostate Cancer Consortium (consisting of 14 independent studies) and 2632 female controls from a breast cancer GWAS of African-American women (consisting of 9 independent studies). Imputation to 1000 Genomes (March 2012 release) was conducted for regions around six of the previously identified single nucleotide polymorphisms [SNPs] (the HLA region harboring rs2285803 is still being imputed, results will be presented). A case-control analysis of SNPs/indels >1% frequency within 250 kb of each index variant was conducted using unconditional multivariable logistic regression adjusting for age, sex and five leading principal components. Region-specific alpha levels were determined through permutation tests. The minimum alpha level across the six regions was α=0.002. All previously reported risk variants were common in African-Americans (minor allele frequency [MAF] >0.05). For five of the six SNPs, we had ≥94% power to detect the same effect observed in non-Hispanic whites, and 64% power for the less common variant rs10936599 (MAF=0.07). We observed directionally consistent effects (odds ratio [OR]>1) for the six risk variants tested, with three replicating at p≤0.05 (7p15.3, p=1.4x10-7; 17p11.2, p=0.05; 22q13.1, p=0.02). For three of the six regions, we observed better markers of risk in African-Americans that were correlated with the index SNP in Europeans (7p15.3, rs56333627, p=1.5x10-5, r2=0.89; 17p11.2, rs34562254, p=2.9x10-3, r2=0.90; 22q13.1, rs2092410, p=1.1x10-4 r2=.71). The missense variant identified in the 17p11.2 region (rs34562254, Pro251Leu) is located in TNFRSF13B, which encodes the protein TACI, a B cell surface receptor which plays a role in B cell maturation, apoptosis and antibody production by inducing activation of transcription factors including NFAT and NFκβ. In addition, there is evidence suggesting that TACI is involved in MM pathogenesis. Our results demonstrate that many of the risk loci for MM found in European ancestry populations are also risk loci in men and women of African ancestry and that by fine-mapping, we are able to identify variants that better capture risk in populations of African ancestry. Disclosures Terebelo: Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.