The peak incidence of osteosarcoma (OMIM 259500) occurs during the pubertal growth spurt.^1-3 Osteosarcoma risk factors include tall height,^4,5 high birth-weight,^4,5 previous radiotherapy,⁶ and at least 8 established cancer predisposition syndromes,^7,8 including autosomal-dominant disorders (Li-Fraumeni syndrome [OMIM 151623],^9,10 hereditary retinoblastoma [OMIM 180200],^11,12 and Diamond-Blackfan anemia [OMIM 105650]^13,14) and autosomal-recessive disorders (primarily DNA helicase disorders,^15-18 such as Rothmund-Thomson syndrome [OMIM 268400], RAPADILINO syndrome [OMIM 266280], Werner syndrome [OMIM 277700], and Bloom syndrome [OMIM 210900]). Candidate gene and genome-wide association studies suggest that common single-nucleotide polymorphisms are also associated with osteosarcoma,^19-21 affirming a complex underlying architecture for its genetic etiology but one that appears to be weighted disproportionately toward rare variants.

Background: HPV16 is a common sexually transmitted infection although few infections lead to cervical precancer/cancer; we cannot distinguish nor mechanistically explain why only certain infections progress. HPV16 can be classified into four main evolutionary-derived variant lineages (A, B, C, D) that have been previously suggested to have varying disease risks. Methods: We used a high-throughput HPV16 whole-genome sequencing assay to investigate variant lineage risk among 3215 HPV16-infected women. Using sublineages A1/A2 as the reference, we assessed all variant lineage associations with infection outcome over three or more years of follow-up: 1107 control subjects (<CIN2), 906 CIN2, 1008 CIN3, 69 squamous cell carcinomas (SCC), 85 adenocarcinomas in situ (AIS), and 40 adenocarcinomas. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results: A4 sublineage was associated with an increased risk of cancer, specifically adenocarcinoma (OR = 9.81, 95% CI = 2.02 to 47.69, P =  4.7x10 ⁻⁰³ ). Lineage B had a lower risk of CIN3 (OR = 0.51, 95% CI = 0. 28 to 0.91, P =  .02) while lineage C showed increased risk (OR = 2.06, 95% CI = 1.09 to 3.89, P =  .03). D2/D3 sublineages were strongly associated with an increased risk of CIN3 and cancer, particularly D2 (OR for cancer = 28.48, 95% CI = 9.27 to 87.55, P =  5.0x10 ⁻⁰⁹ ). D2 had the strongest increased risk of glandular lesions, AIS (OR = 29.22, 95% CI = 8.94 to 95.51, P =  2.3x10 ⁻⁰⁸ ), and adenocarcinomas (OR = 137.34, 95% CI = 37.21 to 506.88, P =  1.5x10 ⁻¹³ ). Moreover, the risk of precancer and cancer for specific variant lineages varied by a women’s race/ethnicity; those women whose race/ethnicity matched that of the infecting HPV16 variant had an increased risk of CIN3 + ( P <  .001). Conclusions: Specific HPV16 variant sublineages strongly influence risk of histologic types of precancer and cancer, and viral genetic variation may help explain its unique carcinogenic properties.

Human papillomavirus (HPV) causes virtually all cervical cancers and many cancers at other anatomical sites in both men and women. However, only 12 of 448 known HPV types are currently classified as carcinogens, and even the most carcinogenic type - HPV16 - only rarely leads to cancer. HPV is therefore necessary but insufficient for cervical cancer, with other contributing factors including host and viral genetics. Over the last decade, HPV whole genome sequencing has established that even fine-scale within-type HPV variation influences precancer/cancer risks, and that these risks vary by histology and host race/ethnicity. In this review, we place these findings in the context of the HPV life cycle and evolution at various levels of viral diversity: between-type, within-type, and within-host. We also discuss key concepts necessary for interpreting HPV genomic data, including features of the viral genome; events leading to carcinogenesis; the role of APOBEC3 in HPV infection and evolution; and methodologies that use deep (high-coverage) sequencing to characterize within-host variation, as opposed to relying on a single representative (consensus) sequence. Given the continued high burden of HPV-associated cancers, understanding HPV carcinogenicity remains important for better understanding, preventing, and treating cancers attributable to infection.

Despite successful primary tumor treatment, the development of pulmonary metastasis continues to be the most common cause of mortality in patients with osteosarcoma. A conventional drug development path requiring drugs to induce regression of established lesions has not led to improvements for patients with osteosarcoma in more than 30 years. On the basis of our growing understanding of metastasis biology, it is now reasonable and essential that we focus on developing therapeutics that target metastatic progression. To advance this agenda, a meeting of key opinion leaders and experts in the metastasis and osteosarcoma communities was convened in Bethesda, Maryland. The goal of this meeting was to provide a “Perspective” that would establish a preclinical translational path that could support the early evaluation of potential therapeutic agents that uniquely target the metastatic phenotype. Although focused on osteosarcoma, the need for this perspective is shared among many cancer types. The consensus achieved from the meeting included the following: the biology of metastatic progression is associated with metastasis-specific targets/processes that may not influence grossly detectable lesions; targeting of metastasis-specific processes is feasible; rigorous preclinical data are needed to support translation of metastasis-specific agents into human trials where regression of measurable disease is not an expected outcome; preclinical data should include an understanding of mechanism of action, validation of pharmacodynamic markers of effective exposure and response, the use of several murine models of effectiveness, and where feasible the inclusion of the dog with naturally occurring osteosarcoma to define the activity of new drugs in the micrometastatic disease setting. Clin Cancer Res; 20(16); 4200–9. ©2014 AACR.