WYMM Tour: Mid Atlantic

Cervical cancer (CC) causes ~660,000 new cases and 350,000 deaths annually, with the greatest burden in low- and middle-income countries. In Guatemala and Venezuela, CC incidence remains high, yet the molecular basis of aggressive disease subtypes remains poorly defined.

We analyzed 700 cervical tumors using Oxford Nanopore long-read sequencing and complementary genomic approaches. Among 52 tumors carrying one of 11 rare or probable hrHPVs (HPV26, 32, 35, 39, 51, 52, 53, 58, 59, 68, 69). The most frequent were HPV52 (19%) and HPV58 (17%). Out of two HPV patterns, integrated forms were slightly more common than episomal (54% vs 46%). Classification by HPV genera revealed representation of alpha 5, 6, 7, and 9, with alpha 7 and 9 predominating. Notably, one tumor contained a novel extrachromosomal DNA hybrid of human and HPV sequences, suggesting an alternative route of oncogene activation.

In parallel, YAP1 amplification was identified in 45 of 380 tumors and confirmed in 24 by barcode sequencing. Deep sequencing of these tumors showed frequent HPV integration (80%) and recurrent co-amplification of YAP1 with BIRC2/3, consistent with Breakage-Fusion-Bridge events. Clinically, YAP1 amplification defined a distinct aggressive subtype, with diagnosis a median of 12 years earlier, with significantly poorer survival and greater prevalence in minority populations.

Together, these findings highlight two major contributors to cervical carcinogenesis in underserved populations: rare hrHPV-driven tumors and YAP1-amplified aggressive subtypes. Integration of viral and host genomic landscapes provides new insights into CC disparities and points to potential biomarkers for early detection and therapeutic targeting.

Cervical cancer (CC) causes ~660,000 new cases and 350,000 deaths annually, with the greatest burden in low- and middle-income countries. In Guatemala and Venezuela, CC incidence remains high, yet the molecular basis of aggressive disease subtypes remains poorly defined.

We analyzed 700 cervical tumors using Oxford Nanopore long-read sequencing and complementary genomic approaches. Among 52 tumors carrying one of 11 rare or probable hrHPVs (HPV26, 32, 35, 39, 51, 52, 53, 58, 59, 68, 69). The most frequent were HPV52 (19%) and HPV58 (17%). Out of two HPV patterns, integrated forms were slightly more common than episomal (54% vs 46%). Classification by HPV genera revealed representation of alpha 5, 6, 7, and 9, with alpha 7 and 9 predominating. Notably, one tumor contained a novel extrachromosomal DNA hybrid of human and HPV sequences, suggesting an alternative route of oncogene activation.

In parallel, YAP1 amplification was identified in 45 of 380 tumors and confirmed in 24 by barcode sequencing. Deep sequencing of these tumors showed frequent HPV integration (80%) and recurrent co-amplification of YAP1 with BIRC2/3, consistent with Breakage-Fusion-Bridge events. Clinically, YAP1 amplification defined a distinct aggressive subtype, with diagnosis a median of 12 years earlier, with significantly poorer survival and greater prevalence in minority populations.

Together, these findings highlight two major contributors to cervical carcinogenesis in underserved populations: rare hrHPV-driven tumors and YAP1-amplified aggressive subtypes. Integration of viral and host genomic landscapes provides new insights into CC disparities and points to potential biomarkers for early detection and therapeutic targeting.

Cervical cancer (CC) causes ~660,000 new cases and 350,000 deaths annually, with the greatest burden in low- and middle-income countries. In Guatemala and Venezuela, CC incidence remains high, yet the molecular basis of aggressive disease subtypes remains poorly defined.

We analyzed 700 cervical tumors using Oxford Nanopore long-read sequencing and complementary genomic approaches. Among 52 tumors carrying one of 11 rare or probable hrHPVs (HPV26, 32, 35, 39, 51, 52, 53, 58, 59, 68, 69). The most frequent were HPV52 (19%) and HPV58 (17%). Out of two HPV patterns, integrated forms were slightly more common than episomal (54% vs 46%). Classification by HPV genera revealed representation of alpha 5, 6, 7, and 9, with alpha 7 and 9 predominating. Notably, one tumor contained a novel extrachromosomal DNA hybrid of human and HPV sequences, suggesting an alternative route of oncogene activation.

In parallel, YAP1 amplification was identified in 45 of 380 tumors and confirmed in 24 by barcode sequencing. Deep sequencing of these tumors showed frequent HPV integration (80%) and recurrent co-amplification of YAP1 with BIRC2/3, consistent with Breakage-Fusion-Bridge events. Clinically, YAP1 amplification defined a distinct aggressive subtype, with diagnosis a median of 12 years earlier, with significantly poorer survival and greater prevalence in minority populations.

Together, these findings highlight two major contributors to cervical carcinogenesis in underserved populations: rare hrHPV-driven tumors and YAP1-amplified aggressive subtypes. Integration of viral and host genomic landscapes provides new insights into CC disparities and points to potential biomarkers for early detection and therapeutic targeting.

Effective treatment of pediatric acute leukemia is dependent on accurate genomic classification, typically derived from a combination of multiple time-consuming and costly techniques such as flow cytometry, fluorescence in situ hybridization (FISH), karyotype analysis, targeted PCR, and microarrays. We investigated the feasibility of a comprehensive single-assay classification approach using long-read sequencing, with real-time genome target enrichment, to classify chromosomal abnormalities and structural variants characteristic of acute leukemia. We performed whole genome sequencing on DNA from diagnostic peripheral blood or bone marrow for 57 pediatric acute leukemia cases with diverse genomic subtypes. We demonstrated the characterization of known, clinically relevant karyotype abnormalities and structural variants concordant with standard-of-care clinical testing. Subtype-defining genomic alterations were identified in all cases following a maximum of 48 h of sequencing. In 18 cases, we performed real-time analysis— concurrent with sequencing—and identified the driving alteration in as little as 15 min (for karyotype) or up to 6 h (for complex structural variants). Whole genome sequencing with adaptive sampling utilizing Oxford Nanopore platform has the potential to provide genomic classification of acute leukemia specimens with reduced cost and turnaround time compared to the current standard of care.

The complexity of laboratory diagnostic algorithms for respiratory pathogens hinders a clear understanding of the association between infrequently screened viruses, symptomatic infections, and disease severity. The absence of rapid diagnostic approaches for novel pathogens further delays early diagnosis and outbreak containment. The COVID-19 pandemic underscored critical gaps in diagnostics, surveillance, and early detection protocols.

To address these gaps, it is essential to establish a robust infrastructure for the surveillance of respiratory pathogens. While genomic surveillance of SARS-CoV-2—and to a lesser extent, influenza—is a nationally coordinated effort, surveillance of other clinically significant respiratory viruses remains limited. For example, adenovirus has recently been implicated in cases of acute hepatitis in children, and Enterovirus D68 was associated with severe illness and increased ICU admissions across the U.S. in 2022. Despite their clinical impact, both virus groups lack structured surveillance systems, and data linking viral genomic changes to clinical outcomes are scarce. Additionally, the effects of newly recommended RSV vaccines on viral evolution remain unknown. Collectively, these factors highlight the urgent need to systematically analyze the clinical outcomes associated with the most prevalent respiratory viruses and to understand how circulating genotypes and viral evolution contribute to disease severity and outbreak dynamics. The goal of our research is to develop an efficient genomic surveillance framework to track respiratory virus evolution and identify genomic features linked to severe disease or emerging outbreaks.