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PubMed2026

Long-Read Haplotype Phasing Resolves Allelic Configuration as a Missing Layer of Precision Oncology.

Short-read sequencing cannot determine whether co-occurring variants within a cancer gene lie on the same allele (cis) or opposing alleles (trans), a distinction with direct therapeutic consequences: trans configurations confirm biallelic tumor suppressor inactivation, whereas cis configurations generate compound oncogenic alleles with enhanced activity. Among 768 patients with prostate, breast, or ovarian cancers, we used mutational signatures to nominate cryptic genomic instability cases lacking a causative biallelic event on short-read sequencing. Long-read nanopore sequencing resolved 32 of 46 cryptic cases (69.6%) through methylation detection, long insertion resolution, and structural variant characterization, confirming trans inactivation in every resolved tumor suppressor case. Analysis of 4,496 MiOncoSeq samples identified 17,519 multi-hit gene pairs, 78.7% of which exceeded the 500 bp short-read phasing limit, and long-read phasing revealed recurrent compound cis alleles in NOTCH1, PIK3CA, PDGFRB, and KIT. Haplotype phasing addresses an overlooked gap in cancer variant interpretation and warrants integration into precision oncology.

Journal Article↗

PubMed2006

Mutational analysis of AKT1, AKT2 and AKT3 genes in common human carcinomas.

OBJECTIVE: Mounting evidence indicates that alterations in AKT proteins play an important role in the pathogenesis of cancer. The objective of this study was to see whether common human carcinomas harbor AKT mutations that might contribute to the development of cancer. METHODS: We performed mutational analysis of the kinase domains of AKT1-AKT3 by a single-strand conformation polymorphism assay in 294 carcinoma tissues from the stomach, lung, colon and breast. RESULTS: Overall, we detected three somatic mutations in AKT2, but no mutations in AKT1 or AKT3 in the 294 cancer tissues. The AKT2 mutations were detected in 1 of 51 gastric carcinomas (2.0%) and 2 of 79 lung carcinomas (2.5%). AKT2 mutations consisted of one missense mutation and 2 splice site mutations in the intron. We simultaneously analyzed somatic mutations in EGFR, ERBB2, K-RAS, PIK3CA and BRAF genes in the 3 samples with the AKT2 mutations, and found a lung adenocarcinoma with the AKT2 missense mutation harbored an EGFR mutation. CONCLUSION: This study demonstrated that somatic mutations in the kinase domain of AKT2 occur in a small fraction of common human cancers, and suggested that alterations in the AKT2-mediated signaling pathway by AKT2 mutation could contribute to the development of some cases of human cancers.

Carcinoma↗

PubMed2006

Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer.

EGFR is frequently mutated and amplified in lung adenocarcinomas sensitive to EGFR inhibitors gefitinib and erlotinib. A secondary mutation, T790M, has been associated with acquired resistance but has not been shown to be sufficient to render EGFR mutant/amplified lung cancers resistant to EGFR inhibitors. We created a model for studying acquired resistance to gefitinib by prolonged exposure of a gefitinib-sensitive lung carcinoma cell line (H3255; EGFR mutated and amplified) to gefitinib in vitro. The resulting resistant cell line acquired a T790M mutation in a small fraction of the amplified alleles that was undetected by direct sequencing and identified only by a highly sensitive HPLC-based technique. In gefitinib-sensitive lung cancer cells with EGFR mutations and amplifications, exogenous introduction of EGFR T790M effectively conferred resistance to gefitinib and continued ErbB-3/PI3K/Akt signaling when in cis to an activating mutation. Moreover, continued activation of PI3K signaling by the PIK3CA oncogenic mutant, p110alpha E545K, was sufficient to abrogate gefitinib-induced apoptosis. These findings suggest that allelic dilution of biologically significant resistance mutations may go undetected by direct sequencing in cancers with amplified oncogenes and that restoration of PI3K activation via either a T790M mutation or other mechanisms can provide resistance to gefitinib.

Alleles↗

PubMed2026

Circulating Tumor DNA in Breast Cancer: A Liquid Biopsy Revolution for Non-Invasive Genomic Profiling and Clinical Decision-Making.

Breast cancer remains the most frequently diagnosed cancer and a leading cause of cancer-related mortality among women worldwide, underscoring the need for accurate, minimally invasive biomarkers to support precision oncology. Conventional tissue biopsy remains the standard for molecular characterization but is limited by its invasiveness, inability to capture spatial and temporal tumor heterogeneity, and challenges in serial monitoring. Circulating tumor DNA (ctDNA), a tumor-derived fraction of cell-free DNA, has emerged as a promising liquid biopsy biomarker capable of providing real-time genomic information throughout disease progression. This narrative review examines recent advances in ctDNA biology, analytical technologies, clinical applications, current limitations, and future directions in breast cancer management. A structured literature search of PubMed/MEDLINE, Scopus, Embase, Web of Science, and Google Scholar identified relevant English-language publications from 2015 to 2026. Current evidence indicates that highly sensitive platforms, including digital PCR, BEAMing, and next-generation sequencing, can detect clinically actionable alterations in genes such as PIK3CA, ESR1, TP53, ERBB2, AKT1, and BRCA1/2. ctDNA has demonstrated particular utility in identifying minimal residual disease, monitoring therapeutic response, detecting emerging resistance mechanisms, and guiding targeted treatment selection in advanced breast cancer. However, applications in early cancer detection, population screening, and artificial intelligence-assisted clinical decision-making remain investigational. Widespread clinical implementation is constrained by low ctDNA abundance in early-stage disease, analytical variability, limited assay standardization, and cost considerations. Continued technological innovation, prospective multicenter validation, standardized testing protocols, and evidence-based clinical guidelines are essential to fully integrate ctDNA into routine precision breast cancer care.

breast cancer↗

PubMed2002

Amplification and overexpression of JUNB is associated with primary cutaneous T-cell lymphomas.

Primary cutaneous lymphomas (PCLs) represent a heterogeneous group of extranodal T- and B-cell malignancies. The underlying molecular pathogenesis of this malignancy remains unclear. This study aimed to characterize oncogene abnormalities in PCLs. Using genomic microarray, we detected oncogene copy number gains of RAF1 (3p25), CTSB (8p22), PAK1 (11q13), and JUNB (19p13) in 5 of 7 cases of mycosis fungoides (MF)/Sezary syndrome (SS) (71%), gains of FGFR1 (8p11), PTPN (20q13), and BCR (22q11) in 4 cases (57%), and gains of MYCL1 (1p34), PIK3CA (3q26), HRAS (11p15), MYBL2 (20q13), and ZNF217 (20q13) in 3 cases (43%). Amplification of JUNB was studied in 104 DNA samples from 78 PCL cases using real-time polymerase chain reaction. Twenty-four percent of cases, including 7 of 10 cases of primary cutaneous CD30(+) anaplastic large-cell lymphoma (C-ALCL), 4 of 14 MF, 4 of 22 SS, and 2 of 23 primary cutaneous B-cell lymphoma (PCBCL) showed amplification of JUNB, and high-level amplification of this oncogene was present in 3 C-ALCL and 2 MF cases. JUNB protein expression was analyzed in tissue sections from 69 PCL cases, and 44% of cases, consisting of 21 of 23 SS, 6 of 8 C-ALCL, 5 of 10 MF, and 9 of 21 PCBCL, demonstrated nuclear expression of JUNB by tumor cells. Overexpression of JUNB also was detected in 5 C-ALCL and 2 SS cases. These results have revealed, for the first time, amplification and expression patterns of JUNB in PCL, suggesting that JUNB may be critical in the pathogenesis of primary cutaneous T-cell lymphomas.

DNA, Neoplasm↗

PubMed2006

Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma.

To determine whether the PI3K/Akt signaling pathway is involved in the pathogenesis of mantle cell lymphoma (MCL), we investigated the phosphorylation status of Akt and multiple downstream targets in primary MCL cases and cell lines. Akt was phosphorylated in 12 of 12 aggressive blastoid MCL variants and in 4 of 4 MCL cell lines. In contrast, phosphorylated Akt was present in only 5 of 16 typical MCL, 3 at comparable levels to the blastoid cases, and 2 at low levels. The presence of p-Akt was accompanied by the phosphorylation of p27(kip1), FRKHL-1, MDM2, Bad, mTOR, and p70S6K. Inhibition of the PI3K/Akt pathway in the MCL cell lines abrogated or reduced the phosphorylation of Akt, p27(kip1), FRKHL-1, MDM2, Bad, mTOR, GSK-3beta, IkappaB, and led to cell-cycle arrest and apoptosis. Six MCL cases (5 with activated Akt and 1 with inactive Akt) and 3 of 4 cell lines showed loss of PTEN expression. PIK3CA mutations were not detected. We conclude that constitutive activation of the PI3K/Akt pathway contributes to the pathogenesis of MCL and preferentially occurs in blastoid variants. One possible mechanism of activation is loss of PTEN expression. These data suggest that PI3K/Akt inhibitors may be effective in the treatment of Akt-activated MCL.

Cell Cycle↗

PubMed2007

Somatic sequence alterations in twenty-one genes selected by expression profile analysis of breast carcinomas.

INTRODUCTION: Genomic alterations have been observed in breast carcinomas that affect the capacity of cells to regulate proliferation, signaling, and metastasis. Re-sequence studies have investigated candidate genes based on prior genetic observations (changes in copy number or regions of genetic instability) or other laboratory observations and have defined critical somatic mutations in genes such as TP53 and PIK3CA. METHODS: We have extended the paradigm and analyzed 21 genes primarily identified by expression profiling studies, which are useful for breast cancer subtyping and prognosis. This study conducted a bidirectional re-sequence analysis of all exons and 5', 3', and evolutionarily conserved regions (spanning more than 16 megabases) in 91 breast tumor samples. RESULTS: Eighty-seven unique somatic alterations were identified in 16 genes. Seventy-eight were single base pair alterations, of which 23 were missense mutations; 55 were distributed across conserved intronic regions or the 5' and 3' regions. There were nine insertion/deletions. Because there is no a priori way to predict whether any one of the identified synonymous and noncoding somatic alterations disrupt function, analysis unique to each gene will be required to establish whether it is a tumor suppressor gene or whether there is no effect. In five genes, no somatic alterations were observed. CONCLUSION: The study confirms the value of re-sequence analysis in cancer gene discovery and underscores the importance of characterizing somatic alterations across genes that are related not only by function, or functional pathways, but also based upon expression patterns.

Breast Neoplasms↗

PubMed2026

Clinicopathological and genetic analysis of primary intraosseous carcinoma not otherwise specified (PIOC NOS).

BACKGROUND: Primary intraosseous carcinoma not otherwise specified (PIOC NOS) is an extremely rare jawbone cancer, accounting for approximately 1-2% of all oral cancers. Considering its rarity, no established standard treatment exists for postoperative recurrence or metastasis. This study aimed to analyse the clinical manifestations of this disease and identify novel genomic abnormalities to aid identification of potential treatment strategies. METHODS: We examined the clinical information of 14 PIOC NOS cases treated at our institution in recent years and compared it with previous reports. Genomic analysis was conducted on seven formalin-fixed paraffin-embedded surgical specimens, assessing 523 DNA and 55 RNA cancer-related genes using next-generation sequencing. RESULTS: Our findings, along with previous literature, revealed the posterior mandible as the primary site in most cases, though this was rarely identified at the time of initial diagnosis. Recurrence within two years of surgery was common. Hotspot mutations in PIK3CA were observed in 60% of cases. Additionally, one patient had high TMB status. CONCLUSIONS: Given the challenges in diagnosis and the potential for rapid recurrence or metastasis, early detection is crucial. Comprehensive genomic profiling is highly desirable, as genomic analysis may direct the development of targeted therapeutic agents to treat relapse.

Humans↗

PubMed2026

Age-related genomic characterization and therapeutic targets in Chinese breast cancer: insights from prospective targeted sequencing and clinical data analysis.

BACKGROUND: In China, breast cancer occurs at a much younger age and has a higher recurrence and mortality rate. However, with changes in lifestyle, there has been a trend towards an older age of breast cancer incidence in Chinese women. There is a paucity of large-scale next-generation sequencing cohorts for the analysis of genomic characterization in these populations and the identification of potential therapeutic targets. METHODS: To address this gap, we performed prospective targeted sequencing of tumor and blood samples from Chinese patients and collected detailed clinical information. We then categorized patients into two groups based on age (< 40 years, n = 637; ≥ 40 years, n = 3442) and proceeded to provide comprehensive descriptions of somatic and germline mutations in both groups. RESULTS: The somatic mutation analysis revealed that PIK3CA, FOXA1, and TBX3 mutations were more prevalent in elderly patients. By leveraging the aforementioned mutational characteristics, we employed our institution's FUTURE-SUPER clinical trial, an umbrella study targeting metastatic breast cancer, to confirm the potential benefits of PI3K-AKT-mTOR pathway inhibitors among elderly patients with breast cancer. Furthermore, TP53 and ERBB2 were more likely to be co-mutated in young women. Patients with TP53 and ERBB2 co-mutation tend to have a poorer prognosis, but through investigation of the SPARK cohort, patients carrying the TP53 and ERBB2 co-mutation are more likely to benefit from immune checkpoint inhibitor combination with tyrosine kinase inhibitor therapy. In our study, we observed a higher frequency of mutations in the DNA homology-dependent recombination pathway in young patients with breast cancer, which was associated with an elevated Ki67 index. Additionally, we confirmed a significant prevalence of germline breast cancer susceptibility gene 1 (gBRCA1) mutations in young patients, whereas germline checkpoint kinase 2 (gCHEK2) mutations are more common in elderly patients. CONCLUSIONS: Our study, which makes use of the largest Chinese breast cancer sequencing cohort, sought to characterize the age-related genomic profile of breast cancer patients and identify novel therapeutic opportunities for individuals with breast cancer.

Adult↗

PubMed2025

Comprehensive clinical and genetic characterization of hyperprogressive biliary tract cancer during PD-1 blockade monotherapy: case report and literature review.

BACKGROUND: Some genetically characterized patients show the rapid disease progression during immune checkpoint inhibitors (ICIs) monotherapy, a phenomenon known as hyperprogressive disease (HPD). CASE PRESENTATION: Herein we report a relevant case of biliary tract cancer (BTC) that initially responded to gemcitabine plus oxaliplatin (GEMOX) and PD-1 blockade but subsequently developed HPD in the process of PD-1 blockade maintenance therapy, leading to death within two weeks. Genomic analysis revealed mutations in CDKN2A, PIK3CA, KRAS and EPHA2 in both baseline and hyperprogressive plasma and tumor samples. Notably, higher KRAS mutation abundance was observed in plasma and ascites after disease progression. CONCLUSIONS: These findings suggest a potential association between these negative genes especially KRAS mutation and HPD. Therefore, administration of PD-1 blockade monotherapy in this subgroup of patients harboring KRAS mutation should be performed with caution. Further studies are warranted to confirm these results and explore the correlation between genomic mutations and HPD.

Humans↗

PubMed2026

Clinicopathologic Features, Treatment Patterns, and Outcomes of Microsatellite Instability-High Gastric and Gastroesophageal Junction Adenocarcinoma: A Single-Institution Retrospective Analysis.

PURPOSE: Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) gastric or gastroesophageal junction (GEJ) adenocarcinomas are biologically distinct tumors with established sensitivity to immune checkpoint inhibitors (ICIs). However, real-world treatment patterns, response heterogeneity, and predictors of durable benefit remain poorly defined. METHODS: We retrospectively analyzed patients with biopsy-confirmed MSI-H/dMMR gastric/GEJ adenocarcinoma treated at a single center. Clinicopathologic, genomic, treatment, and outcome data were collected. Molecular profiling included ARID1A, RNF43, TP53, PIK3CA, KRAS, TGFBR2, and human epidermal growth factor 2 (HER2). ICIs-treated patients were classified as achieving clinical benefit (complete response, partial response, or durable stable disease ≥16 weeks) or no clinical benefit using iRECIST v1.1 and clinical assessment. Overall survival (OS) was estimated by using the Kaplan-Meier method. RESULTS: Thirty-four patients were identified (median age, 66 years; 53% male), including 21 with stage IV disease. Tumors were predominantly poorly differentiated (65%) and HER2-negative (94%), and 18% of patients had Lynch syndrome. Among 22 ICI-treated patients, 55% achieved clinical benefit, which was strongly associated with prolonged OS (P < .01). Most responses occurred at the first radiographic assessment (approximately 12 weeks). Elevated tumor mutational burden (TMB; ≥20 mutations/Mb) was present in 56% of patients but was not associated with clinical benefit (P = .40), and no individual genomic alteration significantly correlated with treatment outcome. Exploratory analyses suggested longer OS among patients with liver versus peritoneal metastases. Treatment was well tolerated, with predominantly low-grade immune-related adverse events. Baseline Eastern Cooperative Oncology Group performance status (0-1 v ≥ 2) was associated with clinical benefit (P = .049). CONCLUSION: Approximately half of the patients with MSI-H/dMMR gastric/GEJ adenocarcinoma cancers derived durable clinical benefit from ICIs, and treatment response was strongly associated with survival. Conventional genomic features, including TMB, did not predict clinical benefit, highlighting the need for additional biomarkers.

Humans↗

PubMed2006

Analysis of gene amplification and prognostic markers in ovarian cancer using comparative genomic hybridization for microarrays and immunohistochemical analysis for tissue microarrays.

To identify oncogene amplification involved in ovarian carcinogenesis, we studied 21 ovarian carcinomas and 5 serous borderline tumors using conventional comparative genomic hybridization (CGH) and CGH to a genomic DNA microarray. Immunohistochemical analysis of the proteins encoded by the genes that were amplified frequently (FGF3/4, FGFR1, CCNE1, PAK1, JUNB, and MDM2) was performed on a tissue microarray comprising 254 cases of ovarian neoplasms. Regarding histologic type, characteristic patterns of copy number changes were revealed. They correlated with histologic tumor type and with intratumoral heterogeneity. Gain of FGF3/4 and CCNE1 was found in all serous carcinomas. Endometrioid carcinomas most frequently showed gain of JUNB (83%), KRAS2 (67%), MYCN (50%), ESR (50%), and CCND2 (50%). Of the serous borderline tumors, 80% harbored amplification of FGFR1 and MDM2 and a 75% gain of PIK3CA. Only CCNE1 immunoreactivity was significantly correlated with CGH results (P < .05) and postoperative survival (P < .05). Microarray-based genomic analysis in combination with immunohistochemical analysis was found to be a powerful technique for identification of clinically relevant gene amplification in human ovarian cancer.

Biomarkers, Tumor↗

PubMed2005

The phosphoinositide 3-kinase signalling pathway as a therapeutic target in squamous cell carcinoma of the head and neck.

Squamous cell carcinoma of the head and neck (SCCHN) is associated with high morbidity and mortality. Despite significant surgical advances and refinement in the delivery of chemotherapy and radiotherapy, prognosis has improved little in recent decades. Better local control has led to the late presentation of distant metastases and novel therapeutic agents are urgently required to prevent relapse, control disseminated disease and thus improve survival. PIK3CA encodes the p110alpha isoform of phosphoinositide 3-kinase (PI3-K) and is important in SCCHN, aberrations in its activity occurring early in the oncogenic process. PI3-K signalling promotes cell survival, proliferation, invasion and angiogenesis, all contributing to tumour progression. Activation of the PI3-K pathway may also mediate resistance to chemotherapy, radiotherapy and novel therapeutic agents such as epidermal growth factor receptor inhibitors. Elements of this signalling matrix, therefore, offer attractive therapeutic targets in SCCHN as inhibition of many malignant characteristics, as well as sensitisation to multiple treatment modalities, could be anticipated.

Antineoplastic Agents↗

PubMed2026

Tumor Mutational Landscape and Its Correlation With Histopathological Characteristics in Breast Cancer.

BACKGROUND/AIM: In breast cancer, knowledge of the associations between clinicopathologic characteristics, genetic changes, and subtype-specific patterns is expanding. This study investigated how pathological and clinical variables affect the actionability of Next Generation Sequencing (NGS)-based tumor molecular data. MATERIALS AND METHODS: 227 breast cancer patients referred to Genekor's laboratory for tumor molecular profile analysis were included in the study. Pathology records were used to assess critical clinicopathological features, including HER2, ER, PR, Ki67, grade, metastatic site, and age. A 1021-gene NGS-based multigene panel was utilized to assess tumor biology alongside tumor mutational burden (TMB) and microsatellite instability (MSI). RESULTS: Comprehensive genomic profiling revealed that 95.6% of the patients harbored at least one oncogenic or likely oncogenic alteration, highlighting the high diagnostic yield of NGS-based testing. Distinct subtype-specific patterns were observed: HR+/HER2- tumors were enriched for PIK3CA and ESR1 gene alterations, whereas triple-negative breast cancer (TNBC) was dominated by TP53 alterations. Clinically actionable alterations were most common in HR+/HER2- tumors (~60% on-label), whereas TNBC more often harbored off-label or trial-associated targets. The inclusion of tumor-agnostic biomarkers (TMB/MSI) increased on-label actionability up to 64.5% in HR+/HER2- tumors, primarily driven by TMB-high cases. Median TMB values were low, and age was the only independent predictor. Furthermore, the presence of actionable alterations was significantly higher in metastatic tumors, and TP53 alterations were associated with aggressive tumor characteristics. CONCLUSION: Comprehensive NGS-based genomic profiling identifies clinically actionable alterations in over half of breast cancer patients, with substantial variability across molecular subtypes. The HR+/HER2- subtype demonstrates the highest prevalence of on-label actionable biomarkers. These findings support the routine implementation of comprehensive genomic profiling, especially in metastatic HER2-negative breast cancer, to guide precision oncology strategies and enable enrollment in biomarker-driven clinical trials.

Humans↗

PubMed2006

PI 3-kinases: hidden potentials revealed.

The potential oncogenicity of PI 3-kinases is revealed by two principal mechanisms: mutations causing gain of function and overexpression of wild-type proteins. Cancer-specific mutations in PIK3CA, the gene coding for the catalytic subunit p110alpha of PI 3-kinase, are oncogenic in the animal. These mutations are therefore significant determinants of the oncogenic cellular phenotype in human tumors and are appropriate and promising targets for small molecule inhibitors. Overexpression of wild-type p110beta, gamma and delta induces oncogenic transformation in cell culture. Although these non-alpha isoforms of PI 3-kinase have not been found mutated in human cancer, deregulated expression could contribute to cellular oncogenic properties and deserves increased attention.

Animals↗

PubMed2025

Analysis of genomic traits of oral and laryngeal cancer: A comparative study.

Oral and laryngeal cancers exhibit overlapping clinical features but distinct genomic profiles. In a study of 60 Head and neck squamous cell carcinomas(HNSCC) cases (30 OSCC, 30 LSCC), NGS revealed TP53 mutations in 70% of oral squamous cell carcinoma (OSCC) and 83% of laryngeal squamous cell carcinoma (LSCC). CDKN2A alterations were more common in OSCC (40%) than LSCC (20%), while PIK3CA mutations were higher in LSCC (30%). NOTCH1 mutations were more frequent in OSCC (27%) than LSCC (10%). Pathway analysis showed disruptions in p53 and PI3K-Akt, with stronger enrichment in LSCC (ES: 3.42). The results suggest site-specific tumor biology influencing therapeutic targets. Molecular profiling is crucial for precision treatment in head and neck cancers.

Oral cancer↗

PubMed2026

Long-Read Haplotype Phasing Resolves Allelic Configuration as a Missing Layer of Precision Oncology.

Conventional short-read sequencing cannot determine whether co-occurring variants within a cancer gene reside on the same allele (cis) or on opposing alleles (trans), a distinction with direct biological and therapeutic consequences. Trans configurations confirm biallelic tumor suppressor inactivation and inform therapy selection, while cis configurations generate compound oncogenic alleles with enhanced activity. We analyzed 768 patients with prostate, breast, or ovarian cancers in the PROBLEM cohort, using mutational signatures to nominate cryptic genomic instability cases where the causative biallelic event was not apparent from short-read sequencing. Long-read nanopore sequencing resolved 32 of 46 cryptic cases (69.6%), leveraging its unique advantages in direct methylation detection, long insertion resolution, and complex structural variant characterization, confirming trans biallelic inactivation in all resolved tumor suppressor cases. Systematic analysis of 4,496 MiOncoSeq samples identified 17,519 multi-hit gene pairs, of which 78.7% exceeded the 500 bp short-read phasing limit. Long-read phasing further revealed recurrent compound cis oncogenic alleles in NOTCH1, PIK3CA, PDGFRB, and KIT with functionally synergistic activity. Haplotype phasing resolves a systematically overlooked gap in cancer variant interpretation and warrants broader integration into precision oncology workflows.

Journal Article↗

PubMed2026

Liquid Biopsy of HPV Cell-Free DNA Enables Blood-Based Early Detection and Molecular Stratification of HPV-Associated Cancer and Precancer Stages.

Liquid biopsies targeting circulating tumor DNA enable noninvasive cancer detection but lack sensitivity in pre- and early- cancer stages, where clinical benefits would be greatest. Human papillomavirus (HPV) causes six cancer types, accounting for 5% of all cancers worldwide. Targeting HPV cell-free (cf)DNA offers a compelling opportunity to overcome current liquid biopsy constraints due to its unique tumor-specific origin, lack of sequence homology to the human genome, and the high viral-to-human copy ratio per cell. Utilizing HPV-associated anal cancer and precancer as a model, here we applied a custom, multi-feature HPV whole-genome liquid biopsy to biobanked and prospective screening cohorts spanning the HPV infection-precancer-cancer continuum. HPV cfDNA was detected years before cancer diagnosis and as early as the infection stage, with increasing detection as stages advanced. Genomic hallmarks of HPV malignancy, including HPV integration, PIK3CA mutations, and 3q amplification, were detected exclusively in cancer, while precancers exhibited distinct HPV genotypes. Fragmentomics analysis of HPV cfDNA revealed stage-informative signatures reflecting viral epigenetic changes during carcinogenesis. A unified classifier incorporating genomic and fragmentomics features achieved a mean AUC of 0.77 for identifying cancer and high-grade precancer, stages requiring clinical intervention. Together, these findings demonstrate the feasibility of blood-based screening and molecular risk stratification for HPV-associated cancer and precancer.

Journal Article↗