bims-ovdlit 2023-07-30 papers

Issue of 2023–07–30
five papers selected by
Lara Paracchini, Humanitas Research

Transl Res. 2023 Jul 25. pii: S1931-5244(23)00126-3. [Epub ahead of print]

Noninvasive early differential diagnosis and progression monitoring of ovarian cancer using the copy number alterations of plasma cell-free DNA.

Lu Chen, Rong Ma, Chang Luo, Qin Xie, Xin Ning, Kaidi Sun, Fanling Meng, Meng Zhou, Jie Sun.

Ovarian cancer (OV) is the most lethal gynecological malignancy and requires improved early detection methods and more effective intervention to achieve a better prognosis. The lack of sensitive and noninvasive biomarkers with clinical utility remains a challenge. Here, we conducted a genome-wide copy number variation (CNV) profiling analysis using low-coverage whole genome sequencing (LC-WGS) of plasma cfDNA in patients with non-malignant and malignant ovarian tumors, and identified 10 malignancy-specific and 12 late-stage-specific CNV markers from plasma cfDNA LC-WGS data. Concordance analysis indicated a significant correlation of identified CNV markers between CNV profiles of plasma cfDNA and tissue DNA (Pearson's r=0.64, p=0.006 for the TCGA cohort and r=0.51, p=0.04 for the Dariush cohort). By leveraging these specific CNV markers and machine learning algorithms, we developed robust predictive models showing excellent performance in distinguishing between malignant and non-malignant ovarian tumors with F1-scores of 0.90 and ranging from 0.75-0.99, and prediction accuracy of 0.89 and ranging from 0.66-0.98, respectively, as well as between early- and late-stage ovarian tumors with F1-scores of 0.84 and ranging from 0.61-1.00, and prediction accuracy of 0.82 and ranging from 0.63-0.96 in our institute cohort and other external validation cohorts. Furthermore, we also discovered and validated certain CNV features associated with survival outcomes and platinum-based chemotherapy response in multicenter cohorts. In conclusion, our study demonstrated the clinical utility of CNV profiling in plasma cfDNA using LC-WGS as a cost-effective and accessible liquid biopsy for OV.

Keywords: low-coverage whole-genome sequencing; noninvasive diagnosis; ovarian cancer; plasma cell-free DNA; progression monitoring

DOI: https://doi.org/10.1016/j.trsl.2023.07.005

Pathogens. 2023 Jul 05. pii: 908. [Epub ahead of print]12(7):

The Clinical Utility of Circulating HPV DNA Biomarker in Oropharyngeal, Cervical, Anal, and Skin HPV-Related Cancers: A Review.

Ioana Maria Andrioaie, Ionut Luchian, Costin Dămian, Giorgio Nichitean, Elena Porumb Andrese, Theodor Florin Pantilimonescu, Bogdan Trandabăț, Liviu Jany Prisacariu, Dana Gabriela Budală, Daniela Cristina Dimitriu, Luminita Smaranda Iancu, Ramona Gabriela Ursu.

Human papillomavirus (HPV) is recognized as being related to a wide variety of known cancers: cervical, oropharyngeal, anal, vaginal, penile, and skin. For some of these cancers, rigorous algorithms for screening, therapeutical interventions, and follow-up procedures have been established. Vaccination using the nonvalent anti-HPV vaccine, which prevents infection regarding the most frequently involved high-risk HPV types (16, 18, 31, 33, 45, 52, and 58) and low-risk HPV types (6 and 11), has also extensively prevented, controlled, and even eradicated HPV infections. Still, even with all of these multidisciplinary interventions, the burden of HPV cancers is still high worldwide. The circulating DNA of HPV-induced cancers is thought to be an adequate biomarker for optimizing the control of these virus-related cancers. We analyzed the literature published in the last 5 years regarding ctDNA and four of the above-mentioned cancers. The most frequently used assay for ctDNA detection was the droplet digital PCR assay, used for the management of therapy in the late stages of cancer. ctDNA could not be used for early detection in any of the studied cancers. The OPSCCs were the most frequent cancers analyzed via ctDNA assays. Larger, properly designed cohort studies might establish the clinical utility of this biomarker.

Keywords: HPV; biomarker; ctDNA; early detection; relapse

DOI: https://doi.org/10.3390/pathogens12070908

Int J Mol Sci. 2023 Jul 18. pii: 11570. [Epub ahead of print]24(14):

Combined Tumor-Based BRCA1/2 and TP53 Mutation Testing in Ovarian Cancer.

Edith Borcoman, Elizabeth Santana Dos Santos, Catherine Genestie, Patricia Pautier, Ludovic Lacroix, Sandrine M Caputo, Odile Cabaret, Marine Guillaud-Bataille, Judith Michels, Aurelie Auguste, Alexandra Leary, Etienne Rouleau.

Somatic/germline BRCA1/2 mutations (m)/(likely) pathogenic variants (PV) (s/gBRCAm) remain the best predictive biomarker for PARP inhibitor efficacy. As >95% of high-grade serous ovarian cancers (HGSOC) have a somatic TP53m, combined tumor-based BRCA1/2 (tBRCA) and TP53 mutation testing (tBRCA/TP53m) may improve the quality of results in somatic BRCAm identification and interpretation of the 'second hit' event, i.e., loss of heterozygosity (LOH). A total of 237 patients with HGSOC underwent tBRCA/TP53m testing. The ratio of allelic fractions (AFs) for tBRCA/TP53m was calculated to estimate the proportion of cells carrying BRCAm and to infer LOH. Among the 142/237 gBRCA results, 16.2% demonstrated a pathogenic/deleterious variant (DEL) gBRCA1/2m. Among the 195 contributive tumor samples, 43 DEL of tBRCAm (22.1%) were identified (23 gBRCAm and 20 sBRCAm) with LOH identified in 37/41 conclusive samples. The median AF of TP53m was 0.52 (0.01-0.93), confirming huge variability in tumor cellularity. Initially, three samples were considered as wild type with <10% cellularity. However, additional testing detected a very low AF (<0.05) in both BRCA1/2m and TP53m, thus reidentifying them as sBRCA1/2m. Combined tBRCA/TP53m testing is rapid, sensitive, and identifies somatic and germline BRCA1/2m. AF TP53m is essential for interpreting sBRCA1/2m in low-cellularity samples and provides indirect evidence for LOH as the 'second hit' of BRCA1/2-related tumorigenesis.

Keywords: BRCA1/2 tumoral testing; TP53m; allelic frequency; high-grade serous ovarian cancers; loss of heterozygosity; ovarian cancer

DOI: https://doi.org/10.3390/ijms241411570

Nat Genet. 2023 Jul 27.

Single-molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer.

Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from 2,511 individuals in the Pan-Cancer Analysis of Whole Genomes (PCAWG) study as well as 489 individuals from four prospective cohorts and found distinct regional mutation type-specific frequencies in tissue and cell-free DNA from patients with cancer that were associated with replication timing and other chromatin features. A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected >90% of patients with lung cancer, including those with stage I and II disease. The fixed model was validated in an independent cohort, detected patients with cancer earlier than standard approaches and could be used to monitor response to therapy. This approach lays the groundwork for non-invasive cancer detection using genome-wide mutation features that may facilitate cancer screening and monitoring.

DOI: https://doi.org/10.1038/s41588-023-01446-3

Nat Rev Cancer. 2023 Jul 24.

Cancers make their own luck: theories of cancer origins.

Amir Jassim, Eric P Rahrmann, Ben D Simons, Richard J Gilbertson.

Cancer has been a leading cause of death for decades. This dismal statistic has increased efforts to prevent the disease or to detect it early, when treatment is less invasive, relatively inexpensive and more likely to cure. But precisely how tissues are transformed continues to provoke controversy and debate, hindering cancer prevention and early intervention strategies. Various theories of cancer origins have emerged, including the suggestion that it is 'bad luck': the inevitable consequence of random mutations in proliferating stem cells. In this Review, we discuss the principal theories of cancer origins and the relative importance of the factors that underpin them. The body of available evidence suggests that developing and ageing tissues 'walk a tightrope', retaining adequate levels of cell plasticity to generate and maintain tissues while avoiding overstepping into transformation. Rather than viewing cancer as 'bad luck', understanding the complex choreography of cell intrinsic and extrinsic factors that characterize transformation holds promise to discover effective new ways to prevent, detect and stop cancer before it becomes incurable.

DOI: https://doi.org/10.1038/s41568-023-00602-5