Search | Preprints.org

Preprint ARTICLE | doi:10.20944/preprints201807.0476.v1

Validation of a Digital Identification Tool for Individuals at Risk for Hereditary Cancer Syndromes

Leslie Bucheit, Katherine Johansen Taber, Kaylene Ready

Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: BRCA1, BRCA2, Hereditary Breast and Ovarian Cancer, Lynch Syndrome, Hereditary cancer, Family history screening. Risk assessment, Digital tool, Health information technology

Online: 25 July 2018 (09:59:26 CEST)

Show abstract| Download PDF| Share

The number of individuals meeting criteria for genetic counseling and testing for hereditary cancer syndromes (HCS) is far less than the number that actually receive it. To facilitate identification of patients at risk for HCS, Counsyl developed a digital identification tool (digital ID tool) to match personal and family cancer history to National Comprehensive Cancer Network (NCCN) BRCA-related Hereditary Breast and Ovarian Cancer (HBOC), Lynch syndrome, and polyposis testing criteria in one-to-one, automated fashion. The purpose of this study was to validate the ability of the digital ID tool to accurately identify histories that do and do not meet NCCN testing criteria. Methods: Third-party recorded three-generation pedigrees were retrospectively reviewed by a certified genetic counselor (CGC) to determine if independent events included in pedigree histories met NCCN guidelines, and were then sorted into groups: high risk events (meets criteria) and low risk events (does not meet criteria). Events were entered into the digital ID tool to determine the extent of its concordance with events sorted by CGC review. Statistical tests of accuracy were calculated at a 95% confidence interval (CI). Results: 197 pedigrees were reviewed consecutively representing 765 independent events for analysis across groups. 382/382 (100%) high risk events identified by the digital ID tool and 381/383 (99.47%) low risk events identified by the digital ID tool were concordant with CGC sorting. The digital ID tool had a sensitivity of 100% (99.04-100% CI) and specificity of 99.48% (98.13-99.94% CI). The overall accuracy of the digital ID tool was estimated to be 99.74% (99.06-99.97% CI), reflecting the rate at which the digital ID tool reached the same conclusion as that of CGC review of pedigree events for the recommendation of genetic testing for individuals at risk for HCS. Conclusions: The digital ID tool accurately matches NCCN criteria in one-to-one fashion to identify at-risk individuals for HCS and may be useful in clinical practice, specifically for BRCA-related HBOC and Lynch Syndrome.

Preprint ARTICLE | doi:10.20944/preprints202404.0636.v1

BRCA1/2 Testing Landscape in Ovarian Cancer: A Nationwide, Real-World Data Study

Lieke Lanjouw, Joost Bart, Marian J.E. Mourits, Stefan M. Willems, Annemieke H. van der Hout, Arja ter Elst, Geertruida H. de Bock

Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: BRCA1/2 pathogenic variants; ovarian carcinoma; tumor test; next generation sequencing; real-world data

Online: 9 April 2024 (11:45:17 CEST)

Show abstract| Download PDF| Supplementary Files| Share

Preprint ARTICLE | doi:10.20944/preprints202107.0430.v1

In BRCA1 and BRCA2 Breast Cancers, Chromosome Breaks Occur near Herpes Tumor Virus Sequences

Bernard Friedenson

Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Breast cancer infection; breast cancer immunity; breast cancer virus; nasopharyngeal cancer; EBV cancer; hereditary breast cancer; BRCA1; BRCA2

Online: 20 July 2021 (09:29:06 CEST)

Show abstract| Download PDF| Share

Inherited mutations in BRCA1 and BRCA2 genes increase risks for breast, ovarian, and other cancers. Both genes encode proteins for accurately repairing chromosome breaks. If mutations inactivate this function, broken chromosomes may not be restored correctly, allowing breaks to persist or rearrange chromosomes. These abnormalities are potentially catastrophic events that can originate from viral infections. I used bioinformatic analyses of publicly available breast cancer patient data to show that the distribution of chromosome breaks in hereditary breast cancers differs markedly from sporadic breast cancers. Then I tested hereditary breast cancer sequence data around chromosome breaks for DNA similarity to all known viruses. Human DNA flanking breakpoints usually had decisive matches to Epstein-Barr virus (EBV / HHV4) tumor variants HKHD40 and HKNPC60. Many breakpoints were near EBV genome anchor sites, human EBV tumor-like sequences, EBV-associated epigenetic marks, and some fragile sites. On chromosomes 2 and 12, sequences near EBV genome anchor sites accounted for 90% and 88% of breakpoints (p<0.0001), respectively. On chromosome 4, 51/52 inter-chromosomal breakpoints were close to EBV-like sequences in 19 hereditary breast cancers. In contrast, 19 sporadic breast cancers only had 12 interchromosomal breakpoint regions on chromosome 4 near EBV-like sequences. On various other chromosomes, five EBV genome anchor sites were near hereditary breast cancer breakpoints at precisely defined, disparate gene or LINE locations. Independent evidence further implicating EBV in hereditary breast cancer breakpoints is that 25 breast cancer break positions are within 1.25% of breakpoints in model EBV cancers. In addition to BRCA1 or BRCA2 mutations, all the hereditary breast cancers had mutated genes essential for immune responses. This compromise facilitates reactivation of herpes viruses which produce nucleases capable of breaking chromosomes. EBV also causes other deleterious effects: anchored EBV episomes can interfere with normal replication and obstruct DNA break repairs; even very early infection causes massive transcription changes. The results, therefore, imply proactive treatment and prevention of herpes viral infections may prevent some chromosome breaks and benefit BRCA mutation carriers.

Preprint ARTICLE | doi:10.20944/preprints202105.0490.v1

In BRCA1 and BRCA2 Breast Cancers, Chromosome Breaks Occur Near Herpes Tumor Virus Sequences

Bernard Friedenson

Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Breast cancer infection; breast cancer immunity; breast cancer virus; genome biochemistry; nasopharyngeal cancer; herpes viruses; hereditary breast cancer; BRCA1; BRCA2; Burkitt's lymphoma; homologous recombination; DNA repair; viral cancer; chromosome breaks; Breast cancer infection; breast cancer immunity; breast cancer virus; nasopharyngeal cancer; hereditary breast cancer; BRCA1; BRCA2; Burkitt's lymphoma

Online: 20 May 2021 (12:43:11 CEST)

Show abstract| Download PDF| Supplementary Files| Share

Inherited mutations in BRCA1 and BRCA2 genes increase risks for breast, ovarian, and other cancers. Both genes encode proteins for accurately repairing chromosome breaks. If mutations inactivate this function, chromosome fragments may not be restored correctly. Resulting chromosome rearrangements can become critical breast cancer drivers. Because I had data from thousands of cancer structural alterations that matched viral infections, I wondered whether infections contribute to chromosome breaks and rearrangements in hereditary breast cancers. There are currently no interventions to prevent chromosome breaks because they are thought to be unavoidable. However, if chromosome breaks come from infections, they can be treated or prevented. I used bioinformatic analyses to test publicly available breast cancer sequence data around chromosome breaks for DNA similarity to all known viruses. Human DNA flanking breakpoints usually had the strongest matches to Epstein-Barr virus (EBV) tumor variants HKHD40 and HKNPC60. Many breakpoints were near sites that anchor EBV genomes, human EBV tumor-like sequences, EBV-associated epigenetic marks, and fragile sites. On chromosome 2, sequences near EBV genome anchor sites accounted for 90% of breakpoints (p<0.0001). On chromosome 4, 51/52 inter-chromosomal breakpoints were close to EBV-like sequences. Five EBV genome anchor sites were near breast cancer breakpoints at precisely defined, disparate gene or LINE locations. Breakpoint flanking regions resembled known EBV-cancers. Twenty-five breakpoints in breast cancers were within 1.25% of EBV cancer breakpoints. In addition to BRCA1 or BRCA2 mutations, all the breast cancers had mutated genes essential for immune responses. Because of this immune compromise, herpes viruses can activate and produce nucleases that break chromosomes. Alternatively, anchored viral episomes can obstruct break repairs, whatever the cause. The results, therefore, imply proactive treatment and prevention of herpes viral infections may prevent some chromosome breaks and benefit BRCA mutation carriers.

Preprint REVIEW | doi:10.20944/preprints202312.2153.v1

Different Mechanisms in Doxorubicin-induced Cardiomyopathy: Impact of BRCA1 and BRCA2 Mutations

Hien C. Nguyen, Jefferson C. Frisbee, Krishna K. Singh

Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: BRCA2; BRCA1; doxorubicin; breast cancer; heart failure

Online: 28 December 2023 (05:10:03 CET)

Show abstract| Download PDF| Share

Preprint REVIEW | doi:10.20944/preprints202304.0736.v1

Biological Therapies Beyond PARP-Inhibitors in Advanced Breast Cancer Patients with Germline BRCA1/2 Mutations

Marta Nerone, Lorenzo Rossi, Rosaria Condorelli, Vilma Ratti, Fabio Conforti, Antonella Palazzo, Rossella Graffeo

Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: advanced breast cancer; germline BRCA1/2 mutations; pathogenic/likely pathogenic variants; CDK4/6 inhibitors; Pi3Ka inhibitors; HER2-low

Online: 23 April 2023 (03:12:48 CEST)

Show abstract| Download PDF| Share

Preprint ARTICLE | doi:10.20944/preprints202308.0332.v2

A Benchmark of In-House Homologous Recombination Repair Deficiency Testing Solutions for High-Grade Serous Ovarian Cancer Diagnosis

Rodrigo Guarischi-Sousa, José Eduardo Kroll, Adriano Bonaldi, Paulo Marques Pierry, Darine Villela, Camila Alves Souza, Juliana Santos Silva, Matheus Carvalho Burger, Felipe de Azevedo Oliveira, Marcelo Gomes De Paula, Fabiana Marcelino Meliso, Luiz Gustavo De Almeida, Priscilla Morais Monfredini, Ana Gabriela De Oliveira, Fernanda Milanezi, Cristovam Scapulatempo-Neto, Guilherme Lopes Yamamoto

Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: homologous recombination deficiency (HRD); biomarkers; ovarian cancer; DNA repair; BRCA1/2; poly (ADP–ribose) polymerase inhibitors (PARPi); next generation sequencing (NGS)

Online: 6 September 2023 (09:09:09 CEST)

Show abstract| Download PDF| Supplementary Files| Share

Preprint ARTICLE | doi:10.20944/preprints202110.0198.v1

Cell Cycle Regulation and DNA Damage Response Networks in Diffuse-and Intestinal-Type Gastric Cancer

Shihori Tanabe, Sabina Quader, Ryuichi Ono, Horacio Cabral, Kazuhiko Aoyagi, Akihiko Hirose, Hiroshi Yokozaki, Hiroki Sasaki

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: BRCA1; cancer stem cell; cell cycle; epithelial-mesenchymal transition; DNA damage response; gastric cancer; molecular network

Online: 13 October 2021 (11:06:51 CEST)

Show abstract| Download PDF| Share

Preprint CASE REPORT | doi:10.20944/preprints201911.0200.v1

Somatic BRCA Mutation in Cholangiocarcinoma Patient Utilized to Individualize an HBOC Syndrome

Angelo Paradiso, Margherita Patruno, Maria Digennaro, Stefania Tommasi, Brunella Pilato, Antonella Argentiero, Oronzo Brunetti, Nicola Silvestris

Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: BRCA1; BRCA2; biliary tract cancers; ereditary BRCA cancer; somatic mutations

Online: 17 November 2019 (10:44:44 CET)

Show abstract| Download PDF| Share

Preprint ARTICLE | doi:10.20944/preprints202008.0307.v1

Bringing onco-innovation to Europe’s healthcare systems: the unexploited potential of biomarker testing, real world evidence and the potential of Tumour Agnostics. The lesson from BRCA1/2 genetic testing

Denis Horgan, Gennaro CILIBERTO, Pierfranco Conte, Giuseppe CURIGLIANO, Luis Seijo, Luis M. Montuenga, Luis Paz-Ares, Marina Chiara Garassino, Penault-Llorca Frederique, Fabrizia GALLI, Isabelle Ray-Coquard, Denis Querleu, David R. Baldwin, Susana Banerjee, Peter H.J. Riegman, Keith Kerr, Benjamin Horbach, Reinhard Büttner, Hendrik Van Poppel, Anders Bjartell, Giovanni Codacci-Pisanelli, Westphalen Christoph Benedikt, Fabien CALVO, Jasmina Koeva-Balabanova, Stephen Hall, Angelo Virgilio Paradiso, Dipak. Kalra, Christa M. Cobbaert, Rocio Varea Mendez, Zorana Maravic, Vassiliki Fotaki, Jaafar Bennouna, Estelle Cauchin, Núria Malats, Iñaki Gutiérrez-Ibarluzea, Benjamin Gannon, Ken Mastris, Chiara Benini, William M. Gallagher, Simonetta Buglioni, Alastair Kent, Elisabetta Munzone, Ivica Belina, Jan P. van Meerbeeck, Michael Joe Duffy, Elzbieta. Sarnowska, Beata Jagielska, Sarah Mee, Ettore Domenico Capoluongo

Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: cancer biomarkers, BRCA1/2, genomics; European recommendation

Online: 14 August 2020 (04:27:45 CEST)

Show abstract| Download PDF| Share

Working Paper ARTICLE

Bringing Onco-innovation to Europe's Healthcare Systems: The Potential of Biomarker Testing, Real World Evidence, Tumour Agnostic Therapies to Empower Personalised Medicine

Denis Horgan, Gennaro Ciliberto, Pierfranco Conte, Giuseppe Curigliano, Luis Seijo, Luis M. Montuenga, Marina Garassino, Frederique Penault-Llorca, Fabrizia Galli, Isabelle Ray-Coquard, Denis Querleu, Peter Riegman, Keith Kerr, Hendrik Van Poppel, Anders Bjartell, Giovanni Codacci-Pisanelli, Benedikt Westphalen, Jasmina Koeva-Balabanova, Angelo Paradiso, Zorana Maravic, Vassiliki Fotaki, Nuria Malats, Chiara Bernini, Simonetta Buglioni, Alastair Kent, Elisabetta Munzone, Ivica Belina, Jan Van Meerbeeck, Michael Duffy, Beata Jagielska, Ettore Capoluongo

Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: cancer biomarkers; BRCA1/2; genomics; European recommendation

Online: 18 August 2020 (16:30:04 CEST)

Show abstract| Download PDF| Share

Preprint REVIEW | doi:10.20944/preprints201811.0541.v1

RAD-ical New Insights into RAD51 Regulation

Meghan R. Sullivan, Kara A. Bernstein

Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: homologous recombination; RAD51 paralogs; BRCA1; BRCA2; RAD51B; RAD51C; RAD51D; XRCC2; XRCC3; Shu complex; cancer

Online: 22 November 2018 (06:49:34 CET)

Show abstract| Download PDF| Share

Preprint REVIEW | doi:10.20944/preprints201902.0090.v1

Germline Missense Variants in BRCA1: New Trends and Challenges for Clinical Annotation

Volha Golubeva, Thales Nepomuceno, Alvaro Monteiro

Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: BRCA1; variants of uncertain clinical significance; VUS; germline variants; hereditary breast and ovarian cancer; breast cancer; genetic testing, ovarian cancer; variant classification; clinical annotation

Online: 11 February 2019 (16:12:03 CET)

Show abstract| Download PDF| Share

Search Results

13 articles found