Article
Oncology
Jianbang Chiang, Tze Hao Chia, Jeanette Yuen, Tarryn Shaw, Shao-Tzu Li, Nur Diana Binte Ishak, Ee Ling Chew, Siao Ting Chong, Sock Hoai Chan, Joanne Ngeow
Summary: Genetic testing has clinical utility in managing patients with hereditary cancer syndromes, but encountering variants of uncertain significance in non-European populations such as Asians may pose challenges. A study in an Asian country found that most variants of uncertain significance were downgraded to benign, with a smaller proportion upgraded to pathogenic variants. Reclassification affected 31.0% of patients, with follow-up recommended every 2 years for clinically relevant variants.
JCO PRECISION ONCOLOGY
(2021)
Article
Multidisciplinary Sciences
Wenying Peng, Bin Li, Jin Li, Lianpeng Chang, Jing Bai, Yuting Yi, Rongrong Chen, Yanyan Zhang, Chen Chen, Xingxiang Pu, Meilin Jiang, Jia Li, Rui Zhong, Fang Xu, Bolin Chen, Li Xu, Ning Wang, Jiaojiao Huan, Pingping Dai, Yanfang Guan, Ling Yang, Xuefeng Xia, Xin Yi, Jiayin Wang, Fenglei Yu, Lin Wu
Summary: This study analyzed the germline mutation landscape in 1,794 Chinese lung cancer patients and found significantly higher incidence of these mutations compared to non-cancer individuals. BRCA1/2 mutations were associated with earlier onset age. BRCA2 mutations were more common in Chinese patients, and they also exhibited different prevalence of somatic mutations compared to non-mutation carriers.
NATURE COMMUNICATIONS
(2022)
Review
Oncology
Raffaella Casolino, Vincenzo Corbo, Philip Beer, Chang-il Hwang, Salvatore Paiella, Valentina Silvestri, Laura Ottini, Andrew V. Biankin
Summary: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with lack of effective screening strategies and limited treatment options. However, germline variants in certain genes are emerging as potential targets for PDAC treatment and prevention, with important implications for broad cancer prevention.
Article
Oncology
Nadine Tung, Kali Chatham Dougherty, Emily Stern Gatof, Kim DeLeonardis, Lauren Hogan, Hanna Tukachinsky, Erica Gornstein, Geoffrey R. Oxnard, Kimberly McGregor, Rachel B. Keller
Summary: Existing guidance for germline testing in cancer patients is effective but may miss rare or occult hereditary risk. Comprehensive genomic profiling can help identify potential pathogenic germline variants (PPGV) in select cancer susceptibility genes (CSG) and may serve as a complementary tool to traditional evaluation. In a study of over 125,000 patients with advanced cancer, PPGVs were identified in 9.7% of cases across various cancer types, suggesting the importance of tumor CGP in determining inherited susceptibility.
NPJ PRECISION ONCOLOGY
(2023)
Article
Genetics & Heredity
Xi Luo, Jamie L. Maciaszek, Bryony A. Thompson, Huei San Leong, Katherine Dixon, Sonia Sousa, Michael Anderson, Maegan E. Roberts, Kristy Lee, Amanda B. Spurdle, Arjen R. Mensenkamp, Terra Brannan, Carolina Pardo, Liying Zhang, Tina Pesaran, Sainan Wei, Grace-Ann Fasaye, Chimene Kesserwan, Brian H. Shirts, Jeremy L. Davis, Carla Oliveira, Sharon E. Plon, Kasmintan A. Schrader, Rachid Karam
Summary: Germline pathogenic variants in CDH1 are associated with increased risk of diffuse gastric cancer and lobular breast cancer. Accurate interpretation of these variants is critical for physicians deciding on risk reduction strategies, such as prophylactic surgery. The development of CDH1-specific interpretation guidelines by experts has led to improved clinical management recommendations.
JOURNAL OF MEDICAL GENETICS
(2023)
Article
Oncology
Hideyuki Hayashi, Kei Kunimasa, Shigeki Tanishima, Kohei Nakamura, Marin Ishikawa, Yasutaka Kato, Eriko Aimono, Ryutaro Kawano, Hiroshi Nishihara
Summary: Germline BRCA1/2 variants detected in comprehensive genomic profiling (CGP) often have high variant allele frequency (VAF), but when there is genomic loss at the same allele, the VAF can be low. This case report presents a uterine sarcoma patient with a pathogenic BRCA2 mutation and low VAF in tumor-only CGP, later identified as a germline variant. Therefore, when genomic alterations in BRCA1/2 are found in tumor-only CGP, the potential germline origin of the variants should be considered, even with a very low VAF.
Article
Biochemistry & Molecular Biology
Rabea Wagener, Julia Taeubnerl, Carolin Walter, Layal Yasin, Deya Alzoubil, Christoph Bartenhagen, Andishe Attarbaschi, Carl-Friedrich Classen, Udo Kontny, Julia Hauer, Ute Fischer, Martin Dugas, Michaela Kuhlen, Arndt Borkhardt, Triantafyllia Brozou
Summary: This study identified a portion of pediatric cancer patients carrying pathogenic germline variants through trio whole-exome sequencing, accounting for 13.8% of the cases. Clinical screening also revealed suspicions of underlying cancer predisposition syndrome in some patients, but only a small number were confirmed to have pathogenic variants.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2021)
Review
Genetics & Heredity
Debyani Chakravarty, David B. Solit
Summary: Profiling tumors by next-generation sequencing has the potential to improve diagnostic accuracy, assess heritable cancer risk, and guide treatment selection. Through integrative analyses of tumor and germline variants, as well as identifying mutational signatures that influence therapy response, the clinical utility of cancer genomic profiling is being enhanced. Rapid technological innovation and reduced sequencing costs have enabled the profiling of hundreds of cancer-associated genes as part of routine cancer care.
NATURE REVIEWS GENETICS
(2021)
Article
Biochemistry & Molecular Biology
Carlos D. H. Lopes, Fernanda F. Antonacio, Priscila M. G. Moraes, Paula F. Asprino, Pedro A. F. Galante, Denis L. Jardim, Mariana P. de Macedo, Renata L. Sandoval, Artur Katz, Gilberto de Castro Jr, Maria Isabel Achatz
Summary: The TP53 founder variant c.1010G>A (R337H) is prevalent in southern and southeastern Brazil and is associated with an increased incidence of lung adenocarcinomas (LUADs). In this study, lung cancer patients from the Brazilian Li-Fraumeni Syndrome Study (BLISS) database were analyzed. LUADs were found to be the predominant malignancies among the patients, particularly in females above 50 years old who were non-smokers. The presence of TP53 R337H mutation was also found to be an initial clinical presentation of Li-Fraumeni Syndrome in most cases. Molecular profiling revealed EGFR family alterations in a majority of the patients. Overall, TP53 R337H carriers have a higher predisposition to develop LUAD, and environmental pollution may play a role in the carcinogenesis of lung tumors in these individuals.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Adrienne G. Waks, Dewey Kim, Esha Jain, Craig Snow, Gregory J. Kirkner, Shoshana M. Rosenberg, Coyin Oh, Philip D. Poorvu, Kathryn J. Ruddy, Rulla M. Tamimi, Jeffrey Peppercorn, Lidia Schapira, Virginia F. Borges, Steven E. Come, Elena F. Brachtel, Ellen Warner, Laura C. Collins, Ann H. Partridge, Nikhil Wagle
Summary: The study identified significant differences in somatic alterations of three genes (PIK3CA, GATA3, and ARID1A) in young versus older women with luminal A breast cancer. Additionally, a portion of young women with breast cancer carried pathogenic germline variants, with BRCA1/2 mutations being the most common. Further investigation into these genetic differences may help improve treatment options for young patients with breast cancer.
CLINICAL CANCER RESEARCH
(2022)
Article
Oncology
Sukh Makhnoon, Brooke Levin, Megan Ensinger, Kristin Mattie, Robert J. Volk, Zhongming Zhao, Tito Mendoza, Sanjay Shete, Laila Samiian, Generosa Grana, Andrew Grainger, Banu Arun, Brian H. Shirts, Susan K. Peterson
Summary: This study found that reclassification of variants of uncertain significance (VUS) in oncology care settings has significant implications for clinical management and precision cancer prevention. There were significant variations in reclassification rates between different cancer care settings, as well as among racial/ethnic groups.
Article
Genetics & Heredity
Valentina Favalli, Giulia Tini, Emanuele Bonetti, Gianluca Vozza, Alessandro Guida, Sara Gandini, Pier Giuseppe Pelicci, Luca Mazzarella
Summary: A machine learning tool called RENOVO has been developed to accurately classify genetic variants as pathogenic or benign, providing a pathogenicity likelihood score. The tool outperformed existing automated interpretation tools and showed great potential in reducing the fraction of uninterpreted or misinterpreted variants.
AMERICAN JOURNAL OF HUMAN GENETICS
(2021)
Article
Genetics & Heredity
Lucy Loong, Alice Garrett, Sophie Allen, Subin Choi, Miranda Durkie, Alison Callaway, James Drummond, George J. Burghel, Rachel Robinson, Beth Torr, Ian R. Berry, Andrew J. Wallace, Diana M. Eccles, Sian Ellard, Emma Baple, D. Gareth Evans, Emma R. Woodward, Anjana Kulkarni, Fiona Lalloo, Marc Tischkowitz, Anneke Lucassen, Helen Hanson, Clare Turnbull
Summary: This study developed a consensus framework for variant reclassification in cancer susceptibility genes and other clinical areas, based on surveys and evaluations of a multidisciplinary network in the United Kingdom. The framework provides recommendations for clinical and laboratory management.
GENETICS IN MEDICINE
(2022)
Article
Oncology
Jiil Chung, Logine Negm, Vanessa Bianchi, Lucie Stengs, Anirban Das, Zhihui Amy Liu, Sumedha Sudhaman, Melyssa Aronson, Ledia Brunga, Melissa Edwards, Victoria Forster, Martin Komosa, Scott Davidson, Jodi Lees, Patrick Tomboc, David Samuel, Roula Farah, Anne Bendel, Jeffrey Knipstein, Kami Wolfe Schneider, Agnes Reschke, Shayna Zelcer, Alexandra Zorzi, Robert McWilliams, William D. Foulkes, Raymond Bedgood, Lindsay Peterson, Sara Rhode, An Van Damme, Isabelle Scheers, Sharon Gardner, Gabriel Robbins, Magimairajan Issai Vanan, M. Stephen Meyn, Rebecca Auer, Brandie Leach, Carol Burke, Anita Villani, David Malkin, Eric Bouffet, Annie Huang, Michael D. Taylor, Carol Durno, Adam Shlien, Cynthia Hawkins, Gad Getz, Yosef E. Maruvka, Uri Tabori
Summary: The LOGIC assay is a robust tool for diagnosing MMRD in various cancer types and normal tissues. It outperforms current diagnostic methods and can inform therapeutic decisions and provide rapid diagnosis of germline MMRD.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Genetics & Heredity
Hui-Lin Chin, Nour Gazzaz, Stephanie Huynh, Iulia Handra, Lynn Warnock, Ashley Moller-Hansen, Pierre Boerkoel, Julius O. B. Jacobsen, Christele du Souich, Nan Zhang, Kent Shefchek, Leah M. Prentice, Nicole Washington, Melissa Haendel, Linlea Armstrong, Lorne Clarke, Wenhui Laura Li, Damian Smedley, Peter N. Robinson, Cornelius F. Boerkoel
Summary: This study developed a clinical variant analysis tool (CVAT) to assist in the interpretation of genomic test results. By applying CVAT to 289 clinical exome reports, the researchers found that it achieved performance comparable to experienced medical geneticists. However, there were some issues with reported variants, including reporting variants in genes without established disease association and in genes without sufficient phenotypic concordance.
GENETICS IN MEDICINE
(2022)
