Article
Immunology
Pallavi Gaikwad, Umair Ahmed Bargir, Shweta Shinde, Pranoti Kini, Rajesh Chaurasia, Usha Yadav, Amruta Dhawale, Merin George, Neha Jodhawat, Priyanka Setia, Disha Vedpathak, Aparna Dalvi, Ankita Parab, Maya Gupta, Reetika Malik Yadav, Mayuri Goriwale, Baburao Vundinti, Nagesh Bhat, B. K. Sapra, Madhumati Otiv, Ratna Sharma, Manisha Madkaikar
Summary: Living organisms are exposed to agents that cause DNA double strand breaks, which are repaired by DNA repair proteins to maintain genomic integrity. Defects in DNA repair pathways affect lymphocyte development and maturation, as double strand breaks are crucial for V(D)J recombination. Recent classifications for inborn errors of immunity have listed DNA repair defect genes separately, highlighting their importance for adaptive and innate immunity. We present a case of a young female with mutations in two different DNA repair pathway genes, resulting in clinical manifestations associated with both defects. Next-generation sequencing and functional assays aid in determining the pathogenicity of these mutations and providing appropriate management and genetic counseling.
JOURNAL OF CLINICAL IMMUNOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Gaurang Trivedi, Daichi Inoue, Lingbo Zhang
Summary: Myelodysplastic syndrome (MDS) patients often suffer from anemia, with many not responding to traditional therapies. Hence, new treatment strategies targeting splicing defects and enhancing erythroid output are being developed to improve therapeutic efficacy.
TRENDS IN MOLECULAR MEDICINE
(2021)
Review
Biochemistry & Molecular Biology
Lismeri Wuicik Merfort, Mateus de Oliveira Lisboa, Luciane Regina Cavalli, Carmem Maria Sales Bonfim
Summary: Fanconi Anemia is a genomic instability disease characterized by sensitivity to DNA cross-linking agents and chromosomal abnormalities. Diagnosis relies on cytogenetic analysis, which reveals chromosomal breaks induced by cross-linking agents. Understanding the genetic abnormalities and monitoring patients' prognosis is important for clinical management.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Cell Biology
Laure Guitton-Sert, Yuandi Gao, Jean-Yves Masson
Summary: Fanconi anemia (FA) is a genetic disorder characterized by developmental abnormalities, bone marrow failure, and susceptibility to cancer. Zebrafish and mouse models have been developed to simulate FA, showing phenotypes such as bone defects, sterility, and marrow failure. Studies highlight the role of aldehydes in FA pathogenesis and potential therapeutic agents like aldehyde scavengers, TGFβ inhibitors, and gene therapy have been discussed for FA treatment. The diversity of FA animal models contributes to understanding the disease etiology and developing new therapies.
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
(2021)
Article
Oncology
Anna Huguet Ninou, Jemina Lehto, Dimitrios Chioureas, Hannah Stigsdotter, Korbinian Schelzig, Emma Akerlund, Greta Gudoityte, Ulrika Joneborg, Joseph Carlson, Jos Jonkers, Brinton Seashore-Ludlow, Nina Marie Susanne Gustafsson
Summary: DNA-damaging chemotherapeutics, such as platinum drugs, rely on the DNA repair capacity of cancer cells for efficacy, but cancer cells often develop resistance by altering their DNA damage response pathways. Targeting PFKFB3, which is commonly overexpressed in cancer, sensitizes cancer cells to platinum drugs and improves treatment efficacy by modulating the Fanconi anemia DNA repair pathway. Inhibition of PFKFB3 disrupts the assembly of key FA repair factors, prevents fork restart, and ultimately leads to an accumulation of DNA damage in replicating cells and fork collapse, enhancing the effectiveness of ICL-inducing cancer treatments.
Article
Environmental Sciences
Yun Zhao, Linqing Wei, Abderrahmane Tagmount, Alex Loguinov, Amin Sobh, Alan Hubbard, Cliona M. McHale, Christopher J. Chang, Chris D. Vulpe, Luoping Zhang
Summary: This study identified genes affecting formaldehyde toxicity in human hematopoietic cells using CRISPR screening, including those that increase sensitivity and resistance, along with related pathways and mechanisms. Results indicated a significant role for formaldehyde metabolism and the Fanconi anemia pathway in toxicity tolerance, and new network analyses revealed potential roles for one-carbon metabolism, fatty acid synthesis, and mTOR signaling in modulating formaldehyde toxicity.
Article
Oncology
Tomoharu Mori, Yusuke Okamoto, Anfeng Mu, Yoshimi Ide, Akiyo Yoshimura, Noriko Senda, Yukiko Inagaki-Kawata, Masahiro Kawashima, Hiroyuki Kitao, Eriko Tokunaga, Yasuo Miyoshi, Shozo Ohsumi, Koichiro Tsugawa, Tomohiko Ohta, Toyomasa Katagiri, Shigeru Ohtsuru, Kaoru Koike, Seishi Ogawa, Masakazu Toi, Hiroji Iwata, Seigo Nakamura, Keitaro Matsuo, Minoru Takata
Summary: The ALDH2 enzyme's ability to break down aldehydes is impaired by a specific gene polymorphism, leading to alcohol flushing and an increased risk of esophageal cancer in East Asians. Recent studies suggest that this gene variant may result in higher levels of DNA damage caused by naturally occurring aldehydes. However, in breast epithelial cells, this loss of function does not appear to have an impact on the initiation and development of cancer.
Article
Biochemistry & Molecular Biology
Matthew Nolan, Kenneth Knudson, Marina K. Holz, Indrajit Chaudhury
Summary: mTOR interacts and cooperates with FANCD2 during replication stress to provide cellular stability, mediate stalled replication fork restart, and prevent nucleolytic degradation of the nascent DNA strands. This study reveals a novel functional cross-talk between the mTOR and FA DNA repair pathways to ensure genomic stability.
Review
Hematology
Anna Gueiderikh, Frederique Maczkowiak-Chartois, Filippo Rosselli
Summary: Described by Guido Fanconi almost 100 years ago, Fanconi anemia (FA) is a rare genetic disease characterized by developmental abnormalities, bone marrow failure (BMF) and cancer predisposition. The proteins encoded by FA-mutated genes and assembled in the FANC/BRCA pathway have key functions in DNA repair and replication safeguarding. Recent findings have revealed additional roles of FANC proteins in nucleolar homeostasis and ribosome biogenesis, impacting cellular proteostasis.
Article
Medicine, Research & Experimental
Gerardo Lopez-Perez, Ranjula Wijayatunge, Kelly B. McCrum, Sam R. Holmstrom, Victoria E. Mgbemena, Theodora S. Ross
Summary: In mice, the combined deficiency of the Brca1 and Trp53 genes leads to erythroproliferative disorder, providing a model for hematopoietic neoplasia. This model replicates sensitivity to the PARP inhibitor olaparib seen in breast cancer models and allows for monitoring disease progression and drug responses via peripheral blood analyses.
Article
Hematology
Moonjung Jung, Parinda A. Mehta, Caroline S. Jiang, Rasim O. Rosti, Gabriel Usleaman, Joel M. Correa da Rosa, Francis P. Lach, Erica Goodridge, Arleen D. Auerbach, Stella M. Davies, Agata Smogorzewska, Farid Boulad
Summary: Among siblings with Fanconi anaemia, there is significant correlation in hematological progression, while constitutional abnormalities do not show strong concordance except for kidney abnormalities and microcephaly.
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Article
Genetics & Heredity
Lixian Chang, Li Zhang, Beibei Zhao, Xuelian Cheng, Yang Wan, Ranran Zhang, Weiping Yuan, Xingjie Gao, Xiaofan Zhu
Summary: This study elucidates the functional links between FA and MDS/AML, providing insights into their association.
BMC MEDICAL GENOMICS
(2023)
Article
Oncology
Donna M. Edwards, Dana K. Mitchell, Zahi Abdul-Sater, Ka-Kui Chan, Zejin Sun, Aditya Sheth, Ying He, Li Jiang, Jin Yuan, Richa Sharma, Magdalena Czader, Pei-Ju Chin, Yie Liu, Guillermo de Carcer, Grzegorz Nalepa, Hal E. Broxmeyer, D. Wade Clapp, Elizabeth A. Sierra Potchanant
Summary: The study highlights the importance of mitotic regulation in the development of malignancies associated with the FA pathway deficiency. By introducing heterozygosity of the spindle assembly checkpoint regulator Mad2 in Fancc-/- mice, researchers were able to create a mouse model that better replicates the high risk of myeloid malignancies seen in FA patients. This suggests that error-prone cell division may play a key role in cancer development in FA patients.
FRONTIERS IN ONCOLOGY
(2021)
Editorial Material
Cell Biology
Jasmine D. Peake, Kalisse I. Horne, Chiaki Noguchi, John P. Gilligan, Eishi Noguchi
Summary: Alcohol can cause cellular accumulation of acetaldehyde, a major carcinogen, and individuals with deficiency in acetaldehyde detoxification or the Fanconi anemia DNA repair pathway have an increased risk of esophageal squamous-cell carcinoma. This study reveals that acetaldehyde induces DNA damage at the replication fork, leading to replication stress and activation of cell cycle checkpoints. It also demonstrates that the p53 DNA damage response is elevated in response to acetaldehyde and the FA pathway limits genomic instability. These findings highlight the importance of the FA pathway and p53 DNA damage response in protecting against genomic instability and esophageal carcinogenesis.
Article
Biochemistry & Molecular Biology
Christopher J. Sipe, Mitchell G. Kluesner, Samuel P. Bingea, Walker S. Lahr, Aneesha A. Andrew, Minjing Wang, Anthony P. DeFeo, Timothy L. Hinkel, Kanut Laoharawee, John E. Wagner, Margaret L. MacMillan, Gregory M. Vercellotti, Jakub Tolar, Mark J. Osborn, R. Scott McIvor, Beau R. Webber, Branden S. Moriarity
Summary: Fanconi anemia is a rare genetic disease characterized by a lack of genes essential for DNA repair. Researchers have used digital genome editing to correct the mutated genes in patient cells, resulting in phenotypic rescue.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Hematology
Neelam Giri, Blanche P. Alter, Sharon A. Savage, Pamela Stratton
Summary: Research shows that women with dyskeratosis congenita (DC) and related telomere biology disorders (TBD) may experience adverse impacts on reproductive health, leading to frequent gynaecological problems and pregnancy complications. Women with TBDs would benefit from multidisciplinary, coordinated care by haematology, gynaecology, and maternal-fetal medicine specialists.
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Article
Oncology
Leatrisse Oba, Ana F. Best, Phuong L. Mai, Maria Isabel Achatz, Paul S. Albert, Sharon A. Savage, Payal P. Khincha
Summary: Intermediate 4- and 8-monthly screening blood tests may not provide independent benefit for early cancer detection in Li-Fraumeni syndrome (LFS) patients, but annual comprehensive screening and personalized follow-up remain essential.
Article
Multidisciplinary Sciences
Fiorella Ghisays, Aitor Garzia, Hexiao Wang, Claudia Canasto-Chibuque, Marcel Hohl, Sharon A. Savage, Thomas Tuschl, John H. J. Petrini
Summary: Telomere repeat containing RNAs (TERRAs) are a family of long non-coding RNAs transcribed from the subtelomeric regions of eukaryotic chromosomes. The helicase RTEL1 influences the abundance and localization of TERRA in human cells, with its preferred binding to G-quadruplex structures in TERRA. The regulation of TERRA by RTEL1 is crucial for cell viability and its loss may contribute to disease phenotypes in patients with RTEL1 mutations.
NATURE COMMUNICATIONS
(2021)
Article
Hematology
Marena R. Niewisch, Neelam Giri, Lisa J. McReynolds, Rotana Alsaggaf, Sonia Bhala, Blanche P. Alter, Sharon A. Savage
Summary: This study examined the associations between mode of inheritance in Dyskeratosis congenita related telomere biology disorders (DC/TBDs) and the clinical manifestations and long-term outcomes. The results showed that different modes of inheritance were correlated with different clinical presentations, and they also had an impact on the survival of patients.
Editorial Material
Hematology
Sharon A. Savage
Summary: In this study, novel pathogenic variants in RPA1 were discovered as a new cause of TBDs. The researchers investigated the clinical manifestations in patients from different families, and revealed the role of RPA1 in hematopoiesis and telomeric DNA binding and unfolding. The discovery enhances our understanding of RPA function in telomere biology and provides valuable information for families in understanding the cause of their illness.
Letter
Dermatology
Jessica N. Hatton, Michael R. Sargen, Megan N. Frone, Kelvin C. de Andrade, Sharon A. Savage, Payal P. Khincha
JOURNAL OF INVESTIGATIVE DERMATOLOGY
(2022)
Article
Medicine, General & Internal
Mone't B. Thompson, Daniel Muldoon, Kelvin C. de Andrade, Neelam Giri, Blanche P. Alter, Sharon A. Savage, Robert D. Shamburek, Payal P. Khincha
Summary: The study found that oral androgen therapy in DC patients altered lipid and lipoprotein levels, potentially increasing the risk of atherogenic cardiovascular disease. Individuals on androgens for DC-related BMF should undergo cardiovascular disease monitoring.
Editorial Material
Oncology
Martha S. Linet, Graca M. Dores, Sharon A. Savage
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
(2022)
Article
Genetics & Heredity
Sharon A. Savage, Kristine Jones, Kedest Teshome, Adriana Lori, Lisa J. McReynolds, Marena R. Niewisch
Summary: This study identified a limitation of Next-generation sequencing (NGS) in sequencing through homopolymers. Additionally, a polymorphic site in the WRAP53 gene was reported, and it was recommended that all variants in regions of the genome with homopolymers be validated by Sanger sequencing before clinical action.
Editorial Material
Oncology
Sharon A. Savage
JOURNAL OF CLINICAL ONCOLOGY
(2022)
Letter
Oncology
Ixtaccihuatl H. Obregon, Kelvin C. de Andrade, Renee C. Bremer, Payal P. Khincha, Sharon A. Savage
Article
Hematology
Hannah A. Raj, Tsung-Po Lai, Marena R. Niewisch, Neelam Giri, Youjin Wang, Stephen R. Spellman, Abraham Aviv, Shahinaz M. Gadalla, Sharon A. Savage
Summary: Individuals with telomere biology disorders (TBDs) have significantly shortened telomeres in blood cells, which is associated with increased risk of bone marrow failure and reduced survival. The mean telomere length is estimated to be 5 kilobases, but it is the shortest telomeres that indicate cellular senescence. By using the Telomere Shortest Length Assay (TeSLA), it was found that TBD patients have much shorter mean telomere length and an increased number of telomeres less than 3 kilobases. In addition, TBD patients with severe bone marrow failure and multiple organ manifestations have even shorter telomeres.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Article
Multidisciplinary Sciences
Chiara Pederiva, Davide M. Trevisan, Dimitra Peirasmaki, Shan Chen, Sharon A. Savage, Ola Larsson, Jernej Ule, Laura Baranello, Federico Agostini, Marianne Farnebo
Summary: Posttranscriptional modifications of mRNA, including pseudouridylation, play a crucial role in gene expression regulation. In this study, dyskerin, a pseudouridine synthase, was found to bind to RNA polymerase II and be responsible for pseudouridylation of thousands of mRNAs. Dyskerin-mediated pseudouridylation was shown to interfere with translation and reduction of the modification led to enhanced protein synthesis. Furthermore, dyskeratosis congenita patients with mutations in the dyskerin-encoding gene showed severe reduction in mRNA pseudouridylation.
Review
Geriatrics & Gerontology
Sharon A. Savage
Summary: Telomere length is crucial in genomic stability and cancer risk, with both too short and too long telomeres associated with increased cancer risks.
Article
Oncology
Megan N. Frone, Douglas R. Stewart, Sharon A. Savage, Payal P. Khincha
Summary: The use of ACMG and AMP guidelines has improved germline variant classification concordance, but discrepancies still persist, affecting medical management. In a study of families with germline TP53 variants, 39% showed discordant interpretations, with 11% having variants that could significantly impact medical management. Centralized data sharing and provider education for consistent variant interpretation are crucial for optimal patient care.
JCO PRECISION ONCOLOGY
(2021)
Article
Oncology
Toma S. Omofoye, Anganile Kalinga, Ramapriya Ganti, Frank J. Minja, Timothy B. Rooney
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
(2024)
Article
Oncology
Prarthna V. Bhardwaj, Renuka Dulala, Senthil Rajappa, Chandravathi Loke
Summary: The management of breast cancers in India needs greater emphasis on awareness, early detection, standard pathologic testing, and cost-effective solutions. With standardized management, outcomes similar to those of developed countries can be expected. Additionally, clinical trials aimed at a more diverse population in LMICs like India should be undertaken.
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
(2024)
Article
Oncology
Victoria E. Forbes, Mary D. Chamberlin, Vincent Dusabejambo, Tim Walker, Steve P. Bensen, Norrisa Haynes, Kathryn Nunes, Veauthyelau Saint-Joy, Frederick L. Makrauer
Summary: Global health education needs to adapt to the challenges we face, such as inequities and pandemics. Virtual teaching models are effective in delivering global health education and improving outcomes through bidirectional learning and equitable partnerships.
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
(2024)
Article
Oncology
Tefta Isufaj Haliti, Ilir Hoxha, Rubena Mojsiu, Rohini Mandal, Goksu Goc, Kreshnike Dedushi Hoti
Summary: The IOTA Simple Rules have high diagnostic performance in distinguishing between benign and malignant adnexal masses, providing a reliable tool for early diagnosis of ovarian cancer.
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
(2024)
Article
Oncology
Cecilia Felix Penido Mendes de Sousa, Jared Pasetsky, Gustavo Nader Marta, Megan Kassick, Fabio Ynoe Moraes, Luqman K. Dad
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
(2024)
Article
Oncology
Mary D. Chamberlin, Dafina Ademi Islami, Shqiptar Demaci, Richard J. Barth Jr
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
(2024)
Review
Oncology
Jeta Bunjaku, Arber Lama, Tawanda Pesanayi, Jeton Shatri, Mary Chamberlin, Ilir Hoxha
Summary: The evidence suggests that lifestyle factors such as alcohol and coffee intake may increase the risk of lung cancer, while tea intake may have a protective effect. However, the quality of evidence is currently low and further research is needed.
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
(2024)
Article
Oncology
Mary Chamberlin, Christopher Booth, Gabriel A. Brooks, Achille Manirakiza, Fidel Rubagumya, Verna Vanderpuye
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
(2024)
Article
Oncology
Anne Christine Buteau, Alicia Castelo-Loureiro, Regina Barragan-Carrillo, Suyapa Bejarano, Alba J. Kihn-Alarcon, Enrique Soto-Perez-de-Celis
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
(2024)
Review
Oncology
Ilir Hoxha, Fitim Sadiku, Lot Hoxha, Midhet Nasim, Marie Anne Christine Buteau, Krenare Grezda, Mary D. Chamberlin
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
(2024)