Review
Biochemistry & Molecular Biology
Nozomu Kawashima, Valentino Bezzerri, Seth J. Corey
Summary: Hereditary bone marrow failure syndromes (IBMFSs) are a group of rare genetic disorders, including Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, dyskeratosis congenita, severe congenital neutropenia, and others. Mutations in specific genes involved in DNA damage response, ribosome structure or assembly, or telomere maintenance are responsible for the development of these syndromes. This review discusses the pathogenetic mechanisms of IBMFSs and proposes a potential role for pro-inflammatory cytokines in mediating cytopenias and the transformation to myeloid neoplasia. Anti-inflammatory therapies may hold promise in the treatment of these disorders.
Article
Biochemistry & Molecular Biology
Nadia Bertola, Silvia Bruno, Cristina Capanni, Marta Columbaro, Andrea Nicola Mazzarello, Fabio Corsolini, Stefano Regis, Paolo Degan, Enrico Cappelli, Silvia Ravera
Summary: Fanconi anemia is a rare genetic disorder characterized by bone marrow failure and aplastic anemia. Recent studies have shown that FA cells also exhibit mitochondrial metabolism defects, which lead to intracellular lipid accumulation and oxidative damage. However, the molecular mechanisms underlying these metabolic alterations are still unclear.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Genetics & Heredity
Zhixian Zhou, Huan Yin, Suye Suye, Jiarong He, Chun Fu
Summary: FANCE gene is upregulated in various cancers and is associated with tumor immunity and prognosis. Mouse experiments confirm that Fance gene mutations increase tumor incidence and worsen prognosis.
FRONTIERS IN GENETICS
(2023)
Article
Multidisciplinary Sciences
Abdul K. K. Siraj, Rong Bu, Sandeep Kumar Parvathareddy, Kaleem Iqbal, Saud Azam, Zeeshan Qadri, Maha Al-Rasheed, Wael Haqawi, Mark Diaz, Ingrid G. G. Victoria, Ismail A. A. Al-Badawi, Asma Tulbah, Fouad Al-Dayel, Dahish Ajarim, Khawla S. S. Al-Kuraya
Summary: By screening 918 breast cancer/ovarian cancer patients from Saudi Arabia, we identified six cases with pathogenic/likely pathogenic variants in the PALB2 gene, accounting for 0.65% of the entire cohort. Among these cases, two carried pathogenic variants and four carried likely pathogenic variants. All affected carriers had breast cancer, with a median age of diagnosis at 39.5 years, and only two cases had a documented family history of cancer.
SCIENTIFIC REPORTS
(2023)
Article
Genetics & Heredity
Lisa J. McReynolds, Neelam Giri, Lisa Leathwood, Maureen O. Risch, Ann G. Carr, Blanche P. Alter
Summary: The risk of cancer is not increased in individuals with single pathogenic FA gene variant, according to a study on relatives of patients with FA. This finding is crucial for counseling and managing individuals with FA variants.
GENETICS IN MEDICINE
(2022)
Article
Chemistry, Multidisciplinary
Sally B. Morton, L. David Finger, Roxanne van der Sluijs, William D. Mulcrone, Michael Hodskinson, Christopher L. Millington, Christina Vanhinsbergh, Ketan J. Patel, Mark J. Dickman, Puck Knipscheer, Jane A. Grasby, David M. Williams
Summary: DNA interstrand cross-links (ICLs) have significant implications for DNA replication and transcription, and understanding their repair is crucial. This study presents an efficient method for generating reduced acetaldehyde ICLs, which can be used to study their recognition and repair. The methodology described here shows promising results and will facilitate further research in cross-link repair.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
David M. Williams, Sally B. Morton, L. David Finger, Roxanne van der Sluijs, William D. Mulcrone, Michael Hodskinson, Christopher L. Millington, Christina Vanhinsbergh, Ketan J. Patel, Mark J. Dickman, Puck Knipscheer, Jane A. Grasby
Summary: DNA cross-link (ICLs) can cause lethal events such as cancer or bone marrow failure during replication and transcription. The Fanconi Anemia (FA) pathway proteins are responsible for repairing ICLs, but the details of the pathway are not fully known. Methods to create DNA containing ICLs are crucial for further understanding cross-link repair. A major method to form ICLs in vivo is through DNA reaction with acetaldehyde from ethanol metabolism. This research presents an efficient approach using a novel N2-((R)-4-trifluoroacetamidobutan-2-yl)-2'-deoxyguanosine phosphoramidite for preparing reduced acetaldehyde ICLs. The simplicity, efficiency, and stability of this method will contribute to future studies on cross-link repair.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Hematology
Maurizio Miano, Alice Grossi, Gianluca Dell'Orso, Marina Lanciotti, Francesca Fioredda, Elena Palmisani, Tiziana Lanza, Daniela Guardo, Andrea Beccaria, Silvia Ravera, Vanessa Cossu, Paola Terranova, Fiorina Giona, Michelina Santopietro, Enrico Cappelli, Isabella Ceccherini, Carlo Dufour
Summary: This study found that a considerable number of patients with single/multi-lineage MF may have underlying PIDs, and MF may serve as an important clinical sign in PID patients. An accurate immunological work-up should be performed in all MF patients, and PID-related genes should be considered during MF screening to identify disorders that may receive targeted treatments and appropriate conditioning regimens before transplant.
AMERICAN JOURNAL OF HEMATOLOGY
(2021)
Article
Oncology
Daijing Nie, Jing Zhang, Fang Wang, Xvxin Li, Lili Liu, Wei Zhang, Panxiang Cao, Xue Chen, Yang Zhang, Jiaqi Chen, Xiaoli Ma, Xiaosu Zhou, Qisheng Wu, Ming Liu, Mingyue Liu, Wenjun Tian, Hongxing Liu
Summary: The study suggests that heterozygous mutations in Fanconi anemia genes can contribute to hematologic disorders, particularly aplastic anemia and leukemia. Different genes have varying frequencies of mutations, with some genes showing associations with specific subgroups of hematologic malignancies.
FRONTIERS OF MEDICINE
(2022)
Article
Medical Laboratory Technology
Lixian Chang, Li Zhang, Wenbin An, Yang Wan, Yuli Cai, Yang Lan, Aoli Zhang, Lipeng Liu, Min Ruan, Xiaoming Liu, Ye Guo, Wenyu Yang, Xiaojuan Chen, Yumei Chen, Shuchun Wang, Yao Zou, Weiping Yuan, Xiaofan Zhu
Summary: A study investigated the clinical features and genotype/phenotype correlation of 148 Chinese pediatric Fanconi anemia (FA) patients. FA-A was the most common subtype in the cohort, and finger and skin deformities were the most frequent malformations. New mutation sites and their association with prognosis were identified, and chromosome abnormalities were found to be closely linked to the progression of FA to leukemia.
CLINICA CHIMICA ACTA
(2023)
Article
Oncology
Yilin Bao, Huajun Feng, Feipeng Zhao, Lijun Zhang, Shengen Xu, Conghong Zhang, Chong Zhao, Gang Qin
Summary: In this study, the role of FANCD2 in nasopharyngeal carcinoma (NPC) was investigated. Silencing of FANCD2 affected the sensitivity of CNE-2 cells to ionizing radiation by regulating cell proliferation, apoptosis, and cell cycle distribution, potentially through changes in the expression of NUPR1, FLI1, and FGF21 proteins. These findings provide a promising target for NPC radiotherapy.
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)
Article
Oncology
Junichi Takahashi, Takaaki Masuda, Akihiro Kitagawa, Taro Tobo, Yusuke Nakano, Tadashi Abe, Yuki Ando, Keisuke Kosai, Yuta Kobayashi, Yoshihiro Matsumoto, Tomoharu Yoshizumi, Masaki Mori, Koshi Mimori
Summary: This study found that FANCE is highly expressed in HCC cells and is associated with poor prognosis. By facilitating cell cycle signaling activation, FANCE may promote HCC proliferation. This suggests that FANCE may be a potential therapeutic target and prognostic biomarker for HCC.
Article
Biochemistry & Molecular Biology
Anfeng Mu, Zimu Cao, Denggao Huang, Hiroshi Hosokawa, Shingo Maegawa, Minoru Takata
Summary: Formaldehyde-induced DNA damage is a major cause of Fanconi anemia (FA), a hereditary disorder. In a zebrafish model, overexpression of ADH5 enzyme partially restored the phenotype of FA, suggesting the potential therapeutic utility of an ADH5 activator for the treatment of FA.
MOLECULAR BIOLOGY REPORTS
(2023)
Article
Biochemistry & Molecular Biology
Swarna Beesetti, Shyam Sirasanagandla, Sadie Miki Sakurada, Shondra M. Pruett-Miller, Rhea Sumpter, Beth Levine, Malia B. Potts
Summary: Fanconi anemia is a common inherited bone marrow failure syndrome. FANCL protein is found in mitochondria and its localization is not dependent on its ubiquitin ligase activity. Knockout of FANCL results in increased sensitivity to mitochondrial stress and defective clearing of damaged mitochondria, which can be reversed by reintroduction of wild-type or ubiquitin ligase-deficient FANCL.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2022)
Article
Medicine, General & Internal
Maria Luisa Pena-Pena, Juan Pablo Ochoa, Roberto Barriales-Villa, Marcos Cicerchia, Julian Palomino-Doza, Joel Salazar-Mendiguchia, Arsonval Lamounier, Juan Pablo Trujillo, Diego Garcia-Giustiniani, Xusto Fernandez, Martin Ortiz-Genga, Lorenzo Monserrat, Maria Generosa Crespo-Leiro
Summary: This study aimed to describe the genetic basis of dilated cardiomyopathy (DCM) in a cohort with a high proportion of transplanted patients. The clinical prevalence of familial disease was found to be 37%, with most genetic variants located in sarcomeric genes. The yield of genetic testing was high, reaching 69% in familial cases, providing valuable prognostic information.
Article
Biochemistry & Molecular Biology
Maria Pena-Chilet, Gema Roldan, Javier Perez-Florido, Francisco M. Ortuno, Rosario Carmona, Virginia Aquino, Daniel Lopez-Lopez, Carlos Loucera, Jose L. Fernandez-Rueda, Asuncion Gallego, Francisco Garcia-Garcia, Anna Gonzalez-Neira, Guillermo Pita, Rocio Nunez-Torres, Javier Santoyo-Lopez, Carmen Ayuso, Pablo Minguez, Almudena Avila-Fernandez, Marta Corton, Miguel Angel Moreno-Pelayo, Matias Morin, Alvaro Gallego-Martinez, Jose A. Lopez-Escamez, Salud Borrego, Guillermo Antinolo, Jorge Amigo, Josefa Salgado-Garrido, Sara Pasalodos-Sanchez, Beatriz Morte, Angel Carracedo, Angel Alonso, Joaquin Dopazo
Summary: The Collaborative Spanish Variability Server (CSVS) is a database containing genomes and exomes of unrelated Spanish individuals, generated through a crowdsourcing effort. It provides data support for studying disease variants and population genetic variations, with a web interface for querying and conducting pseudo-control studies for diseases.
NUCLEIC ACIDS RESEARCH
(2021)
Letter
Cardiac & Cardiovascular Systems
Juan Pablo Trujillo-Quintero, Elisabeth Gabau Vila, Jose Maria Larranaga Moreira, Anna Ruiz Nello, Lorenzo Monserrat, Roberto Barriales-Villa
REVISTA ESPANOLA DE CARDIOLOGIA
(2021)
Article
Genetics & Heredity
Abir Ben Haj Ali, Olfa Messaoud, Sahar Elouej, Faten Talmoudi, Wiem Ayed, Fethi Mellouli, Monia Ouederni, Sondes Hadiji, Annachiara De Sandre-Giovannoli, Valerie Delague, Nicolas Levy, Massimo Bogliolo, Jordi Surralles, Sonia Abdelhak, Ahlem Amouri
Summary: The population in North Africa exhibits a high consanguinity rate and a potentially high proportion of founder mutations, which may contribute to the prevalence of recessive genetic disorders like Fanconi anemia. In this study, clinical, cytogenetic, and molecular characterization of FANCA in 29 North African FA patients was conducted, revealing high rates of spontaneous chromosome breakages and identifying several causal mutations. Furthermore, three founder mutations were identified in a majority of Tunisian patients, highlighting the importance of considering the mutational landscape in genetic counseling.
FRONTIERS IN GENETICS
(2021)
Article
Hematology
Maria Jose Ramirez, Roser Pujol, Juan Pablo Trujillo-Quintero, Jordi Minguillon, Massimo Bogliolo, Paula Rio, Susana Navarro, Jose A. Casado, Isabel Badell, Estela Carrasco, Judith Balmana, Albert Catala, Julian Sevilla, Cristina Belendez, Bienvenida Argiles, Monica Lopez, Cristina Diaz de Heredia, Gayatri Rao, Eileen Nicoletti, Jonathan D. Schwartz, Juan A. Bueren, Jordi Surralles
Summary: Fanconi anemia is a genetic disorder characterized by chromosome fragility, bone marrow failure, and predisposition to cancer. A study in Spain found that mosaic FA patients had more favorable long-term clinical outcomes, with some showing multilineage mosaicism. This reverse mosaicism was associated with older age, lower percentage of aberrant cells, and more stable hematology in these patients.
AMERICAN JOURNAL OF HEMATOLOGY
(2021)
Article
Genetics & Heredity
Ricardo Errazquin, Esther Sieiro, Pilar Moreno, Maria Jose Ramirez, Corina Lorz, Jorge Peral, Jessica Ortiz, Jose Antonio Casado, Francisco J. Roman-Rodriguez, Helmut Hanenberg, Paula Rio, Jordi Surralles, Carmen Segrelles, Ramon Garcia-Escudero
Summary: The study describes the generation and characterization of FANCA-mutant cell clones in head and neck squamous cell carcinoma cell lines using CRISPR/Cas9 editing. The mutant cells exhibit sensitivity to DNA interstrand crosslink agents and display phenotypes associated with Fanconi anemia.
Review
Genetics & Heredity
Juan Luque, Ingrid Mendes, Beatriz Gomez, Beatriz Morte, Miguel Lopez de Heredia, Enrique Herreras, Virginia Corrochano, Juan Bueren, Pia Gallano, Rafael Artuch, Cristina Fillat, Luis A. Perez-Jurado, Lluis Montoliu, Angel Carracedo, Jose M. Millan, Susan M. Webb, Francesc Palau, Pablo Lapunzina
Summary: CIBERER, a thematic area of CIBER, focuses on rare disease research. It aims to facilitate collaboration between biomedical and clinical research groups and provide new tools for the diagnosis and therapy of low-prevalence diseases.
Article
Genetics & Heredity
J. A. Encarnacion, P. Cerezuela, I Espanol, M. R. Garcia, C. Manso, I De la Fuente, N. Garrigos, A. Viney, J. Minguillon, J. Surralles
Summary: Fanconi anemia is primarily inherited as an autosomal recessive genetic disorder, leading to a high risk of solid tumors in the head and neck or anogenital regions. Mutations in the FANCM gene may be associated with solid tumors, genetic predisposition for breast and ovarian cancer, and hematological malignancies.
EUROPEAN JOURNAL OF MEDICAL GENETICS
(2022)
Article
Oncology
Jordi Minguillon, Maria Jose Ramirez, Llorenc Rovirosa, Pilar Bustamante-Madrid, Cristina Camps-Fajol, Gorka Ruiz de Garibay, Hermela Shimelis, Helena Montanuy, Roser Pujol, Gonzalo Hernandez, Massimo Bogliolo, Pau Castillo, Penny Soucy, Griselda Martrat, Antonio Gomez, Daniel Cuadras, Maria J. Garcia, Javier Gayarre, Conxi Lazaro, Javier Benitez, Fergus J. Couch, Miquel Angel Pujana, Jordi Surralles
Summary: The study discovered that CDK5RAP3 is a new BRCA2-interacting protein that negatively regulates DNA repair. Overexpression of CDK5RAP3 in breast cancer is associated with poorer survival. Additionally, common genetic variations in the CDK5RAP3 locus may be associated with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
Article
Hematology
Jessica A. Pollard, Elissa Furutani, Shanshan Liu, Erica Esrick, Laurie E. Cohen, Jacob Bledsoe, Chih-Wei Liu, Kun Lu, Maria Jose Ramirez de Haro, Jordi Sumalles, Maggie Malsch, Ashley Kuniholm, Ashley Galvin, Myriam Armant, Annette S. Kim, Kaitlyn Ballotti, Lisa Moreau, Yu Zhou, Daria Babushok, Farid Boulad, Clint Carroll, Helge Hartung, Amy Hont, Taizo Nakano, Tim Olson, Sei-Gyung Sze, Alexis A. Thompson, Marcin W. Wlodarski, Xuesong Gu, Towia A. Libermann, Alan D'Andrea, Markus Grompe, Edie Weller, Akiko Shimamura
Summary: This study investigated the feasibility and tolerability of metformin treatment in patients with Fanconi anemia (FA). The results showed that metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefits.
Article
Oncology
Ricardo Errazquin, Angustias Page, Anna Sunol, Carmen Segrelles, Estela Carrasco, Jorge Peral, Alicia Garrido-Aranda, Sonia Del Marro, Jessica Ortiz, Corina Lorz, Jordi Minguillon, Jordi Surralles, Cristina Belendez, Martina Alvarez, Judith Balmana, Ana Bravo, Angel Ramirez, Ramon Garcia-Escudero
Summary: Fanconi anemia (FA) patients often develop oral squamous cell carcinoma (OSCC), which is diagnosed within the first 3-4 decades of life and is often preceded by lesions that undergo malignant transformation. This study found that Fanca gene knockout mice frequently display premalignant lesions in the oral cavity. When these mice were crossed with mice with conditional deletion of the Trp53 gene in the oral mucosa, they spontaneously developed OSCC with high penetrance and a median latency of less than ten months. In conclusion, Fanca and Trp53 genes cooperate to suppress oral cancer in mice, and these mice constitute the first animal model of spontaneous OSCC in FA.
Article
Multidisciplinary Sciences
Marta Palafox, Laia Monserrat, Meritxell Bellet, Guillermo Villacampa, Abel Gonzalez-Perez, Mafalda Oliveira, Fara Braso-Maristany, Nusaibah Ibrahimi, Srinivasaraghavan Kannan, Leonardo Mina, Maria Teresa Herrera-Abreu, Andreu Odena, Monica Sanchez-Guixe, Marta Capelan, Analia Azaro, Alejandra Bruna, Olga Rodriguez, Marta Guzman, Judit Grueso, Cristina Viaplana, Javier Hernandez, Faye Su, Kui Lin, Robert B. Clarke, Carlos Caldas, Joaquin Arribas, Stefan Michiels, Alicia Garcia-Sanz, Nicholas C. Turner, Aleix Prat, Paolo Nuciforo, Rodrigo Dienstmann, Chandra S. Verma, Nuria Lopez-Bigas, Maurizio Scaltriti, Monica Arnedos, Cristina Saura, Violeta Serra
Summary: CDK4/6 inhibitors combined with endocrine therapy show higher antitumor activity in the treatment of estrogen receptor-positive breast cancer. Overexpression of p16 is associated with reduced effectiveness of CDK4/6 inhibitors, while heterozygous RB1 loss is a biomarker of acquired resistance and poor clinical outcome. Combination of CDK4/6 inhibitor ribociclib with PI3K inhibitor alpelisib demonstrates antitumor activity regardless of specific mutations, even without endocrine therapy.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Andrew L. H. Webster, Mathijs A. Sanders, Krupa Patel, Ralf Dietrich, Raymond J. Noonan, Francis P. Lach, Ryan R. White, Audrey Goldfarb, Kevin Hadi, Matthew M. Edwards, Frank X. Donovan, Remco M. Hoogenboezem, Moonjung Jung, Sunandini Sridhar, Tom F. Wiley, Olivier Fedrigo, Huasong Tian, Joel Rosiene, Thomas Heineman, Jennifer A. Kennedy, Lorenzo Bean, Rasim O. Rosti, Rebecca Tryon, Ashlyn-Maree Gonzalez, Allana Rosenberg, Ji-Dung Luo, Thomas S. Carroll, Sanjana Shroff, Michael Beaumont, Eunike Velleuer, Jeff C. Rastatter, Susanne Wells, Jordi Surralles, Grover Bagby, Margaret L. MacMillan, John E. Wagner, Maria Cancio, Farid Boulad, Theresa Scognamiglio, Roger Vaughan, Kristin G. Beaumont, Amnon Koren, Marcin Imielinski, Settara C. Chandrasekharappa, Arleen D. Auerbach, Bhuvanesh Singh, David Kutler, Peter J. Campbell, Agata Smogorzewska
Summary: Fanconi anaemia (FA) is a model syndrome of genome instability caused by a deficiency in DNA interstrand crosslink repair. FA SCCs display high numbers of structural variants and may undergo epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signaling, contributing to their aggressive nature.
Article
Medicine, Research & Experimental
Jose A. Casado, Antonio Valeri, Rebeca Sanchez-Dominguez, Paula Vela, Andrea Lopez, Susana Navarro, Omaira Alberquilla, Helmut Hanenberg, Roser Pujol, Jose-Carlos Segovia, Jordi Minguillon, Jordi Surralles, Cristina Diaz de Heredia, Julian Sevilla, Paula Rio, Juan A. Bueren
Summary: Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome, and the pathophysiological mechanisms of FA have not been fully elucidated. This study found that hematopoietic stem and progenitor cells (HSPCs) in FA patients express stress molecules NKG2D-Ls, which interact with activating receptor NKG2D in NK or CD8(+) T cells, leading to progressive depletion of HSPCs. Blocking NKG2D-NKG2D-L interactions can improve hematopoietic function and alleviate anemia in FA patients.
JOURNAL OF CLINICAL INVESTIGATION
(2022)