Clonal chromosomal aberrations in bone marrow cells of Fanconi anemia patients: gains of the chromosomal segment 3q26q29 as an adverse risk factor.

Published on May 15, 2003in Blood17.543
· DOI :10.1182/BLOOD-2002-10-3243
Holger Tönnies26
Estimated H-index: 26
(Humboldt University of Berlin),
Stefanie Huber1
Estimated H-index: 1
+ 3 AuthorsHeidemarie Neitzel34
Estimated H-index: 34
Fanconi anemia (FA) is a condition that induces susceptibility to bone marrow failure, myelodysplastic syndrome (MDS), and leukemia. We report on a high incidence of expanding clonal aberrations with partial trisomies and tetrasomies of chromosome 3q in bone marrow cells of 18 of 53 FA patients analyzed, detected by conventional and molecular cytogenetics. To determine the clinical relevance of these findings, we compared the cytogenetic data, the morphologic features of the bone marrow, and the clinical course of these patients with those of 35 FA patients without clonal aberrations of 3q. The 2 groups did not differ significantly with respect to age, sex, or complementation group. There was a significant survival advantage of patients without abnormalities of chromosome 3q. Even more pronounced was the risk assessment of patients with gains of 3q material with respect to the development of morphologic MDS and acute myeloid leukemia (AML). Thus, our data from 18 patients with 3q aberrations reveal that gains of 3q are strongly associated with a poor prognosis and represent an adverse risk factor in FA.
📖 Papers frequently viewed together
554 Citations
122 Citations
392 Citations
#1R. BergerH-Index: 1
#2A. BusselH-Index: 1
Last. C. SchenhietzlerH-Index: 1
view all 3 authors...
A case of Fanconi anemia with terminal acute leukemia is reported. Clones with chromosome abnormalities were observed in bone marrow cells. The patterns of marker chromosome distribution in these clones suggests the occurrence of a somatic segregation mechanism.
34 CitationsSource
#1Sarah L. Donahue (UMN: University of Minnesota)H-Index: 7
#2Colin R Campbell (UMN: University of Minnesota)H-Index: 27
Abstract Fanconi anemia (FA) is a heterogeneous autosomal recessive disease characterized by congenital abnormalities, pancytopenia, and an increased incidence of cancer. Cells cultured from FA patients display elevated spontaneous chromosomal breaks and deletions and are hypersensitive to bifunctional cross-linking agents. Thus, it has been hypothesized that FA is a DNA repair disorder. We analyzed plasmid end-joining in intact diploid fibroblast cells derived from FA patients. FA fibroblasts f...
42 CitationsSource
#1Alexandra Folias (OHSU: Oregon Health & Science University)H-Index: 3
#2Mara E Matkovic (OHSU: Oregon Health & Science University)H-Index: 2
Last. Robb E. MosesH-Index: 31
view all 8 authors...
Fanconi anemia (FA) is a rare autosomal recessive disease characterized by skeletal defects, anemia, chromosomal instability and increased risk of leukemia. At the cellular level FA is characterized by increased sensitivity to agents forming interstrand crosslinks (ICL) in DNA. Six FA genes have been cloned and interactions among individual FANC proteins have been found. The FANCD2 protein co-localizes in nuclear foci with the BRCA1 protein following DNA damage and during S-phase, requiring the ...
109 CitationsSource
#1Holger Tönnies (Humboldt University of Berlin)H-Index: 26
Abstract During the past decade, fluorescence in situ hybridization (FISH) has become an important complementing application in genetic diagnostics. The use of variable FISH techniques enhances the thorough interpretation of numerical and complex chromosome aberrations, bridging the gap between conventional chromosome banding analysis and molecular genetic DNA studies. This review gives a brief overview of the different molecular cytogenetic FISH techniques and applications currently used in rou...
43 CitationsSource
#1Toshiyasu Taniguchi (Harvard University)H-Index: 45
#2Alan D. D'Andrea (Harvard University)H-Index: 117
Fanconi anemia (FA) is a rare autosomal recessive chromosomal breakage disorder characterized by the childhood onset of aplastic anemia, developmental defects, cancer susceptibility, and cellular hypersensitivity to DNA—cross-linking agents. FA patients can be divided into at least 8 complementation groups (FA-A, FA-B, FA-C, FA-D1, FA-D2, FA-E, FA-F, and FA-G). FA proteins encoded by 6 cloned FA genes (FANCA,FANCC,FANCD2,FANCE,FANCF, andFANCG) cooperate in a common pathway, culminating in the mo...
36 CitationsSource
#1Makoto Futaki (NIH: National Institutes of Health)H-Index: 4
#2Johnson M. Liu (NIH: National Institutes of Health)H-Index: 26
Abstract Chromosomal instability can occur when the DNA damage response and repair process fails, resulting in syndromes characterized by growth abnormalities, hematopoietic defects, mutagen sensitivity, and cancer predisposition. Mutations in ATM , NBS1 , MRE11 , BLM , WRN , and FANCD2 are responsible for ataxia telangiectasia (AT), Nijmegen breakage syndrome, AT-like disorder, Bloom and Werner syndrome, and Fanconi anemia group D2, respectively. This diverse group of disorders is thought to be...
63 CitationsSource
#1Markus Grompe (OHSU: Oregon Health & Science University)H-Index: 99
#2Alan D. D'Andrea (Harvard University)H-Index: 117
Fanconi anemia (FA) is an autosomal recessive disorder caused by defects in at least eight distinct genes FANCA, B, C, D1, D2, E, F and G. The clinical phenotype of all FA complementation groups is similar and is characterized by progressive bone marrow failure, cancer proneness and typical birth defects. The principal cellular phenotype is hypersensitivity to DNA damage, particularly interstrand DNA crosslinks. The FA proteins constitute a multiprotein pathway whose precise biochemical function...
151 CitationsSource
#1Holger Tönnies (Humboldt University of Berlin)H-Index: 26
#2M. Stumm (MPG: Max Planck Society)H-Index: 2
Last. Heidemarie Neitzel (MPG: Max Planck Society)H-Index: 34
view all 6 authors...
Today, conventional cytogenetics (CC) is the main technique in routine genetic diagnostics for the analysis of genotype/phenotype correlations. Additionally, fluorescence in situ hybridization (FISH) has proven to be useful for the characterization of structural chromosome aberrations found in conventional cytogenetics. Comparative genomic hybridization (CGH) is a molecular cytogenetic FISH approach developed for the detection of genomic imbalances with cytogenetic resolution. CGH allows the gen...
35 CitationsSource
#1Blanche P. Alter (UTMB: University of Texas Medical Branch)H-Index: 64
#2Jared P. Caruso (UTMB: University of Texas Medical Branch)H-Index: 1
Last. M. Tarek Elghetany (UTMB: University of Texas Medical Branch)H-Index: 17
view all 6 authors...
The adverse potential of the development of myelodysplastic syndrome (MDS) in Fanconi anemia (FA) was examined in a retrospective study of 41 FA patients who had bone marrow morphology and chromosomes reviewed by a single group. Thirty-three patients had adequate cytogenetic studies, and 16 (48%) had one or more abnormal studies: nine initially, and seven more on follow-up. Cytogenetic clonal variation was frequent, including disappearance of clones, clonal evolution, and appearance of new clone...
82 CitationsSource
#1Nicoletta TestoniH-Index: 55
#2Gabriela BorsaruH-Index: 3
Last. Sante TuraH-Index: 82
view all 12 authors...
BACKGROUND AND OBJECTIVE: Acute myeloblastic leukemia (AML) with features of myelodysplastic syndrome (MDS) and abnormalities of megakaryocytopoiesis is often characterized by cytogenetic aberrations of the 3q21 and 3q26 bands involving inv(3)(q21q26) and (3;3)(q21;q26). These aberrations have been described in all FAB subtypes with the exception of M3, and in MDS and in megakaryoblastic crisis of chronic myeloid leukemia. We reviewed the biological and clinical features of 10 cases of AML with ...
80 CitationsSource
Cited By90
#1Andrew D Hughes (Children's Hospital of Philadelphia)
#2Peter Kurre (UPenn: University of Pennsylvania)H-Index: 1
Recent advances have facilitated studies of the clonal architecture of the aging haematopoietic system, and provided clues to the mechanisms underlying the origins of hematopoietic malignancy. Much less is known about the clonal composition of haematopoiesis and its impact in bone marrow failure (BMF) disorders, including Fanconi anaemia (FA). Understanding clonality in FA is likely to inform both the marked predisposition to cancer and the rapid erosion of regenerative reserve seen with this di...
Abstract null null Fanconi anemia (FA) due to biallelic mutations in the BRCA2 gene is very rare and associated with an extremely high risk of early-onset of aggressive childhood malignancies, predominantly brain tumors, leukemia, and nephroblastoma. Here, we present a consanguineous family with three affected children of the D1 subtype of FA and describe the clinical consequences of the earliest known biallelic nonsense/stop-gain germ-line mutation in BRCA2, exon 5 c.469A>T, that leads to a pre...
#1Moonjung Jung (Rockefeller University)H-Index: 7
#2Parinda A. Mehta (Cincinnati Children's Hospital Medical Center)H-Index: 26
Last. Farid Boulad (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 49
view all 12 authors...
Fanconi anaemia (FA) is a genetic disorder due to mutations in any of the 22 FANC genes (FANCA-FANCW) and has high phenotypic variation. Siblings may have similar clinical outcome because they share the same variants; however, such association has not been reported. We present the detailed phenotype and clinical course of 25 sibling sets with FA from two institutions. Haematological progression significantly correlated between siblings, which was confirmed in an additional 55 sibling pairs from ...
1 CitationsSource
#1Eunike Velleuer (HHU: University of Düsseldorf)H-Index: 12
#1Eunike Velleuer (Boston Children's Hospital)H-Index: 4
Last. Carsten Carlberg (University of Eastern Finland)H-Index: 78
view all 2 authors...
Fanconi anemia (FA) is a rare disorder with the clinical characteristics of (i) specific malformations at birth, (ii) progressive bone marrow failure already during early childhood and (iii) dramatically increased risk of developing cancer in early age, such as acute myeloid leukemia and squamous cell carcinoma. Patients with FA show DNA fragility due to a defect in the DNA repair machinery based on predominately recessive mutations in 23 genes. Interestingly, patients originating from the same ...
4 CitationsSource
#1Kristen E. Schratz (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 3
#2Amy E. DeZern (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 14
Last. Amy E. DeZern (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 34
view all 2 authors...
Myelodysplastic syndromes (MDSs) are a heterogeneous group of marrow failure disorders that primarily affect older persons but also occur at a lower frequency in children and young adults. There is increasing recognition of an inherited predisposition to MDS as well as other myeloid malignancies for patients of all ages. Germline predisposition to MDS can occur as part of a syndrome or sporadic disease. The timely diagnosis of an underlying genetic predisposition in the setting of MDS is importa...
5 CitationsSource
#2Brian BursicH-Index: 1
Last. Yigal DrorH-Index: 30
view all 15 authors...
Inherited bone marrow failure syndromes, such as Fanconi anemia (FA) and Shwachman-Diamond syndrome (SDS), feature progressive cytopenia and a risk of acute myeloid leukemia (AML). Using deep phenotypic analysis of early progenitors in FA/SDS bone marrow samples, we revealed selective survival of progenitors that phenotypically resembled granulocyte-monocyte progenitors (GMP). Whole-exome and targeted sequencing of GMP-like cells in leukemia-free patients revealed a higher mutation load than in ...
2 CitationsSource
#1Pinkal Desai (Cornell University)H-Index: 11
#2Duane C. Hassane (Cornell University)H-Index: 20
Last. Gail J. Roboz (Cornell University)H-Index: 59
view all 3 authors...
Abstract Acute Myeloid Leukemia, the most common form of acute leukemia in adults, is an aggressive hematopoietic stem cell malignancy that is associated with significant morbidity and mortality. Though AML generally presents de novo, risk factors include exposure to chemotherapy and/or radiation, as well as both familial and acquired bone marrow failure syndromes. Clonal Hematopoiesis (CH) refers to an expansion of blood or marrow cells resulting from somatic mutations in leukemia-associated ge...
6 CitationsSource
#1Alyssa L. Kennedy (Harvard University)H-Index: 10
#2Akiko Shimamura (Harvard University)H-Index: 48
Myelodysplastic syndrome (MDS) typically presents in older adults with the acquisition of age-related somatic mutations, whereas MDS presenting in children and younger adults is more frequently associated with germline genetic predisposition. Germline predisposition is increasingly recognized in MDS presenting at older ages as well. Although each individual genetic disorder is rare, as a group, the genetic MDS disorders account for a significant subset of MDS in children and young adults. Becaus...
37 CitationsSource
#1Miharu Yabe (Tokai University)H-Index: 22
#2Takashi Koike (Tokai University)H-Index: 8
Last. Hiromasa Yabe (Tokai University)H-Index: 37
view all 18 authors...
Fanconi anemia (FA) is a genetically and clinically heterogeneous disorder that predisposes patients to bone marrow failure (BMF), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). To study which genetic and phenotypic factors predict clinical outcomes for Japanese FA patients, we examined the FA genes, bone marrow karyotype, and aldehyde dehydrogenase-2 (ALDH2) genotype; variants of which are associated with accelerated progression of BMF in FA. In 88 patients, we found morphol...
6 CitationsSource
#1Youjin WangH-Index: 9
#2Weiyin Zhou (Leidos)H-Index: 19
Last. Shahinaz M. GadallaH-Index: 15
view all 11 authors...
Abstract Studies of chromosomal aberrations in blood or bone marrow of patients with Fanconi anemia (FA) have focused on their associations with leukemic transformation. The role of such abnormalities on outcomes after hematopoietic cell transplantation (HCT) is unclear. We used genome-wide single nucleotide polymorphism (SNP) arrays to identify chromosomal aberrations in pre-HCT blood samples from 73 patients with FA who received unrelated donor HCT for severe aplastic anemia between 1991-2007....
5 CitationsSource