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Year : 2010  |  Volume : 47  |  Issue : 4  |  Page : 397--399

Incidence of malignancy and clonal chromosomal abnormalities in Fanconi anemia

BR Vundinti, S Korgaonkar, K Ghosh 
 Department of Cytogenetics, National Institute of Immunohaematology, 13th floor, New multistoried building, K.E.M. Hospital campus, Parel, Mumbai - 400 012, India

Correspondence Address:
B R Vundinti
Department of Cytogenetics, National Institute of Immunohaematology, 13th floor, New multistoried building, K.E.M. Hospital campus, Parel, Mumbai - 400 012
India

Abstract

Background: Fanconi anemia (FA) is an autosomal recessive, cancer susceptibility disorder characterized by diverse clinical features, such as short stature, skeletal or skin abnormalities, progressive bone marrow (BM) failure, and increased risk of malignancies. Clonal chromosomal abnormalities are frequently reported in FA patients transformed to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Aim: To study the incidence of malignancy and clonal chromosomal abnormalities in FA patients. Materials and Methods: Thirty-eight clinically diagnosed FA patients were studied at the time of diagnosis and the patients were followed-up for a maximum of 28 months at 3-month intervals. The median duration of follow-up of these patients was 19.8 months. Chromosomal breakage investigation using mitomycin C (MMC)- and diepoxybutane (DEB)-induced peripheral blood cultures were stimulated with phytohemagglutinin. Cytogenetic study was done on the BM cells to detect clonal chromosomal aberrations. Results: Eleven (28.95%) out of 38 patients developed malignancies, including 6 (54.54%) MDS, 4 (36.36%) AML, and 1 (2.63%) squamous cell carcinoma. The clonal chromosomal abnormalities were detected in 5 (45.45%) FA patients who developed malignancies and the type of chromosomal abnormality detected were monosomies 5, 7, trisomy 10, dup(1)(q12-q24), and inv(7)(p11pter). Conclusion: The FA patients have a high risk of developing malignancies, and clonal chromosomal abnormalities play an important role in the prognosis of the disease. Therefore, FA patients need to be followed-up at regular intervals for early diagnosis and optimal management of the disease.



How to cite this article:
Vundinti B R, Korgaonkar S, Ghosh K. Incidence of malignancy and clonal chromosomal abnormalities in Fanconi anemia.Indian J Cancer 2010;47:397-399


How to cite this URL:
Vundinti B R, Korgaonkar S, Ghosh K. Incidence of malignancy and clonal chromosomal abnormalities in Fanconi anemia. Indian J Cancer [serial online] 2010 [cited 2020 Aug 12 ];47:397-399
Available from: http://www.indianjcancer.com/text.asp?2010/47/4/397/73575


Full Text

 Introduction



Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by bone marrow failure and congenital anomalies associated with skin hypo- or hyperpigmentation, combined radial ray, and thumb deformities, cardiac, renal, microcephaly, and increased risk of malignancies. [1],[2],[3] FA has been reported in diverse ethnic groups with an estimated heterozygous carrier frequency of 1 in 300, although this estimate may run higher in certain ethnic groups. [4],[5] The FA patients' cells are hypersensitive to alkylating agents, such as mitomycin C (MMC), diepoxybutane (DEB) and exhibit high frequency of chromosomal breakage. [6] They are at a high risk for bone marrow (BM) failure, aplastic anemia, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and later in life, for epithelial malignancies. [7] Many FA patients acquire chromosomal aberrations in their BM cells. [8] We have investigated clinically diagnosed FA patients, and the patients were followed-up to understand the development and chromosomal aberrations in their BM cells.

 Materials and Methods



Thirty-eight clinically diagnosed FA patients were referred to the cytogenetics laboratory for the diagnosis of FA. The patient's clinical, hematologic, parental age, parental reproductive history, and so on were recorded in the proforma.

Chromosomal breakage study was carried out from the peripheral blood lymphocyte cultures stimulated with phytohemagglutinin induced with MMC (20 ng/mL) at 24 h. Chromosomal preparations obtained from 72-h cultures were stained with Giemsa, and the metaphases were analyzed for chromosome breakage under a bright field microscope. The breakage frequency was compared with age- and sex-matched controls. The chromosomal preparations were also done from BM aspirate in all the patients. The patients were followed-up at every 3-month intervals for a maximum of 28 months. The median duration of follow-up of these patients was 19.8 months. The study protocols were approved by the Institutional Ethical Review Board.

 Results



All the 38 patients had clinical abnormalities, such as short stature, hyperpigmentation, ray defects, thumb anomalies, renal anomalies, and so on, and were diagnosed as having FA. The chromosomal analysis at the time of diagnosis revealed a significantly high frequency of chromosomal breakage compared with equal number (38) of healthy age- and sex-matched controls, without any phenotypic abnormalities and without any family history of genetic diseases. All the patients with FA were followed up to a maximum of 28 months at 3-month intervals. The frequency of malignancies in FA is presented in [Table 1]. Among the 38 FA patients, 11 (28.94%) patients developed malignancies, including 10 patients with leukemia and 1 patient with squamous cell carcinoma. The patients developed malignancies at intervals from 15- to 28-month period after diagnosis [Table 2]. The chromosomal analysis from BM was carried out in all the 38 patients. Among the 11 patients who developed malignancies, 6 (54.54%) patients had chromosomal aberrations and the remaining 5 (45.46%) patients did not show any chromosomal aberrations. However, chromosomal aberrations were not detected in any of the patients who did not develop malignancy. The chromosomal abnormalities detected were monosomies 5, 7, i(7p), der(1), and trisomy 10 [Table 2]. The interval between the diagnosis and development of malignancy varied depending on the type of malignancy. The median duration of the development of MDS was 14.83 months from diagnosis. The duration of FA progression to AML ranged from 24 to 28 months and the median duration was 26.5 months [Table 2]. The overall median duration of follow-up of these patients was 19.8 months. {Table 1}{Table 2}

 Discussion



The risk of neoplasia is increased in most genetic instability disorders caused by mutations in human caretaker genes. It is thought that this increased risk results from the defects in the cellular response to DNA damage, including DNA damage recognition and DNA repair. The FA patients are reported to have a high risk of cancers, including MDS, AML, solid tumors, and squamous cell carcinoma. [7] To the best of our knowledge, large studies on FA patients in the Indian population are not available in the literature. [9],[10],[11] We have carried out systematic study on FA patients to know the incidence of malignancies. In our study, among the 38 FA patients, 11 (28%) progressed toward malignancies and most of the patients were transformed to MDS. Out of the 11 patients, 6 (54.5%) patients developed MDS, 4 patients developed AML (36.3%), and 1(2.63%) patient developed squamous cell carcinoma [Table 1]. Alter, [12] reported a 7% incidence of MDS in FA patients. Leukemia is the most common malignancy arising in FA and the overall cumulative incidence of leukemia is 37%, the median age of onset being 14 years. [12] FA patients in our study transformed to MDS from the time of diagnosis to maximum 22 months and the median duration of developing MDS was 14.83 months. The median duration of FA progression to AML ranged from 24 to 28 months and the median duration was 26.5 months [Table 2].

Clonal chromosomal abnormalities are frequently reported in FA patients transformed to MDS and AML. [8] The most frequently detected aberrations were duplications of 1q, monosomy 7, deletions of 7q, and deletions of 5q. [8] Butturini and Gale [13] reported a high frequency of monosomy 7, 7q deletion, and rearrangements involving 1q24-q34 in MDS and AML in FA patients. In our study group, among the 11 patients who developed malignancies, 5 (45.5%) patients were found to have clonal chromosomal aberrations [Table 2].We have detected monosomy 5 and 7 in MDS of FA patients, which are common chromosomal aberrations in MDS patients. However, dup(1) and inv(7p) were novel chromosomal abnormalities detected in the FA patients developing MDS; although chromosome 1 abnormalities are frequently reported in MDS, the break point region was different in our patient. The inv(7p) detected in our patient is the first case associated with 7p abnormalities in FA patients. The association of trisomy 10 with AML-M4 is known but is uncommon in the setting of FA as shown in one of our patients. The squamous cell carcinoma was reported in 5% of the FA patients, [7] and in our study, one patient developed squamous cell carcinoma. However, follow-up studies and large sample size are important to know the incidence.

The molecular cytogenetics has greatly improved the detection of clonal chromosomal aberrations in the interphase cells and also other chromosomal aberrations in FA. [14] However, the significance of chromosomal aberrations without apparent evolution to overt AML or MDS will only be understood when more FA patients are cytogenetically studied and followed-up for a sufficient period of time. Recently, molecular studies revealed FA complementation groups, especially FANCD1 or FANCD2 defects play an important role in DNA repair and leukemogenesis. This points to the importance of studying complementation groups to understand leukemia progression in karyotypically normal FA patients.

 Conclusions



We have carried out follow-up study in clinically and cytogenetically confirmed FA patients. Our study results suggest that the FA patients develop malignancies at different time periods. However, systematic long-term follow-up studies are to be carried out in these patients. The early detection of clonal chromosomal aberrations in FA patients is important for the optimal management of the disease. Large series of patients with FA, including asymptomatic cases, is essential to understand the incidence of malignancies accurately in the FA patients.

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