Radiosensitivity in Fanconi's anemia patients

doi:10.1016/S0167-8140(01)00474-1

Radiotherapy and Oncology

Volume 62, Issue 3, March 2002, Pages 345-347

https://doi.org/10.1016/S0167-8140(01)00474-1 Get rights and content

Abstract

The risks of radiation therapy in patients with Fanconi's anemia who have cancer are not clear. Possible toxicity was reported in six of 14 patients: 1/1 with vaginal cancer, 4/10 with head and neck or esophageal cancer, and 1/3 with oral cancer following bone marrow transplant.

Introduction

Patients with Fanconi's anemia (FA) have a high risk of cancer, and cancer treatment by chemotherapy or radiation is complicated because of the possibility of side effects due to the underlying defect in DNA damage response [1], [6]. Marcou et al. [13] recently described marked clinical radiosensitivity in a 32-year-old female with FA and a tonsillar squamous cell carcinoma, and observed that in vitro tests of her fibroblasts did not predict the in vivo radiation sensitivity. This discrepancy is clinically significant, since in other DNA-repair disorders there does appear to be a correlation between in vitro and in vivo sensitivity to radiation [17]. The authors also stated that “clinical radiosensitivity has not previously been reported in FA patients”. However, including their case, at least 14 FA patients who have received radiation therapy have been described in the medical literature, of whom six had complications that may have been related to the radiation.

Section snippets

Materials and methods

All cases of FA which have been reported in the literature were identified by systematic Medline searches using the terms ‘Fanconi's anemia’, ‘inherited bone marrow failure’, and ‘aplastic anemia’, supplemented by examination of citations in the references of published articles. This database was updated weekly using the same terms and Web of Science software [2]. Articles in languages which could not be read by the author were translated into English. All articles referring to FA cases were

Results and discussion

Seventy-five cancers were reported in 64 FA patients who had not received a bone marrow transplant (BMT). Radiation therapy was used in 11 of these cases, one patient with vulvar cancer [23], and ten patients (seven females and three males) with head and neck or esophageal cancer (Table 1A) [4], [8], [10], [11], [12], [13], [16], [18], [19], [22], [23]. There were also eight FA cases who developed oral cancer at 3–14 years following BMT [3], [5], [7], [9], [14], [15], [20], [21], [24]; three of

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Cited by (102)

Oral cancer and oral potentially malignant disorders in patients with Fanconi anemia – A systematic review
2024, Oral Oncology
The purpose of the present study was to perform a systematic review focusing on oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMD) in Fanconi anemia (FA) individuals. Electronic searches were undertaken in five databases supplemented by manual scrutiny and gray literature. Case reports and/or cases series were included. The searches yielded 55 studies describing 112 cases of OSCC (n = 107) and/or OPMD (n = 5) in FA individuals. The mean age at diagnosis of OSCC/OPMD was 27.1 (±9.6) years, and females (51.8 %) were slightly more affected. Ulcer (n = 37) or mass (n = 25) were described as clinical presentations for OSCC and OPMD. White lesions (n = 4) were the most common manifestation in OPMD. Tongue (47.2 %) was the most frequent location. Sixty-one (54.5 %) individuals underwent HSCT. Surgical resection (n = 75) was the main treatment adopted. The estimated rate of OPMD malignant transformation was 1.8 % and recurrences following OSCC excision occurred in 26.8 % of individuals. Overall, at 60 months of follow-up, the probability of survival fell to 25.5 % and at 64 months the probability of recurrence increased to 63.2 %. The present data support the need for strict surveillance of patients with FA, even in the absence of OPMD, for early OSCC detection and reduction of mortality.
The Fanconi anemia ubiquitin E3 ligase complex as an anti-cancer target
2021, Molecular Cell
Agents that induce DNA damage can cure some cancers. However, the side effects of chemotherapy are severe because of the indiscriminate action of DNA-damaging agents on both healthy and cancerous cells. DNA repair pathway inhibition provides a less toxic and targeted alternative to chemotherapy. A compelling DNA repair target is the Fanconi anemia (FA) E3 ligase core complex due to its critical—and likely singular—role in the efficient removal of specific DNA lesions. FA pathway inactivation has been demonstrated to specifically kill some types of cancer cells without the addition of exogenous DNA damage, including cells that lack BRCA1, BRCA2, ATM, or functionally related genes. In this perspective, we discuss the genetic and biochemical evidence in support of the FA core complex as a compelling drug target for cancer therapy. In particular, we discuss the genetic, biochemical, and structural data that could rapidly advance our capacity to identify and implement the use of FA core complex inhibitors in the clinic.
Feasibility of breast radiation therapy in a Fanconi Anemia patient diagnosed with breast cancer: A case report and review of literature
2021, Clinical and Translational Radiation Oncology
Fanconi Anemia (FA) is a rare inherited autosomal recessive disease that results in impaired double stranded DNA repair. This leads to both increased susceptibility to various cancers, as well as hypersensitivity to radiotherapy and systemic therapy; thus, increasing the complexity of oncological treatment paradigm.
Here, we present an FA patient who initially developed invasive breast cancer for which she received breast conserving treatment with no significant treatment related toxicity. This was followed by a diagnosis of high-grade ductal carcinoma-in-situ in the contralateral breast, which was managed successfully by surgery and meticulously planned adjuvant radiotherapy, with no treatment interruptions.
Compromised repair of radiation-induced DNA double-strand breaks in Fanconi anemia fibroblasts in G2
2020, DNA Repair
Fanconi anemia (FA) is a rare chromosomal instability syndrome with various clinical features and high cancer incidence. Despite being a DNA repair disorder syndrome and a frequently observed clinical hypersensitivity of FA patients towards ionizing radiation, the experimental evidence regarding the efficiency of radiation-induced DNA double-strand break (DSB) repair in FA is very controversial. Here, we performed a thorough analysis of the repair of radiation-induced DSBs in G1 and G2 in FA fibroblasts of complementation groups A, C, D1 (BRCA2), D2, E, F, G and P (SLX4) in comparison to normal human lung and skin fibroblasts. γH2AX, 53BP1, or RPA foci quantification after X-irradiation was combined with cell cycle markers. Cytogenetic analyses were performed on first metaphases after irradiation in G1 and by premature chromosome condensation after exposure in G2. Furthermore, the role of canonical-NHEJ and alternative-NHEJ for the fidelity of the repair of radiation-induced DSBs was examined. In FA fibroblasts, DSB repair was normal in G1 but compromised and more error-prone in the slow repair component of G2 as suggested by higher yields of radiation-induced γH2AX and 53BP1 foci as well as chromatid exchanges. However, RPA foci quantification in G2 indicated proficiency for homology-directed repair of DSBs in FA except for FA D1 (BRCA2). In lung fibroblasts, DSB repair in G1 was conducted with normal kinetics but elevated chromosome exchanges compared to skin fibroblasts. The overall repair of radiation-induced DSBs and the formation of chromosome exchanges in normal and FA fibroblasts in G1 and G2 were governed by canonical-NHEJ with no contribution of alternative-NHEJ. Together, we show impaired repair of radiation-induced DSBs in various FA complementation groups in the slow repair component of G2 that might promote the formation of potentially oncogenic aberrations and clinical radiation hypersensitivity.
Diagnosis of Fanconi Anaemia by ionising radiation- or mitomycin C-induced micronuclei
2018, DNA Repair
Fanconi Anaemia (FA) is an autosomal recessive disorder characterised by defects in DNA repair, associated with chromosomal instability and cellular hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC). The FA repair pathway involves complex DNA repair mechanisms crucial for genomic stability. Deficiencies in DNA repair genes give rise to chromosomal radiosensitivity. FA patients have shown increased clinical radiosensitivity by exhibiting adverse normal tissue side-effects. The study aimed to investigate chromosomal radiosensitivity of homozygous and heterozygous carriers of FA mutations using three micronucleus (MN) assays. The G0 and S/G2 MN assays are cytogenetic assays to evaluate DNA damage induced by ionising radiation in different phases of the cell cycle. The MMC MN assay detects DNA damage induced by a crosslinking agent in the G0 phase. Patients with a clinical diagnosis of FA and their parents were screened for the complete coding region of 20 FA genes. Blood samples of all FA patients and parents were exposed to ionising radiation of 2 and 4 Gy. Chromosomal radiosensitivity was evaluated in the G0 and S/G2 phase. Most of our patients were homozygous for the founder mutation FANCG c.637_643delTACCGCC; p.(Tyr213Lysfs*6) while one patient was compound heterozygous for FANCG c.637_643delTACCGCC and FANCG c.1379G > A, p.(Gly460Asp), a novel missense mutation. Another patient was compound heterozygous for two deleterious FANCA mutations. In FA patients, the G0- and S/G2-MN assays show significantly increased chromosomal radiosensitivity and genomic instability. Moreover, chromosomal damage was significantly elevated in MMC treated FA cells. We also observed an increase in chromosomal radiosensitivity and genomic instability in the parents using 3 assays. The effect was significant using the MMC MN assay. The MMC MN assay is advantageous as it is less labour intense, time effective and has potential as a reliable alternative method for detecting FA patients from parents and controls.
Squamous Cell Carcinoma Companionship With Fanconi Anemia: Rare Situation or Increasing Hazard?
2017, Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology
The increased susceptibility of malignancies in Fanconi Anemia (FA), an autosomal recessive disease, is a major concern of this syndrome. According to previous reports, Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently diagnosed solid tumors in these patients. Herein the authors report a unique case of HNSCC in the hard palate of a 31-year old female patient with FA syndrome, which was treated by surgical removal. Additionally, the literature about Squamous Cell Carcinoma companionship with Fanconi Anemia is reviewed.

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Short CommunicationRadiosensitivity in Fanconi's anemia patients

Abstract

Introduction

Section snippets

Materials and methods

Results and discussion

Mol Cell

J Oral Maxillofac Surg

Oral Oncol Eur J Cancer

Radiother Oncol

Radiother Oncol

Blood

Fanconi's anemia and malignancies

Am J Hematol

Inherited bone marrow failure syndromes

Squamous carcinoma of the head and neck in organ transplant recipients: possible role of oncogenic viruses

Laryngoscope

Familial hypoplastic anemia with multiple congenital anomalies (Fanconi's syndrome) – report of three cases

R I Med J

Marrow transplantation for Fanconi anemia with or without leukemic transformation: an update of the Seattle experience

Bone Marrow Transplant

Squamous cell carcinoma of the tongue in a patient with Fanconi anemia post bone marrow transplant

Pediatr Res

Short Communication
Radiosensitivity in Fanconi's anemia patients