Fanconi anaemia presenting as acute myeloid leukaemia and myelodysplastic syndrome in adulthood: a family report on co‐occurring FANCC and CHEK2 mutations
Year: 2018
Type: article
Abstract: For many years, inherited bone marrow failure (BMF) syndromes have been considered to be childhood diseases. However, due to next generation sequencing techniques, this viewpoint has been challenged. We report three siblings, who were diagnosed with myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) in their 30s or 40s in the absence of prior symptoms (siblings 3, 5 and 6; Fig 1). Further family history showed the presence of MDS in mother, breast cancer in sibling 2 and mother, and both head and neck squamous cell carcinoma (HNSCC) and hepatocellular carcinoma in sibling 1 (Fig 1A). Because of the positive family history, this family was referred for genetic testing and counselling. In this setting, whole exome sequencing (WES, Data S1) was performed in order to identify a possible genetic defect underlying the increased risk for malignancies. WES revealed the presence of a homozygous FANCCc.67delG mutation in siblings 1, 3, 5 and 6, as well as the presence of a CHEK2c.1100delC mutation in this family (Table 1, Figure S1). FANCC CHEK2 c.67delG c.1100delC p.D23Ifs p.T367Mfs hom het FANCC CHEK2 c.67delG c.1100delC p.D23Ifs p.T367Mfs het het FANCC CHEK2 c.67delG c.1100delC p.D23Ifs p.T367Mfs hom het FANCC CHEK2 c.67delG c.1100delC p.D23Ifs p.T367Mfs hom hom FANCC CHEK2 IKZF1 IKZF1 ETV6 TP53 c.67delG c.1100delC c.949A>T c.950A>T c.809_810delinsA+823C>A c.892C>A p.D23Ifs p.T367Mfs p.N317Y p.N317I p.P270Tfs*4 p.R298S hom het – – – – 0·096 0·075 0·063 0·053 Fanconi anaemia (FA) is a rare DNA repair disorder caused by defects in one of the 21 currently identified FA genes. Mutations in FA genes result in a variety of clinical symptoms, including congenital malformations (60% of FA cases), development of progressive BMF (mean onset, 7 years of age; cumulative incidence, 90% at 40 years of age) and high risk of developing MDS/AML (median age 13 years, cumulative probability 30–40% at 40 years) (Shimamura & Alter, 2010; Quentin et al, 2011). BMF is considered to be the consequence of excess apoptosis in the haematopoietic stem and progenitor cells (HSPCs), creating a selective environment that favours the evolution of adapted clones, ultimately leading to leukaemic development (Alter, 2007). Besides haematological malignancies, FA strongly predisposes to solid tumour development, particularly HNSCCs and gynecological tumours (Shimamura & Alter, 2010). Although the median age at FA diagnosis was found to be 6·5 years (Shimamura & Alter, 2010), 9% of patients are reported to be diagnosed after 16 years of age (Alter, 2007). This percentage may be an underestimation, as recognition of FA in adult patients can be impeded by several factors. Firstly, a rare disease like FA that is classically regarded to be a childhood disease may not be taken into differential diagnostic consideration by doctors treating adult patients. Furthermore, the presentation of the FA phenotype can be very heterogeneous and tends to be milder in adult FA patients. The presentation of FA in these siblings is highly exceptional with regard to the late age of symptom onset and the absence of typical prior symptoms. The severity of the FA phenotype is thought to depend, at least partially, on the type of mutation. The FANCCc.67delG mutation has been described as resulting in a relatively mild phenotype, which could be explained by the finding that the resultant truncated protein retains partial—however highly imprecise—DNA repair activity (Donahue et al, 2004). However, the median age at FA diagnosis for patients affected by homozygous FANCCc.67delG mutations, based on clinical symptoms, was found to be 10·4 years (range 3·9–25·9) (S. Smetsers, unpublished observation). The observation that all FA patients in this family also carried the CHEK21100delC mutation may be of interest with regard to the delayed phenotype. This mutation results in reduced CHK2 (also termed CHEK2) expression, a protein that has important functions in the response to DNA damage, such as inducing cell cycle arrest (Antoni et al, 2007). CHEK21100delC heterozygosity is relatively common in the Netherlands, with a carrier frequency of 1%, and significantly increases the risk of developing breast cancer (Schmidt et al, 2016). Homozygosity for this mutation, also observed in sibling 5, is a rare condition that may further increase the risk for breast cancer (Adank et al, 2011). Although CHEK21100delC has not yet been associated with increased risk for leukaemia development, reduced levels of activated CHEK2 have been observed in AML (Popp et al, 2017). To our knowledge, the simultaneous presence of mutations in FANCC and CHEK2 has not been found before (Dr Q. Waisfisz, VU University Medical Centre, Amsterdam, the Netherlands, personal communication, 2017). Their co-occurrence in a family affected by several malignancies raises questions about whether the two mutations collaborated in inducing carcinogenesis, and if so, how. One possibility is that reduced CHEK2 protein levels could impede effective cell cycle checkpoint control, resulting in genomically-damaged cells that escape apoptosis. This hypothesis might also explain the absence of prior BMF, as HSPCs would not undergo excess apoptosis during cell cycle checkpoint control, but instead continue to cycle, thereby accumulating DNA damage. Supportive evidence comes from the finding that FA protein deficiency leads to hyper-activation of CHK1, another checkpoint kinase that shares many overlapping functions with CHK2 (Chen et al, 2009). However, the simultaneous occurrence of both mutations might be a coincidence given the high population frequency of CHEK21100delC. Additionally, the mutations may have had limited effect on each other as the biological mechanisms that underlie the risk for cancer development are already affected (Antoni et al, 2007). Another striking finding in this family is the high incidence of AML/MDS. FA-related leukaemias are characterized by specific chromosomal instability patterns, including gains of 1q and 3q and losses of chromosome 7 (Quentin et al, 2011). To determine additional hits that contributed to leukaemogenesis in the FA background, we performed targeted sequencing of 54 frequently mutated genes in myeloid malignancies (Table SII) on MDS BM material from sibling 6. Mutations were detected in IKZF1, ETV6 and TP53, although at low frequencies (Table 1). By screening for a set of 10 genes, others have also reported that mutations commonly found in MDS/AML were rare in FA-related leukaemia (Quentin et al, 2011). These results indicate that gene mutations that are involved in FA-related leukaemia differ from the ones that are recurrently observed in sporadic leukaemia. Furthermore, the presence of multiple low frequency mutations suggests the occurrence of highly clonal haematopoiesis in the context of FA. In summary, this family history illustrates the wide phenotypic variability that can be seen in FA patients. Timely recognition of FA underlying MDS or AML diagnosis is of utmost importance, as this will have extensive impact on treatment modalities, including tailored therapy and donor selection for transplantation, as well as the management of family members. G.B. and E.V. wrote the paper. E.v.d.B and K.M.A performed WES analysis. A.B.M. performed targeted sequencing panel. S.S., B.L. and R.H.S. provided patient material and clinical data, and discussed progress. All authors discussed the results and commented on the manuscript. The authors declare no conflict of interest. Data S1. Supplementary methods. Figure S1. Sangers sequencing. Table SI. Cytogenetic analysis. Table SII. TruSight Myeloid Sequencing Panel gene list (Illumina). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Source: British Journal of Haematology
DOI: 10.1111/bjh.15265
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2803142889