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O.Steinberg-Shemer et al.
FANCA mutations and patients with non-FANCA muta- tions. The mean age of the first cancer was 18.5 years (SD 6.3 years) for patients with FANCA, relative to 5.2 years (SD 3.7 years) for patients with FANCC, FANCD1, FANCG and FANCJ mutations, with a statistically signifi- cant difference (P=0.001). This difference remains statisti- cally significant upon exclusion of solid tumors; patients with FANCA mutations developed MDS/leukemia at a significantly older age as compared to patients with FANCA mutations (P=0.002). All patients with mutations in FANCA developed cancer after the age of 10 years, while all other genetically diagnosed patients developed their first cancer by the age of 10 years. There was a trend towards more MDS in patients with FANCC mutations and less MDS and cancer in patients with FANCG muta- tions, compared with patients with mutations in other genes (NS).
No association was found between the mutation type and survival. In addition, no association was found between the mutation type and the development of MDS, leukemia or solid tumors, although patients with nonsense and splice site mutations developed the first cancer at a sig- nificantly lower age than patients with deletions (P=0.011 and P=0.012, respectively). No association was found between the CAB score and mutation type. However, some significant correlations were found between the mutation type and specific congenital anomalies. Patients with deletions were shorter than patients with nonsense mutations (P=0.018). Patients with splice site mutations had significantly more CNS anomalies and developmental delay, compared with the other patients (P=0.03 and P=0.038, respectively). Patients with missense mutations had significantly less congenital heart disease (P=0.022).
Discussion
We hereby present a large cohort of 111 patients with FA in Israel. In a previous report of Israeli patients with BMF syndromes, 66 of these patients were included.15 Our cohort is unique in a few aspects. First, the vast majority of the patients included in this cohort are genetically diag- nosed. Second, the ethnic diversity in this population is distinct with a larger representation of patients from Arab descent compared to those of Jewish descent; this is in contrast to the general population of Israel comprised of 74% Jews and 21% Arabs. In addition, the patient popu- lation exhibited a high degree of consanguinity, especially in the Arab population, most likely the cause of their skewed representation in this cohort.
The large majority of our patients (90%) had at least one congenital malformation. In an Italian registry, including 97 patients, only 76% had at least one somatic malforma- tion, although abnormal facial features were not includ- ed.16 We calculated a CAB score for all the patients in our cohort as described in a previous publication.10 In the German cohort, including 181 patients, this score predict- ed BMF.12 In agreement, in our cohort, all patients with higher CAB scores (CABS 3-5) developed BMF. In addi- tion, the two patients in our cohort with the highest CAB scores (CABS 4-5) did not develop cancer. This low num- ber of patients does not allow statistical analysis; however it is consistent with previous publications finding an inverse correlation between congenital anomalies and malignancy in patients with FA.10,12
Of the patients in this FA cohort, 82% developed BMF. This is similar to the 80% described by the International Fanconi Anemia Registry.17 In contrast, in the German cohort, only 36% developed BMF.12 Neither of the patients with FANCD1 mutations in our cohort devel- oped BMF, in agreement with previous publications.7 However, it should be noted that one of the patients with a FANCD1 mutation was transplanted at a very young age for the treatment of leukemia, essentially eliminating the risk of BMF development.
Nearly one third of this cohort of patients with FA in Israel developed MDS, leukemia and/or solid tumors. Twelve of the 111 patients had more than one cancer event. The median age at initial diagnosis of cancer was 16 years in our cohort. Hematological malignancies appeared at a significantly earlier age relative to solid tumors. Of note, one patient with a FANCD1 mutation developed medulloblastoma at the age of 3 years. Patients with FANCD1 mutations have been previously described as uniquely developing solid tumors early in life,18 requiring screening for childhood cancer from a very young age. Excluding this particular patient with FANCD1 mutation, initial diagnosis of solid tumors in this cohort ranged from 21-32 years of age. These data support the need to start early cancer surveillance for patients with FA.
Approximately half of the patients in this cohort underwent HSCT, similar to the Italian FA registry report.19 There was no difference in survival between patients who did or did not undergo a HSCT. In the International Fanconi Anemia Registry, HSCT was found to be a predictor of poor prognosis.17 The patients from our cohort were transplanted over a three-decade time frame. Therefore, differences in donor selection and con- ditioning treatment plus patient selection bias may explain the discrepancy. The indication for HSCT had a large impact on survival in our cohort, with patients transplanted due to BMF having a much better survival relative to those transplanted due to MDS/leukemia. These results, if confirmed in future studies, may influ- ence the decision on choosing the right timing for HSCT.
In this cohort, HSCT did not appear to hasten the onset of solid tumors. Similar findings were reported in the International Fanconi Anemia Registry as well as in the Italian Fanconi Anemia Registry, including 754 and 180 patients, respectively.17,19 In contrast, the German registry reported a hazard ratio of 3.8 for developing solid tumors in patients with FA post-transplant, compared to those not transplanted.12 The National Cancer Institute also detected an increased incidence of cancer in FA patients and a younger age at cancer detection post-transplant in their cohorts of patients with FA.20,21 Indeed, reconciling this dis- crepancy holds paramount importance in clinical decision- making regarding optimal timing for initiation of cancer surveillance. More up-to-date studies will be needed to identify if any association exists.
We aimed to perform a genetic diagnosis for all Israeli patients with FA for whom DNA was available. By con- ventional Sanger sequencing and MLPA, we arrived at a genetic diagnosis in almost 95% of those tested. Of the six patients for whom genetic diagnosis was not achieved, only a partial work-up was performed due to the lack of remaining DNA samples. Two of these were found to be heterozygous for a FANCC mutation. In our cohort, 34 different mutations were found, with 20 of
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haematologica | 2020; 105(7)