Page 435 - Hematology_ Basic Principles and Practice ( PDFDrive )

356 Part IV Disorders of Hematopoietic Cell Development

a result of a genetic correction in a stem cell, resulting in one normal population-based study of patients up to the age of 18 years, the IFAR
allele. The mechanisms for this phenomenon include gene conversion prospective registry of 754 patients, a retrospective North American
events, back mutations, or compensatory deletions or insertions. The cohort survey of 145 cases, and a literature review of more than 2000
end result is mixed populations of somatic cells, some with two published cases. The median patient age for the development of all
abnormal alleles and some with one. If FA is strongly suspected, a cancers in the literature review was 16 years of age, which is strikingly
skin biopsy is performed to assess chromosomal breakage in cultured different from the median age of 68 years for the same types of cancer
fibroblasts with DEB or MMC rather than in lymphocyte cultures. in the general population. It was apparent from the above reports that
the crude risk of cancer in patients with FA is extraordinarily high:
Immunoblotting for FANCD2. Immunoblotting of the FANCD2 5% to 10% for leukemia, about 5% for MDS, and 5% to 10% for
protein have been proposed as a diagnostic test for most cases of FA solid tumors. The IFAR data indicate that by the age of 40 years, the
or as a tool to direct specific gene testing. In this assay, primary cumulative incidence of leukemia and nonhematologic cancers is
lymphocytes or fibroblasts are assayed for FANCD2 after exposure 33% and 28%, respectively. In a recently published study of the
to MMC or radiation by immunoblotting, which distinguishes the Canadian cohort, the cumulative risk of clonal and malignant
unubiquitinated and monoubiquitinated forms. The testing is useful myeloid transformation (clones, MDS and AML) by the age of 18
in three situations for screening FA mutations: (1) in patients with years was 75%.
FA with diagnostic MMC-induced chromosomal breakage assays, Previous observations by the IFAR showed that the risk of
FANCD2 null mutations are presumed if no full-length FANCD2 developing MDS and AML was higher for patients in whom a prior
is detected by immunoblotting; (2) if FANCD2 is detected but is not clonal BM cytogenetic abnormality had been detected. Monosomy
monoubiquitinated, mutations of one of the upstream core complex 7, rearrangement or partial loss of 7q, rearrangements of 1p36 and
genes are predicted; and (3) if FANCD2 is detected and is monou- 1q24-34, and rearrangements of 11q22-25 are frequent recurring
biquitinated, a mutation of FANCD1/BRCA2, FANCJ/BACH1/ cytogenetic clonal changes. Additional data indicate a strong cor-
BRIP1, FANCN/PALB2, FANCO/Rad51C, or FANCP/SLX4 is relation in FA BM cells of chromosome 3q26q29 partial trisomies
expected because all five localize downstream of FANCD2. Monou- and tetrasomies and rapid progression to MDS or AML. When
biquitination of FANCD2 is normal in other BM failure syndromes interpreting the significance of clonal cytogenetic abnormalities in
and chromosomal breakage disorders. Nevertheless, with the develop- patients with FA, note that clonal variation is frequent, including
ment of relatively rapid and affordable molecular diagnostic tests such appearances of new clones, inability to detect established clones on
as next generation sequencing, this test is rarely required. repeat examination, and clonal evolution. In a study from France
the investigators used SNP arrays to analyze whole marrow cells of
Other Findings. FA cells exposed to alkylating agents arrest in the patients with FA with MDS/leukemia. They identified a relatively
G 2 /M phase of the cell cycle. The transfected wild-type FA gene that high frequency of somatic RUNX1 gene disruption compared with
reduces G 2 /M arrested cells as determined by cell cycle kinetics using what is typically seen in patients with de novo MDS/leukemia.
flow cytometry pinpoints the mutant gene. Similar to the literature review, the IFAR verified that the risk for
Apparently, the majority of patients with FA have stable, elevated developing hematologic and nonhematologic cancer in FA increased
levels of serum α-fetoprotein expressed constitutively that are inde- with advancing age, but the IFAR did not show an age-related
pendent of liver complications and of androgen therapy. Levels are plateau for the risks for MDS and AML, possibly because both
also unchanged after HSCT. The clinical utility of these findings is diagnoses were analyzed together.
limited. The literature review also identified 320 patients with other forms
Ultrasonographic examination of the abdomen may reveal con- of cancer, 25 of whom had up to three separate types of solid tumors,
genital anomalies of the kidneys and urogenital system. Echocardiog- and 14 additional cases of solid tumors who also had leukemia. None
raphy may reveal cardiac anomalies. Radiography and computed of these patients had received a bone marrow transplant (BMT)
tomography (CT) can be informative in revealing bone, intestinal, or before developing cancer. The most frequent solid tumor reported
other anomalies; however, imaging using radiation should be mini- was squamous cell carcinoma involving head and neck and upper and
mized as much as possible because of the carcinogenic risk. lower esophagus followed by the vulva or anus, cervix, and skin.
There were additional cases of tongue and oral squamous cell carci-
noma that occurred after HSCT. Liver tumors, benign and malignant,
Predisposition to Malignancy were second most frequent. Most of these hepatoma and adenoma
patients had received prior androgen therapy for aplastic anemia.
A major feature of the FA phenotype is the propensity to develop Androgen administration has therefore been implicated in liver
cancer. The chromosome fragility, the defects in DNA repair, the tumor pathogenesis. In descending order of frequency, cancers were
genomic instability, and the cellular damage that occur in patients also reported in brain, kidney, breast, and adrenal gland. The IFAR
with FA translate into a significant predisposition to develop a 20-year prospective observational study and the North American
malignancy. Because there are at least 17 genes that are associated cohort survey corroborated the literature review in terms of type of
with FA and because alterations in the FA pathway are relevant to cancer, site, and risk.
the pathogenesis of common types of cancers, the disorder is a critical
human model of the genetic determinants of hematologic cancers and
solid tumors. Heterozygote Phenotype
FA is a member of two families of cancer predisposition syn-
dromes. The first is composed of genetic disorders of DNA repair Heterozygote carriers of FANC gene mutations do not develop
that include ataxia telangiectasia, xeroderma pigmentosum, and peripheral blood cytopenias or aplastic anemia, and cell lines from
Bloom syndrome. The close relationship between FA and these heterozygote carriers do not show excessive chromosome fragility in
syndromes is underscored by data showing convergence of signaling culture when exposed to DEB or MMC. The mean chromosomal
pathways in these conditions and the identification of ERCC4 muta- breakage level of lymphocytes from FA carriers tested in cultures with
tions in patients who manifest a complex phenotype of both xero- a clastogenic agent may be higher than controls, but individual carrier
derma pigmentosum and FA. The second family of predisposition testing may show overlap with normal values and severely limits its
syndromes consists of other inherited BM failure disorders described diagnostic utility. Literature from the early 1980s describes congenital
herein, including Shwachman-Diamond syndrome (SDS) and DC, anomalies of the hand and the genitourinary system in relatives of
that show a propensity for malignant myeloid transformation or solid patients with FA, and parents of children with FA may have short
tumors. stature. FA carriers may have increased levels of HbF, decreased
The magnitude of the risk of developing malignancy in FA natural killer (NK) cell counts, and diminished reactivity to mitogen
has been defined in several comprehensive reports: a Canadian stimulation.