Shwachman-Diamond syndrome with clonal interstitial deletion of the long arm of chromosome 20 in bone marrow: haematological features, prognosis and genomic instability.

In Shwachman-Diamond syndrome (SDS), deletion of the long arm of chromosome 20, del(20)(q), often acquired in bone marrow (BM), may imply a lower risk of developing myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), due to the loss of the EIF6 gene. The genes L3MBTL1 and SGK2, also on chromosome 20, are in a cluster of imprinted genes, and their loss implies dysregulation of BM function. We report here the results of array comparative genomic hybridization (a-CGH) performed on BM DNA of six patients which confirmed the consistent loss of EIF6 gene. Interestingly, array single nucleotide polymorphisms (SNPs) showed copy neutral loss of heterozygosity for EIF6 region in cases without del(20)(q). No preferential parental origin of the deleted chromosome 20 was detected by microsatellite analysis in six SDS patients. Our patients showed a very mild haematological condition, and none evolved into BM aplasia or MDS/AML. We extend the benign prognostic significance of del(20)(q) and loss of EIF6 to the haematological features of these patients, consistently characterized by mild hypoplastic BM, no or mild neutropenia, anaemia and thrombocytopenia. Some odd results obtained in microsatellite and SNP-array analysis demonstrate a peculiar genomic instability, in an attempt to improve BM function through the acquisition of the del(20)(q).

Case Report: Refractory Cytopenia With a Switch From a Transient Monosomy 7 to a Disease-Ameliorating del(20q) in a NHEJ1-Deficient Long-term Survivor.

We report the case of a male Pakistani patient with a pathogenic homozygous loss of function variant in the non-homologous end-joining factor 1 (NHEJ1) gene. The growth retarded and microcephalic boy with clinodactyly of both hands and hyperpigmentation of the skin suffered from recurrent respiratory infections. He was five and a half years old when he came to our attention with refractory cytopenia and monosomy 7. Hematopoietic stem cell transplantation was considered but not feasible because there was no suitable donor available. Monosomy 7 was not detected anymore in subsequent bone marrow biopsies that were repeated in yearly intervals. Instead, seven and a half years later, a novel clone with a del(20q) appeared and steadily increased thereafter. In parallel, the patient's blood count, which had remained stable for over 20 years without necessitating any specific therapeutic interventions, improved gradually and the erythropoiesis-associated dysplasia resolved.

Asian Population Is More Prone to Develop High-Risk Myelodysplastic Syndrome, Concordantly with Their Propensity to Exhibit High-Risk Cytogenetic Aberrations.

This study explores the hypothesis that genetic differences related to an ethnic factor may underlie differences in phenotypic expression of myelodysplastic syndrome (MDS). First, to identify clear ethnic differences, we systematically compared the epidemiology, and the clinical, biological and genetic characteristics of MDS between Asian and Western countries over the last 20 years. Asian MDS cases show a 2- to 4-fold lower incidence and a 10-year younger age of onset compared to the Western cases. A higher proportion of Western MDS patients fall into the very low- and low-risk categories while the intermediate, high and very high-risk groups are more represented in Asian MDS patients according to the Revised International Prognostic Scoring System. Next, we investigated whether differences in prognostic risk scores could find their origin in differential cytogenetic profiles. We found that 5q deletion (del(5q)) aberrations and mutations in TET2, SF3B1, SRSF2 and IDH1/2 are more frequently reported in Western MDS patients while trisomy 8, del(20q), U2AF1 and ETV6 mutations are more frequent in Asian MDS patients. Treatment approaches differ between Western and Asian countries owing to the above discrepancies, but the overall survival rate within each prognostic group is similar for Western and Asian MDS patients. Altogether, our study highlights greater risk MDS in Asians supported by their cytogenetic profile.

Reduced PLCG1 expression is associated with inferior survival for myelodysplastic syndromes.

The PLCG1 gene, which encodes the phospholipase C γ1 isoform, is located within the commonly deleted region of the long arm of chromosome 20 (del(20q)) observed in myelodysplastic syndromes (MDS). Phospholipase C is involved in diverse physiological and pathological cellular processes through inositide signaling. We hypothesized that reduced PLCG1 expression because of haploinsufficiency by del(20q) plays a role in the molecular pathogenesis of MDS. Therefore, we analyzed PLCG1 expression in bone marrow mononuclear cells at diagnosis in 116 MDS patients with or without del(20q) by quantitative RT-PCR to evaluate its clinical significance. The expression level of PLCG1 was significantly lower not only in MDS patients with del(20q) but also in those without del(20q) compared to that of the controls, which suggests that reduced PLCG1 expression is a common molecular event in MDS. Patients in the lowest quartile (Q4) group for PLCG1 expression had lower overall survival (OS) compared to that of other patients (Q1-Q3) (log-rank test, P = .0004) with estimated median OS times of 22 in the Q4 group and 106 months in the Q1-3 group. Univariate and multivariate analysis indicated reduced PLCG1 expression (Q4) was associated with lower OS (hazard ratio 2.58, 95% CI 1.35-4.84, P = .0049), which suggests that reduced PLCG1 expression is an independent prognostic factor for OS. In addition, patients were well-stratified for OS by combining PLCG1 expression level (Q4 vs Q1-3) and bone marrow blast percentage (5% or more vs less than 5%). Thus, the level of PLCG1 expression at time of diagnosis is a prognostic biomarker for MDS.

Persistent clonal cytogenetic abnormality with del(20q) from an initial diagnosis of acute promyelocytic leukemia.

A 68-year-old male was diagnosed with acute promyelocytic leukemia (APL). A G-banding chromosomal analysis revealed the co-existence of two clones: one with del(20q) and t(15;17)(q22;q12) and another with del(20q) alone. During the remission of APL following treatment with all-trans-retinoic acid, del(20q) was persistently identified, indicating a diagnosis of cytogenetic abnormalities of undetermined significance (CCAUS) with isolated del(20q). Bicytopenia developed 48 months after the remission of APL. The presence of isolated del(20q) was detected in the G-banding analysis, whereas morphological dysplasia of hematopoietic cells was not confirmed. This case showed indolent progression from CCAUS after the remission of APL to clonal cytopenia of undetermined significance (CCUS). CCUS with isolated del(20q) persisted for 24 months without any finding of hematological malignancies. At the most recent follow-up, targeted capture sequencing showed the U2AF1 S34F mutation. Considerable attention needs to be paid in follow-ups for CCAUS with del(20q) after the treatment of leukemia.

Patients With a History of Chemotherapy and Isolated del(20q) With Minimal Myelodysplasia Have an Indolent Course.

OBJECTIVES: Isolated deletion (20q) is relatively common in myeloid neoplasms and has been rarely reported in cases of therapy-related myelodysplastic syndrome (MDS). Our aim was to characterize cases of isolated del(20q) in bone marrow biopsy specimens from patients with a history of chemotherapy with morphologic findings insufficient for a diagnosis of MDS. METHODS: In this retrospective study from one institution, we identified 22 patients with isolated del(20q) and no or minimal dysplasia and evaluated clinical and pathologic characteristics. RESULTS: Eleven of the patients had a history of chemotherapy for mostly lymphoproliferative disorders. There were no statistically significant differences in peripheral blood or bone marrow features between patients with a history of chemotherapy and those without. Three patients with a history of chemotherapy had died at last follow-up; cause of death was recurrent nonmyeloid neoplasm. None of the patients with a history of chemotherapy subsequently developed a high-grade myeloid neoplasm, whereas one of the patients who had not received prior chemotherapy developed refractory anemia with excess blasts 2. CONCLUSIONS: The presence of del(20q) as an isolated bone marrow cytogenetic abnormality in the absence of morphologic findings sufficient for a diagnosis of acute myeloid leukemia, myeloproliferative neoplasm, or MDS portends an indolent clinical course, regardless of previous exposure to chemotherapy.

Clinical and molecular cytogenetic studies in ten patients with hematological malignancies characterized by t(20;21)(q11;q11) resulted from del(20q).

This study reports 10 patients with hematological malignances with t(20;21)(q11;q11) resulting from del(20q) (for example, der(20)del(20)(q11q13)t(20;21)(q11;q11) and der(21)t(20;21)(q11;q11)) and described their clinical features and the possible prognostic significance of this abnormality. The t(20;21)(q11;q11) was a rare but recurrent abnormality secondary to del(20q) besides i(20q-). The frequency of der(20)del(20)(q11q13)t(20;21)(q11;q11) among our patients with del(20q) was 2.4%. It was considered that the 20q deletion preceded translocation with chromosome 21. This abnormality is often cryptic, occurs predominantly in older men and is observed most often in myelodysplastic syndromes. Patients with this abnormality have an unfavorable prognosis, similar to patients with i(20q-). The molecular consequences of der(20)del(20)(q11q13)t(20;21)(q11;q11) may be different from patients with i(20q-). To the best of our knowledge this is the largest dataset published to date.

Marginal zone lymphoma-derived interfollicular diffuse large B-cell lymphoma harboring 20q12 chromosomal deletion and missense mutation of BIRC3 gene: a case report.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) typically leads to effacement of the nodal architecture by an infiltrate of malignant cells. Rarely (<1%), DLBCL can present with an interfollicular pattern (DLBCL-IF) preserving the lymphoid follicles. It has been postulated that DLBCL-IF is derived from marginal zone B cells and may represent a large-cell transformation of marginal zone lymphoma (MZL), however no direct evidence has been provided to date. Here we describe a rare case of a diagnostically challenging DLBCL-IF involving a lymph node in a patient with a prior history of lymphadenopathy for several years and MZL involving skin. CASE PRESENTATION: A 53-year old man presented to our Dermatology Clinic due to a 1-year history of generalized itching, fatigue of 2-3 month's duration, nausea and mid back rash that was biopsied. PET (positron emission tomography)/CT (computed tomography) was performed and revealed inguinal, pelvic, retroperitoneal, axillary, and cervical lymphadenopathy. The patient was referred to surgery for excisional biopsy of a right inguinal lymph node. Diagnostic H&E stained slides and ancillary studies were reviewed for the lymph node and skin specimens. B-cell clonality by PCR and sequencing studies were performed on both specimens. We demonstrate that this patient's MZL and DLBCL-IF are clonally related, strongly suggesting that transformation of MZL to DLBCL had occurred. Furthermore, we identified a novel deletion of the long arm of chromosome 20 (del(20q12)) and a missense mutation in BIRC3 (Baculoviral IAP repeat-containing protein 3) in this patient's DLBCL that are absent from his MZL, suggesting that these genetic alterations contributed to the large cell transformation. CONCLUSIONS: To our knowledge, this is the first report providing molecular evidence for a previously suspected link between MZL and DLBCL-IF. In addition, we describe for the first time del(20q12) and a missense mutation in BIRC3 in DLBCL. Our findings also raise awareness of DLBCL-IF and discuss the diagnostic pitfalls of this rare entity.

Microarray CGH analysis of hematological patients with del(20q).

Deletion of the long arm of chromosome 20 is a common abnormality underlying hematological malignancy. We analyzed 21 patients with hematologic diseases confirmed to carry the del(20q) by conventional cytogenetics and fluorescence in situ hybridization using microarray comparative genomic hybridization (aCGH). Seventeen patients were positive for del(20q), but this deletion was not detected in four patients. All deletions detected were interstitial of which continuous deletions were seen in 12 patients and discrete deletions in five. Three commonly deleted regions (CDRs) and two commonly retained regions (CRRs) were defined: CDR1 spanning 3.05Mb (34560497-37608229) within 20q11.23, CDR2 spanning 1.76Mb (37851501-39615698) within 20q12, CDR3 spanning 116Kb (48120412-48236791) within 20q13.13, CRR1 spanning 1.1Mb (29374726-30428250) within 20q11.21, and CRR2 spanning 2.5Mb (60484668-62963548) within 20q13.33. Duplications of retained regions (20q11.21) were found in five cases with similar erythroid hyperplasia (2 M6, 3 MDS). Moreover, duplication of 20p13-p11.21 was also found in two cases with M6. Using the CDRs and CRRs, we identified the candidate genes we searched for using the UCSC Genome Browser. Our data suggest that aCGH analysis is useful for more precisely defining breakpoints on 20q. Further work is required to identify candidate pathogenic genes within these CDRs and CRRs.

The characteristics and prognostic analysis in 213 myeloid malignancy patients with del(20q): a report of a single-center case series.

The clinical and hematological characteristics and the prognostic significance of del(20q) were investigated in a consecutive series of 213 myeloid malignancies. In the analyses, the cases were divided into three subgroups according to diagnosis or four subgroups according to cytogenetic data. Patients in the myeloproliferative neoplasms subgroup had high WBCs and platelet counts at initial diagnosis. The del(20q) occurred predominantly in older men. Sole del(20q) was observed most often in myelodysplastic syndromes, while del(20q) as a part of complex karyotypes was observed predominantly in acute myeloid leukemia. The most frequent additional abnormalities accompanying del(20q) were -5/del(5q), -7/del(7q) and +8; t(20;21)(q11;q11) and double del(20q) were two rare but recurrent abnormalities secondary to del(20q). In all types of diseases, patients with a sole del(20q) had a favorable prognosis. The presence of any additional abnormality with del(20q) had an unfavorable outcome. Patients with i(20q) had an unfavorable prognosis. Patients with the minor del(20q) clone had a better median survival than those with the major del(20q) clone.

The GNAS1 gene in myelodysplastic syndromes (MDS).

GNAS1 gene is located at the long arm of chromosome 20 (q13.32). GNAS1 gene deletion has never been investigated in MDS. A GNAS1 activating mutation (R201) was recently found in MDS. We applied FISH and DHPLC plus sequencing to investigate GNAS1 gene in MDS cases with and without del(20q) at karyotype.