Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis

Jerez, Andrés; Sugimoto, Yuka; Makishima, Hideki; Verma, Amit; Jankowska, Anna; Przychodzen, Bartlomiej; Visconte, Valeria; Tiu, Ramon V.; O’Keefe, Christine L.; Mohamedali, Azim; Kulasekararaj, Austin; Pellagatti, Andrea; McGraw, Kathy L.; Muramatsu, Hideki; Moliterno, Alison R.; Sekeres, Mikkael A.; McDevitt, Michael A.; Kojima, Seiji; List, Alan F.; Boultwood, Jacqueline; Mufti, Ghulam J.; Maciejewski, Jaroslaw P.

doi:10.1182/blood-2011-12-397620

Cited by 107 publications

(117 citation statements)

References 32 publications

Supporting

Mentioning

109

Contrasting

Unclassified

Order By: Relevance

“…A fundamental contribution to resolve this issue will surely be provided by new molecular technologies, for example, a SNP array study recently demonstrated that haploinsufficiency of defined 7q regions may translate to different clinical outcomes for MDS and AML patients carrying a 7q deletion and dysplastic features [36]. The IPSS [8], the Spanish MDS Cytogenetic Working Group [10] and another study [16] have reported that del(7q) and 27 present a similar poor OS and a similar high risk of MDS/AML evolution.…”

Section: Discussionmentioning

confidence: 99%

Validation of the new comprehensive cytogenetic scoring system (NCCSS) on 630 consecutive de novo MDS patients from a single institution

et al. 2013

View full text Add to dashboard Cite

This study evaluated whether the NCCSS truly improves the prognostic stratification of 630 consecutive de novo MDS patients and established which cytogenetic grouping [NCCSS or International Prognostic Scoring System (IPSS)], when combined with the WHO classification, best predicted the clinical outcome of myelodysplastic syndromes (MDS). The frequency of chromosomal defects was 53.8%. Clinical parameters, including number of cytopenias, WHO classification, IPSS cytogenetic categories and scores, NCCSS were all relevant for overall survival (OS) and leukemia-free survival (LFS) and were included in six distinct multivariate models compared by the Akaike Information Criterion (AIC). The most effective model to predict OS included the number of cytopenias, the WHO classification and the NCCSS, whereas the model including the number of cytopenias, blast cell percentage and the NCCSS and the model including the number of cytopenias the WHO classification and the NCCSS were almost equally effective to predict LFS. In conclusion, the NCCS (i) improves the prognostic stratification of the good and poor IPSS cytogenetic categories by introducing the very good and the very poor categories; (ii) is still incomplete in establishing the prognostic relevance of rare/double defects, (ii) applied to patients who receive supportive treatment only identifies five different prognostic subgroups, but applied to patients treated with specific therapies reveals only a trend toward a significantly different OS and LFS when patients of the poor and intermediate cytogenetic categories are compared, (iii) combined with the WHO classification is much more effective than the IPSS in predicting MDS clinical outcome. Am. J. Hematol. 88:120-129,

show abstract

Section: Discussionmentioning

confidence: 99%

Validation of the new comprehensive cytogenetic scoring system (NCCSS) on 630 consecutive de novo MDS patients from a single institution

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Of the remaining 27 patients, blasts were not increased and criteria for therapy-related myeloid neoplasms were not met in the diagnostic bone marrow sample at the time of del(7q) identification. This group included 10 patients (cases [13][14][15][19][20][21][22][23][24][25] with mild dysplasia, 16 patients (cases 16-18, 26-38) who did not have dysplasia and 1 patient in whom morphological assessment was difficult due to significant involvement by lymphoma (case 39) (Figure 1).…”

Section: Bone Marrow and Peripheral Blood Findingsmentioning

confidence: 99%

Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

et al. 2016

View full text Add to dashboard Cite

Deletion 7q is a common chromosomal abnormality in myeloid neoplasms. Detection of del(7q) in patients following cytotoxic therapies is highly suggestive of an emerging therapy-related myeloid neoplasm. In this study, we describe 39 patients who acquired del(7q) as a sole abnormality in their bone marrow following cytotoxic therapies for malignant neoplasms. The median interval from cytotoxic therapies to detection of del(7q) was 40 months (range, 4-190 months). Twenty-eight patients showed an interstitial and 11 showed a terminal 7q deletion. Fifteen patients (38%) had del(7q) as a large clone and 24 (62%) as a small clone. With a median followup of 21 months (range, 1-135 months), 18 (46%) patients developed therapy-related myeloid neoplasms, including all 15 patients with a large del(7q) clone and 3/24 (12.5%) with a small clone. Of the remaining 21 patients with a small del(7q) clone, 16 showed no evidence of therapy-related myeloid neoplasms and 5 had an inconclusive pathological diagnosis. We conclude that isolated del(7q) emerging in patients after cytotoxic therapy may not always be associated with therapy-related myeloid neoplasms in about half of patients. The clone size of del(7q) is critical; a large clone is almost always associated with therapy-related myeloid neoplasms, whereas a small clone can be a clinically indolent or transient finding. Abnormalities of chromosome 7, either monosomy (−7) or deletion of the long arm (del(7q)), are the most common cytogenetic abnormalities detected in acute myeloid leukemia and myelodysplastic syndromes. 1-3 Del(7q)/ − 7 occurs in~8% of de novo acute myeloid leukemia and~10% of de novo myelodysplastic syndromes. 1,4 Del(7q) has been classified as the intermediate-II risk group in de novo acute myeloid leukemia 5 and the intermediate risk group in de novo myelodysplastic syndromes, respectively. 6 Therapy-related myeloid neoplasm is a late complication of cytotoxic therapies for primary malignant and non-malignant diseases. Cytogenetic abnormalities can be detected in more than 90% of patients with therapy-related myeloid neoplasms, and more than half of these patients have a complex karyotype. 7 Del(7q)/ − 7 presents in~50% of patients with therapy-related myeloid neoplasms and are often associated with prior exposure to alkylating agents or ionizing radiation. 1,[8][9][10][11][12][13] Any newly emerged cytogenetic abnormalities in patients with a prior history of cytotoxic therapies often raises the concern of development of therapy-related myeloid neoplasms, especially when the abnormalities include del(7q)/ − 7.In our practice, we have observed that some patients develop isolated del(7q) in their bone marrow following cytotoxic therapies, yet never develop therapy-related myeloid neoplasms with close follow-up. In order to better understand the

show abstract

“…Two additional studies, using SNP array analysis on de novo and therapy-related myeloid neoplasms, identified CUX1 in the commonly deleted region of 7q22.1 (REFS 4,5). RNA sequencing and reverse transcription PCR analysis showed that CUX1 mRNA expression was reduced approximately twofold in leukaemic cells of affected patients 4,5 , and immunoblotting using a carboxy-terminal antibody showed that the fulllength CUX1 protein was reduced in AML cell lines with chromosome 7 and chromosome 7q loss karyotypes 5 . Reduced CUX1 mRNA expression was also documented in an AML sample that had a chimeric transcript containing CUX1 exon 1 upstream of claudin 7 (CLDN7) exons 2-4, probably resulting from a chromosomal translocation 5 .…”

Section: The Knudson Two-hit Modelmentioning

confidence: 99%

“…4). The complexity of 7q rearrangements suggests that multiple genetic factors, rather than a single tumour suppressor gene, contribute to the pathogenesis of myeloid disorders.…”

Section: The Knudson Two-hit Modelmentioning

confidence: 99%

“…Recent genetic mapping and expression analyses pointed to CUX1 as the tumour suppressor that is the target of loss-of-heterozygosity (LOH) on chromosome 7q22.1 . In cancers with CUX1 LOH, no mutations have been found in the remaining allele [7][8][9][10] and, in tested cases, CUX1 was expressed, albeit at a reduced level 4,5,11 . However, inactivating point mutations were shown in 1-5% of cancers in which the two CUX1 alleles are present 11 (FIG.…”

mentioning

confidence: 90%

See 1 more Smart Citation

CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

2014

View full text Add to dashboard Cite

Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis

Cited by 107 publications

References 32 publications

Validation of the new comprehensive cytogenetic scoring system (NCCSS) on 630 consecutive de novo MDS patients from a single institution

Validation of the new comprehensive cytogenetic scoring system (NCCSS) on 630 consecutive de novo MDS patients from a single institution

Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

Contact Info

Product

Resources

About