A predictive risk-scoring model for survival prognosis of multiple myeloma based on gain/amplification of 1q21: Experience in a tertiary hospital in South-Western China.

BACKGROUND: Chromosomal 1q gains and amplifications (+1q21) are frequently observed in patients with newly diagnosed multiple myeloma (NDMM). However, the interpretation of the high-risk (HR) prognostic implications stemming from 1q21 abnormalities remain challenging to implement effectively. METHODS: In a comprehensive analysis of 367 consecutive patients with symptomatic MM, we assessed the prognostic significance of +1q21 using FISH with a threshold of 7.4%. The patient cohort was randomly divided into a training set (66.5%, n = 244) and a validation set (33.5%, n = 133). A multivariate Cox regression analysis was conducted to identify significant prognostic factors associated with PFS. Weight scores were assigned to each risk factor based on the ß-value of the corresponding regression coefficient. A predictive risk-scoring model involving +1q21 was then developed, utilizing the total score derived from these weight scores. The model's discriminative ability was evaluated using the AUC in both the training and validation sets. Finally, we compared the performance of the +1q21-involved risk with the established R-ISS and R2-ISS models. RESULTS: Upon initial diagnosis, 159 patients (43.32%) exhibited +1q21, with 94 (59.11%) having three copies, referred to as Gain(1q21), and 65 (40.89%) possessing four or more copies, referred to as Amp (1q21). Both were significantly linked to a reduced PFS in myeloma (p < 0.05), which could be effectively mitigated by ASCT. The +1q21-involved risk model, with an AUC of 0.697 in the training set and 0.725 in the validation set, was constructed including Gain(1q21), Amp(1q21), no-ASCT, and TP53 deletion. This model, termed the ultra-high-risk (UHR) model, demonstrated superior performance in predicting shorter PFS compared to the R-ISS stage 3 and R2-ISS stage 4. CONCLUSION: The UHR model, which integrates the presence of +1q21 with no-ASCT and TP53 deletion, is designed to identify the early relapse subgroup among patients with +1q21 in NDMM.

Chromosome 1q21 Aberrations Are Poor Prognostic Factors for Newly Diagnosed Multiple Myeloma Patients.

BACKGROUND: Chromosome 1q21 aberrations are one of the most common cytogenetic abnormalities in patients with multiple myeloma (MM). However, the prognostic value remains controversial. This study aimed to determine the prognostic value of numerical abnormalities of chromosome 1q21 for newly diagnosed patients with MM patients in Chinese population. METHODS: We retrospectively analyzed 629 patients with newly diagnosed MM who received the detection of chromosome 1q21 by fluorescence in situ hybridization in China. RESULTS: Among 629 patients, 309 (49.1%) had 1q21 abnormalities, of which 187 (29.7%) had three copies and 122 (19.4%) had four or more copies. Patients with two copies of 1q21 had a significantly longer median overall survival (OS) than those with three copies or ≥4 copies and also had longer progression-free survival (PFS). However, patients with three or ≥4 copies had similar OS and PFS. Univariate Cox proportional hazards regression analyses determined that 1q21 aberrations are associated with shorter OS and PFS. 1q21 aberrations are also independent poor prognostic factors for OS and PFS in multivariable analyses. Del(17p), t(4;14), and t(14;16) are common high-risk cytogenetic abnormalities (HRCAs) in patients with MM. Patients with 1q21+ alone or 1q21+ combined with HRCAs had shorter OS and PFS than patients without cytogenetic abnormalities. Patients with 1q21+ and t(11;14) also had shorter PFS but had similar OS than patients without cytogenetic abnormalities. CONCLUSION: Our study showed that chromosome 1q21 aberrations are poor prognostic factors for newly diagnosed patients with MM.

Prenatal diagnosis of the recurrent 1q21.1 microdeletions in fetuses with ultrasound anomalies and review of the literature.

Objective: The recurrent 1q21.1 microdeletion syndrome is an autosomal dominant disorder and is characterized by dysmorphic facial features, microcephaly, developmental delay, and congenital defects. However, most studies on the distal deletions in the 1q21.1 region were diagnosed postnatally. This study aimed to provide a better understanding of the ultrasound and molecular findings of fetuses with recurrent 1q21.1 microdeletions in prenatal diagnosis. Methods: In this retrospective study, we reported 21 cases with the recurrent 1q21.1 microdeletion syndrome diagnosed at our prenatal diagnostic center from January 2016 to January 2023. The clinical data were reviewed for these cases, including the maternal demographics, indications for invasive testing, ultrasound findings, CMA results, and pregnancy outcomes. Results: In the study, a total of 21 cases with recurrent 1q21.1 microdeletions were diagnosed prenatally by CMA. Fifteen cases were described with ultrasound indications, and the most common findings are as follows: increased nuchal translucency (NT) (26.7%), intrauterine growth retardation (IUGR) (26.7%), congenital heart defects (CHD) (20%), and congenital anomalies of the kidney and urinary tract (CAKUT) (13.3%). All the cases with the distal 1q21.1 deletions contain the common minimal region (located between BP3 and BP4) and eight OMIM genes. Parental studies to determine the inheritance of the deletion were performed for eight cases, and half of the cases were inherited from one of the parents. Pregnancy outcomes were available for nine cases; eight (88.9%) pregnancies were determined to be terminated and one (11.1%) was full-term delivery. Conclusion: To our knowledge, this is the largest study to find that fetuses with recurrent 1q21.1 microdeletions were closely associated with increased NT, CHD, IUGR, and CAKUT. In addition, ours is the first study to report that cerebral ventriculomegaly might be associated with recurrent 1q21.1 microdeletions. More comprehensive studies are needed for a better understanding of the prenatal phenotype-genotype relationship of the recurrent 1q21.1 microdeletion syndrome in future.

Anti-CD38 monoclonal antibodies in multiple myeloma with gain/amplification of chromosome arm 1q: a review of the literature.

INTRODUCTION: Gain/amplification of 1q (+1q) represents one of the most prevalent cytogenetic abnormalities (CAs) observed in multiple myeloma (MM). Historical studies predating the advent of anti-CD38 monoclonal antibodies (moAbs) implicated + 1q in poor prognoses, prompting its integration into novel staging systems. However, with the emergence of daratumumab and isatuximab, two pivotal anti-CD38 moAbs, the landscape of MM therapy has undergone a profound transformation. AREAS COVERED: This review encompasses a comprehensive analysis of diverse study methodologies, including observational investigations, clinical trials, meta-analyses, and real-world database analyses. By synthesizing these data sources, we aim to provide an overview of the current understanding of + 1q in the context of anti-CD38 moAbs therapies. EXPERT OPINION: Despite the paucity of available data, evidence suggests a potential mitigating effect of daratumumab on the adverse prognostic implications of + 1q. However, this benefit seems to diminish in patients harboring ≥ 4 copies or with concurrent high-risk CAs. On the other hand, isatuximab demonstrated promising outcomes in the relapsed-refractory setting for + 1q MM patients. Nevertheless, direct comparison between the two compounds is currently challenging. The current evidence firmly supports the integration of anti-CD38 moAb-based therapies as the standard of care for + 1q patients, pending further elucidation.

Efficacy Analysis of Bortezomib Combined with Lenalidomide in Newly Diagnosed Multiple Myeloma with 1q21 Gain/Amp.

OBJECTIVE: 1q21 gain/Amp is one of the most common cytogenetic abnormalities. There are controversies about its effects on prognosis and may be associated with inferior outcomes in patients with newly diagnosed multiple myeloma (NDMM). To explore the optimal induction treatment, we analyzed and compared the efficacy of combinations of bortezomib-lenalidomide-dexamethasone (VRD) and only bortezomib-based triplet regimens without lenalidomide (only bortezomib-based) as induction therapy in patients with NDMM with 1q21 gain/Amp. METHODS: Seventy-six NDMM patients with 1q21 gain/Amp who were admitted to our center from 2016 to 2022 were retrospectively analyzed in this study. The progression and efficacy of the patients were observed. RESULTS: Within our study group, the overall survival rate stood at 75.0%, and the progression-free survival (PFS) rate reached 40.8% in NDMM patients with 1q21 gain/Amp. The best outcome assessment was that 17.1% achieved complete response (CR) and 44.7% achieved very good partial response (VGPR). Patients in the VRD group had a deeper response (VGPR: 63.6% vs 37.0%, P = 0.034), lower disease progression rate (31.8% vs 70.3%, P = 0.002), longer sustained remission (median 49.7 months vs 18.3 months, P = 0.030), and longer PFS (median 61.9 months vs 22.9 months, P = 0.032) than those treated with only bortezomib-based induction therapy. No significant differences were found among patients with partial response or better (86.4% vs 77.8%, P = 0.532) or CR (27.3% vs 13.0%, P = 0.180). Multivariate analysis showed that only bortezomib-based induction therapy (P = 0.003, HR 0.246, 95% CI 0.097-0.620), International Staging System stage III (P = 0.003, HR 3.844, 95% CI 1.588-9.308) and LMR <3.6 (P = 0.032, HR 0.491, 95% CI 0.257-0.940) were significantly associated with adverse PFS. CONCLUSIONS: When compared with the sequential administration of bortezomib and lenalidomide or only bortezomib-based protocols, NDMM patients with 1q21 gain/Amp may benefit more from VRD as initial treatments.

The numerous facets of 1q21+ in multiple myeloma: Pathogenesis, clinicopathological features, prognosis and clinical progress (Review).

Multiple myeloma (MM) is a malignant neoplasm characterized by the clonal proliferation of abnormal plasma cells (PCs) in the bone marrow and recurrent cytogenetic abnormalities. The incidence of MM worldwide is on the rise. 1q21+ has been found in ~30-40% of newly diagnosed MM (NDMM) patients.1q21+ is associated with the pathophysiological mechanisms of disease progression and drug resistance in MM. In the present review, the pathogenesis and clinicopathological features of MM patients with 1q21+ were studied, the key data of 1q21+ on the prognosis of MM patients were summarized, and the clinical treatment significance of MM patients with 1q21+ was clarified, in order to provide reference for clinicians to develop treatment strategies targeting 1q21+.

Do Alarmins Have a Role in Multiple Myeloma?

Objective: Calprotectin (CLP), S100A6, and high mobility group nucleosome-binding protein 1 (HMGN1), known as alarmins, are involved in the pathogenesis of many tumors. In this study, we aimed to investigate the relationships of serum CLP, S100A6, and HMGN1 levels with the clinical and laboratory findings of patients with multiple myeloma (MM) and their roles in the pathogenesis of MM. Materials and Methods: We measured the serum CLP, S100A6, and HMGN1 levels of 55 newly diagnosed patients and 32 healthy controls using the sandwich enzyme-linked immunosorbent assay method. The medical records of the patients were also reviewed. Results: Serum CLP, S100A6, and HMGN1 levels were significantly decreased in MM patients compared to the control group (p=0.012, p=0.001, and p=0.030, respectively). Receiver operating characteristic analysis was used to determine diagnostic cut-off values for serum CLP, S100A6, and HMGN1 of <98 ng/mL (area under the curve [AUC]: 0.663, 95% confidence interval [CI]: 0.554-0.761, p=0.009), <1174.5 pg/mL (AUC: 0.706, 95% CI: 0.598-0.799, p=0.001), and <440.18 pg/mL (AUC: 0.640, 95% CI: 0.530-0.740, p=0.03), respectively. CLP levels were found to be statistically significantly higher in patients with light chain MM (91.58±22.57 ng/mL) compared to heavy chain MM (79.42±15.83 ng/mL) (p=0.03). A negative correlation was observed between CLP and M protein, immunoglobulin G, globulin, and beta-2 microglobulin (correlation coefficients: -0.361, -0.370, -0.279, -0.300, respectively; p=0.024, p=0.06, p=0.04, p=0.0033). Conclusion: In this study, we found that serum CLP, S100A6, and HMGN1 levels were statistically lower in patients with newly diagnosed MM compared to the control group. These results suggest that CLP may bind to the paraprotein produced by heavy chain MM in the blood, causing its blood levels to be low. Additionally, low levels of HMGN1, which is involved in DNA repair, suggest that HMGN1 may contribute to the complex genetic abnormalities found in cases of MM.

Efficacy of daratumumab in newly diagnosed multiple myeloma patients with 1q21 gain.

BACKGROUND: Gain and amplification of 1q21 (1q21+) are adverse chromosomal aberrations of multiple myeloma (MM) that lead to refractoriness to a variety of therapies. While it is known that daratumumab, an anti-cancer monoclonal antibody, cannot overcome the disadvantage of 1q21+in relapsed/refractory MM patients, its benefit in newly diagnosed MM (NDMM) patients with 1q21+has not been clarified. PATIENTS: We retrospectively evaluated 11 (55%) 1q21+patients (3 copies: 6, > 4 copies: 5) among 20 NDMM patients (median age, 74 years) who received daratumumab-containing regimens at Shibukawa Medical Center from October 2019 to October 2022. RESULTS: The overall response rate was 82% for patients with 1q21+and 78% for patients without 1q21+. Median progression-free survival (PFS) and median overall survival (OS) were not reached in either group. Neither 1q21 copy number nor co-existence of other high-risk cytogenetic abnormalities significantly affected PFS or OS. CONCLUSION: Our preliminary data suggests that outcomes of daratumumab treatment in NDMM 1q21+patients might be non-inferior to those in non-1q21+patients.

Hub genes and associated drugs for multiple myeloma with 1q21+: identified by bioinformatic analysis.

While 1q21+ was common genetic alteration and found to have adverse effect on prognosis, the underlying genes remain unclear. Identification of related genes may provide additional help for rational intervention. The microarray dataset GSE2658 associated with MM was downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were obtained, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to annotate their functions. The hub genes were derived from the combined results of up-regulated DEGs and weighted gene coexpression network analysis (WGCNA). The receiver operating characteristic (ROC) curves of hub genes were plotted to evaluate correlation with 1q21+. Survival analysis and drug-gene interaction of hub genes were performed separately to find the prognostic value and potential targeted drugs. A total of 55 DEGs were identified. GO and KEGG pathway analyses suggested that the DEGs were related to several pathways of cell proliferation. NVL, IL6R, DUSP23 were proven to be highly correlated with 1q21+ and have adverse effects on prognosis. IL6R, DUSP23 were matched to known interaction-drug. This study revealed potential roles of hub genes in the pathogenesis and progression of MM with 1q21+, further investigations are needed to elucidate the mechanisms.

Isatuximab in combination with carfilzomib and dexamethasone in 1q21+ patients with relapsed/refractory multiple myeloma: Long-term outcomes in the Phase 3 IKEMA study.

Gain/amplification of 1q21 (≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma, can negatively affect prognosis, due to its involvement in resistance to anti-myeloma therapy and disease progression. In this updated subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285) in relapsed/refractory multiple myeloma (RRMM), we evaluated progression-free survival (PFS) and depth of response with the anti-CD38 antibody isatuximab plus carfilzomib-dexamethasone (Isa-Kd) versus Kd, in 1q21+ patients and related subgroups, at long-term follow-up (44.2 months). Our analysis included patients with 1q21+ (≥3 copies, with/without high-risk chromosomal abnormality [HRCA]), isolated 1q21+ (≥3 copies, without HRCA), gain(1q21) (3 copies, with/without HRCA), and amp(1q21) (≥4 copies, with/without HRCA). PFS benefit was achieved with Isa-Kd versus Kd in patients with 1q21+ (HR 0.58, 95% CI: 0.37-0.92), with isolated 1q21+ (HR 0.49, 95% CI: 0.27-0.92), with gain(1q21), or amp(1q21), consistent with the overall population and prior interim 1q21+ subgroup analyses. Median PFS with Isa-Kd versus Kd was 25.8 versus 16.2 months in 1q21+ patients and 38.2 versus 16.2 months in patients with isolated 1q21+. Clinically meaningful, higher rates of very good partial response or better, complete response or better (≥CR), minimal residual disease (MRD) negativity, and MRD negativity and ≥CR were reached with Isa-Kd versus Kd in patients with 1q21+, isolated 1q21+, gain(1q21), or amp(1q21). In Isa-Kd and Kd, the MRD negativity and ≥CR rate was 29.3% versus 15.4% in 1q21+ patients, 36.2% versus 12.9% in patients with isolated 1q21+, 27.9% versus 13.5% in patients with gain(1q21), and 31.3% versus 20.0% in patients with amp(1q21), respectively. In conclusion, addition of Isa to Kd in triplet combination therapy has shown PFS benefit and deeper responses, compared with Kd, in 1q21+ patients at higher risk of progression, including patients with isolated 1q21+, gain(1q21), and amp(1q21), thus supporting Isa-Kd an effective treatment option for patients with RRMM.

1q21+ is associated with poor prognosis in newly diagnosed multiple myeloma patients with extramedullary disease: a retrospective study.

1q21+ is a common cytogenetic abnormality in multiple myeloma (MM) and is considered an independent predictor of poor prognosis; however, its impact on extramedullary disease (EMD) remains unknown. Our study reviewed the clinical relevance and prognostic value of 1q21+ status in 92 patients with NDMM and EMD. 1q21+ was detected in 23.9% (22/92) of patients. Patients with 1q21+ presented with advanced International Staging System stages (P = 0.006), lower level of hemoglobin (P = 0.004), higher percentage of plasma cells in the bone marrow (P < 0.001), higher level of serum ß2-microglobulin (7.24 g/L vs. 3.85 g/L, P = 0.003), and higher levels of lactic dehydrogenase (LDH) (206.5 U/L vs. 177 U/L, P = 0.019). The prevalence of soft tissue-related EMD (EMD-S) (54.5% vs. 18.6%, P < 0.001), renal dysfunction (50.5% vs. 17.7%, P = 0.002), and hypercalcemia (27.3% vs. 7.1%, P = 0.011) was also higher. 1q21+ was strongly associated with other high-risk cytogenetic abnormalities, including IgH/FGFR3 (22.7% vs. 4.3%, P = 0.007) and IgH/MAF translocations (22.7% vs. 1.4%, P < 0.001). 1q21+ patients had significantly shorter overall survival (OS) and progression-free survival (PFS) (OS: 24 months vs. 47 months, P = 0.002; PFS: 14 months vs. 38 months, P < 0.001); the poor survival outcomes could not be reversed by autologous hematopoietic stem cell transplantation. Multivariate analysis suggested that 1q21+ , EMD-S, elevated lactate dehydrogenase (LDH) levels, and P53 deletion were independent risk factors for poor prognosis in patients with EMD. In patients with 1q21+ EMD, hypercalcemia, elevated LDH levels, and P53 deletion were independent adverse risk prognostic factors.

Phenotypic and genotypic characterization of 1q21.1 copy number variants: A report of 34 new individuals and literature review.

Recurrent 1q21.1 copy number variants (CNVs) have been associated with a wide spectrum of clinical features, ranging from normal phenotype to moderate intellectual disability, with congenital anomalies and dysmorphic features. They are often inherited from unaffected parents and the pathogenicity is difficult to assess. We describe the phenotypic and genotypic data for 34 probands carrying CNVs in the 1q21.1 chromosome region (24 duplications, 8 deletions and 2 triplications). We also reviewed 89 duplications, 114 deletions and 5 triplications described in the literature, at variable 1q21.1 locations. We aimed to identify the most highly associated clinical features to determine the phenotypic expression in affected individuals. Developmental delay or learning disabilities and neuropsychiatric disorders were common in patients with deletions, duplications and triplications of 1q21.1. Mild dysmorphic features common in these CNVs include a prominent forehead, widely spaced eyes and a broad nose. The CNVs were mostly inherited from apparently unaffected parents. Almost half of the CNVs were distal, overlapping with a common minimal region of 1.2 Mb. We delineated the clinical implications of 1q21.1 CNVs and confirmed that these CNVs are likely pathogenic, although subject to incomplete penetrance and variable expressivity. Long-term follow-up should be performed to each newly diagnosed case, and prenatal genetic counseling cautiously discussed, as it remains difficult to predict the phenotype in the event of an antenatal diagnosis.

Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers.

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

PRUNE1 (located on chromosome 1q21.3) promotes multiple myeloma with 1q21 Gain by enhancing the links between purine and mitochondrion.

Patients with multiple myeloma (MM) with chromosome 1q21 Gain (1q21+) are clinically and biologically heterogeneous. 1q21+ in the real world actually reflects the prognosis for gain/amplification of the CKS1B gene. In this study, we found that the copy number of prune exopolyphosphatase 1 (PRUNE1), located on chromosome 1q21.3, could further stratify the prognosis of MM patients with 1q21+. Using selected reaction monitoring/multiple reaction monitoring (SRM/MRM) analysis, liquid chromatography-tandem mass spectrometry (LC-MS/MS), transmission electron microscopy (TEM), confocal fluorescence microscopy, calculation of adenosine triphosphate (ATP), intracellular reactive oxygen species (ROS) and mitochondrial oxygen consumption rates (OCRs), we demonstrated for the first time that PRUNE1 promotes the proliferation and invasion of MM cells by stimulating purine metabolism, purine synthesis enzymes and mitochondrial functions, enhancing links between purinosomes and mitochondria. SOX11 was identified as a transcription factor for PRUNE1. Through integrated analysis of the transcriptome and proteome, CD73 was determined to be the downstream target of PRUNE1. Furthermore, it has been determined that dipyridamole can effectively suppress the proliferation of MM cells with high-expression levels of PRUNE1 in vitro and in vivo. These findings provide insights into disease-causing mechanisms and new therapeutic targets for MM patients with 1q21+.

Prenatal phenotypes and pregnancy outcomes of fetuses with recurrent 1q21.1 microdeletions and microduplications.

Objective: Chromosomal 1q21.1 deletions and duplications are genomic disorders that are usually diagnosed postnatally. However, the genotype-phenotype correlations of 1q21.1 copy number variants (CNVs) during the prenatal period are still not clear. This study aimed to provide a systematic summary of prenatal phenotypes for such genomic disorders. Methods: In total, 26 prenatal amniotic fluid samples diagnosed with 1q21.1 microdeletions/microduplications were obtained from pregnant women who opted for invasive prenatal testing. Karyotypic analysis and chromosomal microarray analysis (CMA) were performed for all cases simultaneously. The pregnancy outcomes and health conditions after birth in all cases were followed up. Meanwhile, prenatal cases with 1q21.1 microdeletions or microduplications in the literature were retrospectively collected. Results: In total, 11 pregnancies (11/8,252, 0.13%) with 1q21.1 microdeletions and 15 (15/8,252, 0.18%) with 1q21.1 microduplications were identified. Among these 1q21.1 CNVs, 4 cases covered the thrombocytopenia-absent radius (TAR) region, 16 cases covered the 1q21.1 recurrent microdeletion/microduplication region, and 6 cases covered all regions mentioned above. The prenatal abnormal ultrasound findings were recorded in four participants with 1q21.1 deletions and seven participants with 1q21.1 duplications. Finally, three cases with 1q21.1 deletions and five with 1q21.1 duplications terminated their pregnancies. Conclusion: In the prenatal setting, 1q21.1 microdeletions were associated with increased nuchal translucency (NT), anomalies of the urinary system, and cardiovascular abnormalities, while 1q21.1 microduplications were correlated with cardiovascular malformations, nasal bone dysplasia, and increased NT. In addition, cerebral ventriculomegaly might be correlated with 1q21.1 microduplications. Considering the variable expressivity and incomplete penetrance of 1q21.1 CNVs, long-term follow-up after birth should be carried out in these cases.

Systematic characterization of therapeutic vulnerabilities in Multiple Myeloma with Amp1q reveals increased sensitivity to the combination of MCL1 and PI3K inhibitors.

The development of targeted therapy for patients with Multiple Myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chr1q (Amp1q) is the most frequent arm-level copy number gain in patients with MM, and it is associated with higher risk of progression and death despite recent advances in therapeutics. Thus, developing targeted therapy for patients with MM and Amp1q stands to benefit a large portion of patients in need of more effective management. Here, we employed large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with Amp1q and showed increased sensitivity to the combination of MCL1 and PI3K inhibitors. Using single-cell RNA sequencing, we compared subclones with and without Amp1q within the same patient tumors and showed that Amp1q is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number for part of the chr1q arm, we showed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with Amp1q.

Genetic and ultrasonographic analyses of fetuses with 1q21.1q21.2 microdeletion/microduplication: a retrospective study.

BACKGROUND: 1q21.1q21.2 microdeletions/microduplications are rare and incompletely penetrant genetic mutations, and only a few reports regarding their prenatal diagnosis are currently available. Here, we analyzed the ultrasonographic phenotypic characteristics of fetuses with these mutations to improve the understanding, diagnosis, and screening of these mutations during gestation. METHODS: We retrospectively analyzed 8700 cases of pregnant women who underwent invasive prenatal screening by karyotyping and chromosomal microarray analysis (CMA) between November 2016 and November 2021. RESULTS: CMA revealed copy number changes in the 1q21.1q21.2 region of eleven fetuses, of which five had microdeletions and six had microduplications. These eleven fetuses exhibited variable ultrasonographic phenotypes. Of the five fetuses with the microdeletion, one exhibited a right-dominant heart, permanent right umbilical vein, and mild tricuspid regurgitation, another showed thickened nuchal translucency, and the remaining three had normal ultrasound phenotypes. Two of the six cases with 1q21.1q21.2 microduplication had structural malformations; one of them had a bilateral subependymal cyst, neck mass, and enlarged cardiothoracic ratio, while the other had right ventricular hypoplasia. Of the remaining four cases, two exhibited nasal bone dysplasia, one showed measurement slower than that during menopause and mild tricuspid regurgitation, and another did not show any notable abnormality in ultrasound examination. Among the eleven cases of 1q21.1q21.2 microdeletion/microduplication, only the parents of two fetuses underwent pedigree verification. The parents of these two fetuses with 1q21.1q21.2 microdeletion syndrome chose to continue the pregnancy, and all aspects of postnatal follow-up were normal. The parents of the other nine fetuses refused pedigree verification; of these cases, four cases terminated, and five cases continued the pregnancies. The five continued pregnancies were followed up after birth; no abnormalities were found. CONCLUSIONS: Fetuses with 1q21.1q21.2 microdeletion/microduplication show different ultrasound characteristics and may have congenital heart disease, thickened nuchal translucency, and nasal bone dysplasia or show no notable abnormalities in an ultrasound examination. Our study highlights that CMA as a powerful diagnostic tool for these diseases can provide an accurate genetic diagnosis, while improving prenatal diagnosis standards.

Proximal 1q21 duplication: A syndrome or a susceptibility locus?

Proximal 1q21 microduplication is an incomplete penetrance and variable expressivity syndrome. This study reports 28 new cases and summarizes data on phenotype, gender, and parental origin. Data on isolated proximal 1q21.1 microduplications (g. chr1:145,394,956-145,762,959 GRCh37/hg19) was retrieved in postnatal and prenatal "clinical cases" group, and prenatal "control group." The "clinical cases" cases included cases where chromosomal microarray (CMA) was performed due to congenital anomalies, autism spectrum disorder, seizures, and developmental delay/intellectual disability. The "control group" cases consisted of fetal CMA performed upon parental request despite normal nuchal translucency and anatomical second trimester fetal scans. We analyzed a local database of 27,990 cases and another cohort of 80,000 cases (including both indicated and non-indicated cases) for population frequency analysis. A total of 62 heterozygous cases were found, including 28 index cases and 34 family members. Among the index cases, 13 (9 males, 4 females) were identified in the "clinical cases" group, of which 10 had developmental abnormalities. Parental origin was tested in 9/13 cases, and all were found to be maternally inherited. In the "control group," which comprised non-affected cases, of 15 cases (10 males, 5 females), only 5/11 were maternally inherited. Four cases with clinical follow-up showed no reported neurodevelopmental abnormalities. No de-novo cases were detected, and the population frequency in both cohorts was 1:1000. Proximal 1q21.1 microduplication is a recurrent copy number variant, associated with neurodevelopmental abnormalities. It has a greater impact on males inheriting it from their mothers than females from their fathers.

Concomitant deletion of the short arm (del(1p13.3)) and amplification or gain (1q21) of chromosome 1 by fluorescence in situ hybridization are associated with a poor clinical outcome in multiple myeloma.

BACKGROUND: Chromosome 1 abnormalities in multiple myeloma (MM) are increasingly recognized as high risk-defining features. The authors report the prognostic value of del(1p13.3) by fluorescence in situ hybridization (FISH) at enrollment in subjects treated on total therapy clinical trials 2-6. METHODS: FISH probes were generated from specific BAC DNA clones for the AHCYL1 gene locus (1p13.3) and the CKS1B locus (1q21). RESULTS: A total of 1133 patients were included in this analysis. Although del(1p13.3) was detected in 220 (19.4%) patients, 1q21gain or 1q21amp were observed in 300 (26.5%) and 150 (13.2%) patients, respectively. Concomitant del(1p13.3) with 1q21 gain or amp was observed in 65 (5.7%) and 29 (2.5%) patients, respectively. There was enrichment of high-risk features such as International Staging System (ISS) stage 3 disease and gene expression profiling (GEP)70 high risk (HR) in the group with del(1p13.3). Presence of del(1p13.3) confers inferior progression-free survival (PFS) and overall survival (OS). On multivariate analysis, the presence of ISS stage 3 disease, GEP70 HR, 1q21gain, and 1q21amp were independent predictors of PFS or OS. CONCLUSIONS: The PFS and OS of patients with combined abnormalities of del (1p13.3)/1q21gain or amp was significantly worse compared to del(1p13.3) alone and 1q21gain or 1q21 amp alone, which identifies a subset of patients with poor clinical outcomes.

[The influencing factors of renal response in newly diagnosed multiple myeloma patients with renal impairment].

Objective: To investigate the causative factors of renal function in newly diagnosed multiple myeloma (MM) patients with renal inadequacy. Methods: 181 MM patients with renal impairment from August 2007 to October 2021 at Peking Union Medical College Hospital were recruited, whose baseline chronic kidney disease (CKD) stage was 3-5. Statistical analysis was performed based on laboratory tests, treatment regimens, hematological responses, and survival among various renal function efficacy groups. A logistic regression model was employed in multivariate analysis. Results: A total of 181 patients were recruited, and 277 patients with CKD stages 1-2 were chosen as controls. The majority choose the BCD and VRD regimens. The progression-free survival (PFS) (14.0 months vs 24.8 months, P<0.001) and overall survival (OS) (49.2 months vs 79.7 months, P<0.001) of patients with renal impairment was considerably shorter. Hypercalcemia (P=0.013, OR=5.654) , 1q21 amplification (P=0.018, OR=2.876) , and hematological response over a partial response (P=0.001, OR=4.999) were independent predictive factors for renal function response. After treatment, those with improvement in renal function had a longer PFS than those without (15.6 months vs 10.2 months, P=0.074) , but there was no disparity in OS (56.5 months vs 47.3 months, P=0.665) . Conclusion: Hypercalcemia, 1q21 amplification, and hematologic response were independent predictors of the response of renal function in NDMM patients with renal impairment. MM patients with CKD 3-5 at baseline still have worse survival. Improvement in renal function after treatment is attributed to the improvement in PFS.