Search

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 β‐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. [ABSTRACT FROM AUTHOR]

Abstract 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 β‐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

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. [ABSTRACT FROM AUTHOR]

Abstract Background Plasma cell neoplasm is characterized by complex genetic and prognostic heterogeneity. FAM72D, a gene located on chromosome 1, and the association between its expression and tumor progression and prognosis remain elusive. Methods The present study aims to assess FAM72D mRNA expression in 60 PCM patients and correlate its expression level with clinical and laboratory markers involved in diagnosing and prognosis of PCM using real-time PCR. Results Unpaired t-test revealed a significantly higher FAM72D expression level in the patients than in the control group with a median of 0.890 vs. /0.030, respectively, and p value = 0.000. The highest median level was denoted in newly diagnosed or relapsed patients (1.905, p value = 0.000). A significant positive correlation was found between FAM72D expression level and each of BMPCs count, M band, and β2 microglobulin (p = 0.000, p = 0.002, p = 0.024, respectively), and negative correlations with both serum albumin and hemoglobin level (p = 0.000, p = 0.035, respectively). The risk of relapse was 18.3-fold when the FAM72D level was greater than 1.547. Conclusion The higher FAM72D expression level in newly diagnosed and relapsed myeloma patients and its positive correlation with BMPCs confirm the stimulating effect of FAM72D on myeloma cell proliferation and its poor prognosis.

Background: Plasma cell neoplasm is characterized by complex genetic and prognostic heterogeneity. FAM72D, a gene located on chromosome 1, and the association between its expression and tumor progression and prognosis remain elusive. Methods: The present study aims to assess FAM72D mRNA expression in 60 PCM patients and correlate its expression level with clinical and laboratory markers involved in diagnosing and prognosis of PCM using real-time PCR. Results: Unpaired t-test revealed a significantly higher FAM72D expression level in the patients than in the control group with a median of 0.890 vs. /0.030, respectively, and p value = 0.000. The highest median level was denoted in newly diagnosed or relapsed patients (1.905, p value = 0.000). A significant positive correlation was found between FAM72D expression level and each of BMPCs count, M band, and β2 microglobulin (p = 0.000, p = 0.002, p = 0.024, respectively), and negative correlations with both serum albumin and hemoglobin level (p = 0.000, p = 0.035, respectively). The risk of relapse was 18.3-fold when the FAM72D level was greater than 1.547. Conclusion: The higher FAM72D expression level in newly diagnosed and relapsed myeloma patients and its positive correlation with BMPCs confirm the stimulating effect of FAM72D on myeloma cell proliferation and its poor prognosis. [ABSTRACT FROM AUTHOR]

Chromosome 1q21 aberration is one of the most common cytogenetic abnormalities in multiple myeloma, and is considered an important prognostic factor. The present study analyzed the clinical relevance and prognostic impact of 1q21 gain in 194 patients with newly diagnosed multiple myeloma treated with bortezomib-based regimens. 1q21 gain was detected in 45.9% (89/194) of patients, and those with 1q21 gain had a worse prognosis. Strikingly, our results showed that excluding the effects of other coinciding genetic anomalies, patients carrying at least four copies of 1q21 had worse survival outcome. Moreover, del(13q) strongly correlates with 1q21 gain, and the coexistence of del(13q) and 1q21 gain plays an important role in reducing PFS and OS times. Therefore, 1q21 gain should be considered a high-risk feature in multiple myeloma patients treated with a bortezomibbased regimen. [ABSTRACT FROM AUTHOR]

BackgroundAlthough the reference human genome sequence was declared finished in 2003, some regions of the genome remain incomplete due to their complex architecture. One such region, 1q21.1-q21.2, is of increasing interest due to its relevance to human disease and evolution. Elucidation of the exact variants behind these associations has been hampered by the repetitive nature of the region and its incomplete assembly. This region also contains 238 of the 270 human DUF1220 protein domains, which are implicated in human brain evolution and neurodevelopment. Additionally, examinations of this protein domain have been challenging due to the incomplete 1q21 build. To address these problems, a single-haplotype hydatidiform mole BAC library (CHORI-17) was used to produce the first complete sequence of the 1q21.1-q21.2 region.ResultsWe found and addressed several inaccuracies in the GRCh37sequence of the 1q21 region on large and small scales, including genomic rearrangements and inversions, and incorrect gene copy number estimates and assemblies. The DUF1220-encoding NBPF genes required the most corrections, with 3 genes removed, 2 genes reassigned to the 1p11.2 region, 8 genes requiring assembly corrections for DUF1220 domains (~91 DUF1220 domains were misassigned), and multiple instances of nucleotide changes that reassigned the domain to a different DUF1220 subtype. These corrections resulted in an overall increase in DUF1220 copy number, yielding a haploid total of 289 copies. Approximately 20 of these new DUF1220 copies were the result of a segmental duplication from 1q21.2 to 1p11.2 that included two NBPF genes. Interestingly, this duplication may have been the catalyst for the evolutionarily important human lineage-specific chromosome 1 pericentric inversion.ConclusionsThrough the hydatidiform mole genome sequencing effort, the 1q21.1-q21.2 region is complete and misassemblies involving inter- and intra-region duplications have been resolved. The availability of this single haploid sequence path will aid in the investigation of many genetic diseases linked to 1q21, including several associated with DUF1220 copy number variations. Finally, the corrected sequence identified a recent segmental duplication that added 20 additional DUF1220 copies to the human genome, and may have facilitated the chromosome 1 pericentric inversion that is among the most notable human-specific genomic landmarks.

BackgroundAlthough the reference human genome sequence was declared finished in 2003, some regions of the genome remain incomplete due to their complex architecture. One such region, 1q21.1-q21.2, is of increasing interest due to its relevance to human disease and evolution. Elucidation of the exact variants behind these associations has been hampered by the repetitive nature of the region and its incomplete assembly. This region also contains 238 of the 270 human DUF1220 protein domains, which are implicated in human brain evolution and neurodevelopment. Additionally, examinations of this protein domain have been challenging due to the incomplete 1q21 build. To address these problems, a single-haplotype hydatidiform mole BAC library (CHORI-17) was used to produce the first complete sequence of the 1q21.1-q21.2 region.ResultsWe found and addressed several inaccuracies in the GRCh37sequence of the 1q21 region on large and small scales, including genomic rearrangements and inversions, and incorrect gene copy number estimates and assemblies. The DUF1220-encoding NBPF genes required the most corrections, with 3 genes removed, 2 genes reassigned to the 1p11.2 region, 8 genes requiring assembly corrections for DUF1220 domains (~91 DUF1220 domains were misassigned), and multiple instances of nucleotide changes that reassigned the domain to a different DUF1220 subtype. These corrections resulted in an overall increase in DUF1220 copy number, yielding a haploid total of 289 copies. Approximately 20 of these new DUF1220 copies were the result of a segmental duplication from 1q21.2 to 1p11.2 that included two NBPF genes. Interestingly, this duplication may have been the catalyst for the evolutionarily important human lineage-specific chromosome 1 pericentric inversion.ConclusionsThrough the hydatidiform mole genome sequencing effort, the 1q21.1-q21.2 region is complete and misassemblies involving inter- and intra-region duplications have been resolved. The availability of this single haploid sequence path will aid in the investigation of many genetic diseases linked to 1q21, including several associated with DUF1220 copy number variations. Finally, the corrected sequence identified a recent segmental duplication that added 20 additional DUF1220 copies to the human genome, and may have facilitated the chromosome 1 pericentric inversion that is among the most notable human-specific genomic landmarks.

Robin sequence (RS) has been reported in association with single gene disorders and chromosomal abnormalities; however, it has not previously been described in connection with chromosome 1q21 microduplication. We present the first known case of a neonate diagnosed with chromosome 1q21.1 microduplication syndrome and RS requiring surgical airway intervention. This case demonstrates the value of genetic testing in cases of RS presenting with other congenital anomalies. [ABSTRACT FROM AUTHOR]

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.

Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) in the bone marrow (BM). The amplification of 1q21 is one of the most common cytogenetic abnormalities occurring in around 40% of de novo patients and 70% of relapsed/refractory MM. Patients with this unfavorable cytogenetic abnormality are considered to be high risk with a poor response to standard therapies. The gene(s) driving amplification of the 1q21 amplicon has not been fully studied. A number of clear candidates are under investigation, and some of them (IL6R, ILF2, MCL-1, CKS1B and BCL9) have been recently proposed to be potential drivers of this region. However, much remains to be learned about the biology of the genes driving the disease progression in MM patients with 1q21 amp. Understanding the mechanisms of these genes is important for the development of effective targeted therapeutic approaches to treat these patients for whom effective therapies are currently lacking. In this paper, we review the current knowledge about the pathological features, the mechanism of 1q21 amplification, and the signal pathway of the most relevant candidate genes that have been suggested as possible therapeutic targets for the 1q21 amplicon.

Background: Rearrangement of the 1q21 region of chromosome 1 manifests as multiple phenotypes, including microcephaly, intellectual disability, dysmorphic facial features, eye abnormalities, cardiac defects, genitourinary anomalies, autism spectrum disorder, psychiatric conditions and seizures. Herein, we describe eight patients with 1q21 deletion and duplication syndromes, and novel deletions and findings. Methods: Chromosomal microarray analysis was performed to identify the existence of copy number variation. Quantitative polymerase chain reaction was applied using specific primers for the control and 1q21 region of chromosome 1. Mutational analysis was performed in case 5 using direct genomic sequencing for exons 1–6 in RBM8A. Results: Copy number variation analysis identified seven deletions and one duplication of the 1q21 region in the eight patients. In addition, four variations were de novo, and two deletions are reported here for the first time. One of the cases (case 7) presents moderate intellectual disability and dysmorphic facial findings, whereas chromosomal microarray analysis showed that case 7 had an 889‐kb deletion in the 1q21 proximal region (GPR89A, PDZK1, CD160, POLR3C and NBPF12). Conclusion: Although the deletion in case 5 did not include the thrombocytopenia‐absent radius syndrome critical region or the RBM8A gene, he had pectoral muscle hypoplasia, radius and humerus hypoplasia and short curved ribs, which are indicative of a potential thrombocytopenia‐absent radius region modifier. The findings in case 7 suggest that the proximal part of the 1q21 microdeletion syndrome region might be very important for the onset of clinical manifestations. Some novel findings were observed in the presented cases, such as radius and humerus hypoplasia and brain stem hypoplasia. The presented findings expand the spectrum of 1q21 aberrations and provide evidence of genotype–phenotype correlations for this region. [ABSTRACT FROM AUTHOR]

Background: Multiple myeloma (MM) with 1q21 gains invariably has a poor prognosis. Many recent studies have reported the relationship between micro (mi)RNA expression and MM prognosis. However, there is little information on the association between miRNA alterations and 1q21 gains. Methods: We compared the miRNA expression profiles of MM with 1q21 gains and MM with normal fluorescence in situ hybridisation (FISH) by gene expression array. Differentially expressed miRNAs were identified using Affymetrix TAC software. Thresholds were defined as a false discovery rate <0.05, p value <0.05, and n-fold change >2. Results: Six miRNAs (let-7f-5p and -7g-5p, and miR-29a-3p, -29b-1-5p, -331-3p, and -223-3p) were downregulated and 4 (miR-30e-5p, -17-3p, -18b-5p, and -19a-3p) were upregulated in MM with 1q21 gains relative to MM with normal FISH. Conclusions: The identified set of miRNAs can serve as biomarkers for distinguishing MM with 1q21 gains from MM with normal FISH. [ABSTRACT FROM AUTHOR]

The gain/amplification of the CKS1B gene on chromosome 1q21 region is associated with a poor outcome in patients with multiple myeloma (MM). However, there are limited data on the outcome of patients with CKS1B amplification after a single high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). We retrospectively evaluated the outcome of patients with CKS1B amplification who received an auto-HCT between June 2012 and July 2014 at our institution. We identified 58 patients with MM and CKS1B gene amplification detected by fluorescent in situ hybridization (FISH). We compared their outcomes with a propensity score–matched control group of 58 patients without CKS1B amplification who were treated at approximately the same time. The primary objective was to compare the progression-free (PFS) and overall survival (OS) between the CKS1B and the control groups. Stratified log-rank test with the matched pairs as strata and double robust estimation under the Cox model were used to assess the effect of CKS1B gene amplification on PFS or OS in the matched cohort. Patients in the CKS1B and control groups were well matched for age, gender, disease status, year of auto-HCT, response to pretransplantation therapy, and baseline hemoglobin level. In both groups, 57% patients were in first remission and 43% had relapsed disease at auto-HCT. Twenty-seven (47%) patients with CKS1B amplification had concurrent monosomy 13 or 13q deletion; 6 (10%) by conventional cytogenetics only, 16 (28%) by FISH only, and 5 (9%) by both. Median follow-up after auto-HCT was 25.4 months. The median PFS of the CKS1B and the control groups were 15.0 months and 33.0 months ( P  = .002), respectively. The median OS have not been reached yet. The 2-year OS rates in the CKS1B and the control groups were 62% and 91% ( P  = .02), respectively. In conclusion, Patients with CKS1B amplification are more likely to have additional high-risk cytogenetic abnormalities and a shorter PFS and OS after an auto-HCT. [ABSTRACT FROM AUTHOR]

Objective The authors hypothesized that genetic association between atrial fibrillation (AF)-associated and PR-associated genetic loci was biologically mediated through slower conduction velocities for some or all of these loci. Design Prospectively collected cohort study. Setting Single tertiary care university hospital. Participants A total of 1227 Caucasian patients who underwent coronary artery bypass grafting (CABG). Interventions A total of 677 single nucleotide polymorphisms previously associated with ambulatory AF or PR interval were tested for association with postoperative atrial fibrillation (poAF) and preoperative PR interval, maximum PR interval, maximum change in PR interval, and maximum change in PR interval from preoperative PR interval. Measurements and Main Results The incidence of new-onset poAF was 31%. All of the PR interval variables were longer in the poAF cohort. Two variants on 1q21 and 12 on 4q25 were associated with poAF after adjustment for false discovery rate (FDR), but no variants were associated with PR interval variables after adjustment for FDR. Several variants were associated with both poAF and PR interval variables at p<0.05, but none of them remained significant after adjusting for FDR. Conclusion It was found that patients with poAF have significantly longer PR interval. Genetic variants in both the 1q21 and 4q25 regions associate with poAF after CABG surgery, but the authors were unable to find association between these variants and PR interval after adjusting for FDR. [ABSTRACT FROM AUTHOR]

Background Although the reference human genome sequence was declared finished in 2003, some regions of the genome remain incomplete due to their complex architecture. One such region,1q21.1- q21.2, is of increasing interest due to its relevance to human disease and evolution. Elucidation of the exact variants behind these associations has been hampered by the repetitive nature of the region and its incomplete assembly. This region also contains 238 of the 270 human DUF1220 protein domains, which are implicated in human brain evolution and neurodevelopment. Additionally, examinations of this protein domain have been challenging due to the incomplete 1q21 build. To address these problems, a single-haplotype hydatidiform mole BAC library (CHORI-17) was used to produce the first complete sequence of the 1q21.1-q21.2 region. Results We found and addressed several inaccuracies in the GRCh37sequence of the 1q21 region on large and small scales, including genomic rearrangements and inversions, and incorrect gene copy number estimates and assemblies. The DUF1220-encoding NBPF genes required the most corrections, with 3 genes removed, 2 genes reassigned to the 1p11.2 region, 8 genes requiring assembly corrections for DUF1220 domains (∼91 DUF1220 domains were misassigned), and multiple instances of nucleotide changes that reassigned the domain to a different DUF1220 subtype. These corrections resulted in an overall increase in DUF1220 copy number, yielding a haploid total of 289 copies. Approximately 20 of these new DUF1220 copies were the result of a segmental duplication from 1q21.2 to 1p11.2 that included two NBPF genes. Interestingly, this duplication may have been the catalyst for the evolutionarily important human lineage-specific chromosome 1 pericentric inversion. Conclusions Through the hydatidiform mole genome sequencing effort, the 1q21.1-q21.2 region is complete and misassemblies involving inter- and intra-region duplications have been resolved. The availability of this single haploid sequence path will aid in the investigation of many genetic diseases linked to 1q21, including several associated with DUF1220 copy number variations. Finally, the corrected sequence identified a recent segmental duplication that added 20 additional DUF1220 copies to the human genome, and may have facilitated in the chromosome 1 pericentric inversion that is among the most notable human-specific genomic landmarks. [ABSTRACT FROM AUTHOR]

Chromosome 1q21 aberration is one of the most common cytogenetic abnormalities in multiple myeloma, and is considered an important prognostic factor. The present study analyzed the clinical relevance and prognostic impact of 1q21 gain in 194 patients with newly diagnosed multiple myeloma treated with bortezomib-based regimens. 1q21 gain was detected in 45.9% (89/194) of patients, and those with 1q21 gain had a worse prognosis. Strikingly, our results showed that excluding the effects of other coinciding genetic anomalies, patients carrying at least four copies of 1q21 had worse survival outcome. Moreover, del(13q) strongly correlates with 1q21 gain, and the coexistence of del(13q) and 1q21 gain plays an important role in reducing PFS and OS times. Therefore, 1q21 gain should be considered a high-risk feature in multiple myeloma patients treated with a bortezomib-based regimen., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Jia, Chu, Tian, Gao, Zhang, Zheng, Jia, Liu, Yuan, Zhang, Feng, Dong, Xin, Chang, Cao, Tang and Gao.)

With the introduction of new genetic techniques such as genome-wide array comparative genomic hybridization, studies on the putative genetic etiology of schizophrenia have focused on the detection of copy number variants (CNVs), ie, microdeletions and/or microduplications, that are estimated to be present in up to 3% of patients with schizophrenia. In this study, out of a sample of 100 patients with psychotic disorders, 80 were investigated by array for the presence of CNVs. The assessment of the severity of psychiatric symptoms was performed using standardized instruments and ICD-10 was applied for diagnostic classification. In three patients, a submicroscopic CNV was demonstrated, one with a loss in 1q21.1 and two with a gain in 1p13.3 and 7q11.2, respectively. The association between these or other CNVs and schizophrenia or schizophrenia-like psychoses and their clinical implications still remain equivocal. While the CNV affected genes may enhance the vulnerability for psychiatric disorders via effects on neuronal architecture, these insights have not resulted in major changes in clinical practice as yet. Therefore, genome-wide array analysis should presently be restricted to those patients in whom psychotic symptoms are paired with other signs, particularly dysmorphisms and intellectual impairment. [ABSTRACT FROM AUTHOR]

AbstractHepatocellular carcinoma (HCC) is among the most lethal of human malignancies. During human multistep hepatocarcinogenesis, genomic gain represents an important mechanism in the activation of proto-oncogenes. In many circumstances, activated oncogenes hold clinical implications both as prognostic markers and targets for cancer therapeutics. Gain of chromosome 1q copy is one of the most frequently detected alterations in HCC and 1q21 is the most frequent minimal amplifying region (MAR). A better understanding of the physiological and pathophysiological roles of target genes within 1q21 amplicon will significantly improve our knowledge in HCC pathogenesis, and may lead to a much more effective management of HCC bearing amplification of 1q21. Such knowledge has long term implications for the development of new therapeutic strategies for HCC treatment. Our research group and others, focused on the identification and characterization of 1q21 target genes such as JTB, CKS1B, and CHD1L in HCC progression. In this review, we will summarize the current scientific knowledge of known target genes within 1q21 amplicon and the precise oncogenic mechanisms of CHD1L will be discussed in detail. [ABSTRACT FROM AUTHOR]

The chromosomal region 1q21 has been linked to atopic dermatitis in previous studies. Seven polymorphic repeats were identified in a 0.5 Mb region of chromosome 1q21 encompassing a small proline-rich protein ( SPRR) gene cluster, a few S100 gene family members, loricin, and several uncharacterized genes. These repeats were genotyped by fragment length polymorphism analysis in 133 atopic case–parent trios, of which 111 probands had atopic asthma. Our trio-based analysis for association with atopy and atopic asthma revealed no significant allelic or genotypic association for any of the seven loci tested. However, a significant association was observed with locus 5 (3.65 Mb of contig NT_032962) and log10 serum IgE levels ( F = 3.93, P = 0.0008). Results were also replicated in an independent case-control cohort ( N p = 165, N c = 166), where a significant association with log10 serum IgE levels was observed in the patient group ( P = 0.0005). Interestingly, locus 5 is 6.2 kb upstream of a late cornified envelope-like proline-rich 1 ( LELP1) gene which encodes a novel small proline rich protein. Further, we have also found a significant association of rs7534334 (tagged SNP from LELP1) SNP with log10 serum IgE levels in the patient group ( P = 0.0029). Thus, our results identify a chromosomal region in close proximity to a novel gene and highlight the need for intense research on LELP1 and other genes close by with respect to atopic disorders. [ABSTRACT FROM AUTHOR]

The prevalence and prognostic relevance of recurrent gains of CKS1B (cyclin kinase subunit 1B) gene at chromosome 1q21 region was investigated by interphase fluorescence in situ hybridisation in a cohort of 99 multiple myeloma (MM) patients treated with intensive chemotherapy followed by autologous stem cell transplantation. CKS1B amplification (3–8 CKS1B signals) was detected in 31of 99 (31%) patients and was associated with deletions of p53 ( P = 0·003) and 13q ( P = 0·039) but not with translocation t(11;14) or t(4;14). CKS1B amplification was associated with bone marrow plasmacytosis ( P = 0·02), but there was no correlation with patient age, gender, disease stage, lytic bone lesions, albumin, creatinine, C-reactive protein or beta-2 microglobulin levels. Patients with CKS1B amplification had a significantly shorter progression-free survival than those without such amplification (18·5 vs. 25·7 months, P = 0·035). Likewise, a shorter overall survival (44·8 months vs. not reached) was observed; however, the difference did not reach statistical significance ( P = 0·20). Seven patients had paired bone marrows obtained at diagnosis and at relapse, the percentage of cells with CKS1B amplification and the level of amplification were significantly increased in the relapse marrows. In this cohort of patients, CKS1B was frequently amplified in MM and may represent genetic instability associated with disease progression. [ABSTRACT FROM AUTHOR]

The human repetin gene is a member of the“fused” gene family and localized in the epidermal differentiation complex on chromosome 1q21. The“fused” gene family comprises profilaggrin, trichohyalin, repetin, hornerin, the profilaggrin-related protein and a protein encoded by c1orf10. Functionally, these proteins are associated with keratin intermediate filaments and partially crosslinked to the cell envelope (CE). Here, we report the isolation and characterization of the human repetin gene and of its protein product. The repetin protein of 784 amino acids contains EF (a structure resembling the E helix-calcium-binding loop-F helix domain of parvalbumin) hands of the S100 type and internal tandem repeats typical for CE precursor proteins, a combination which is characteristic for“fused” proteins. Repetin expression is scattered in the normal epidermis but strong in the acrosyringium, the inner hair root sheat and in the filiform papilli of the tongue. Ultrastructurally, repetin is a component of cytoplasmic non-membrane“keratohyalin” F-granules in the stratum granulosum of normal epidermis, similar to profilaggrin. Finally, we show that EF hands are functional and reversibly bind Ca2+. Our results indicate that repetin is indeed a member of the fused gene family similar to the prototypical members profilaggrin and trichohyalin. [ABSTRACT FROM AUTHOR]

The protein encoded by theC1orf10gene was described to be esophageal-specific and a marker for cancer development. This protein, however, has the previously unreported structural features of the“fused gene” family combining sequences and structural similarities of both the S100 proteins and precursor proteins of the cornified cell envelope as in profilaggrin, trichohyalin, and repetin. Since all members of this family are expressed in keratinocytes, we suspected a role in epidermal differentiation and named the protein cornulin. Here, we report that human cornulin mRNA is expressed primarily in the upper layers of differentiated squamous tissues including the epidermis. Using polyclonal peptide antibodies, we show that cornulin is expressed in the granular and lower cornified cell layers of scalp epidermis and foreskin, as well as in calcium-induced differentiated cultured keratinocytes. Ca2+-overlay assay indicated that EF-hand domains of cornulin are functional and bind calcium. In HeLa cells, cornulin, co-transfected with transglutaminase 1, was diffusely distributed throughout the cytoplasm in contrast to small proline-rich 4, which localized to the cell periphery. We conclude that cornulin is a new member of the“fused gene” family, does not appear to be a precursor of the cornified cell envelope by itself, and is a marker of late epidermal differentiation. [ABSTRACT FROM AUTHOR]

The thrombospondin type 1 repeat domain is found in nearly 100 mammalian proteins with diverse biological functions that include cellular adhesion, angiogenesis, and patterning of the developing nervous system. We have characterized a novel thrombospondin type 1 repeat containing gene, TSRC1, encoding a predicted protein with seven thrombospondin repeats, six of which are clustered at the C-terminus. The 17 coding exons and two nontranslated exons of TSRC1 span 10 kb of genomic DNA. The human and mouse genes encode proteins of 1074 and 1036 amino acids, respectively, with 76% amino acid sequence identity. Thirty of the extra amino acids in the human protein are encoded by exon 6. Mouse Tsrc1 is expressed in all fetal and adult tissues tested. Three conserved noncoding sequence elements with potential regulatory function are located in intron 1. Mouse Tsrc1 was genetically mapped to chromosome 3 within the nonrecombinant region for the sodium channel modifier locus Scnm1. The sensitive and resistant alleles of Scnm1 did not differ in Tsrc1 protein sequence, transcript length, or transcript abundance. Human TSRC1 is located on chromosome 1q21 within an 11.7 Mb segment of conserved synteny. TSRC1 and the closely linked gene ADAM15 appear to be derived by a chromosomal inversion that interrupted an ancestral ADAMTS gene. [Copyright &y& Elsevier]

Linkage analysis has identified a susceptibility locus for type 2 diabetes mellitus (T2DM) on chromosome 1q21–q23 in several populations. Results from recent prospective studies indicate that increased levels of C-reactive protein (CRP), a marker of immune system activation, are predictive of diabetes, independent of adiposity. Because CRP is located on 1q21, we considered it a potential positional candidate gene for T2DM. We therefore evaluated CRP and the nearby serum amyloid P-component, APCS, which is structurally similar to CRP, as candidate diabetes susceptibility genes. Approximately 10.9 kb of the CRP-APCS locus was screened for polymorphisms using denaturing high performance liquid chromatography and direct sequencing. We identified 27 informative polymorphisms, including 26 single nucleotide polymorphisms (SNPs) and 1 insertion/deletion, which were divided into 7 linkage disequilibrium clusters. We genotyped representative SNPs in ∼1300 Pima samples and found a single variant in the CRP promoter (SNP 133552) that was associated with T2DM (P=0.014), as well as a common haplotype (CGCG) that was associated with both T2DM (P=0.029) and corrected insulin response, a surrogate measure of insulin secretion in non-diabetic subjects (P=0.050). Linkage analyses that adjusted for the effect of these polymorphisms indicated that they do not in themselves account for the observed linkage with T2DM on chromosome 1q. However, these findings suggest that variation within the CRP locus may play a role in diabetes susceptibility in Pima Indians. [Copyright &y& Elsevier]

Aims/hypothesis.Lamin A/C (LMNA) is located within a region on chromosome 1 q that has been linked with Type II (non-insulin-dependent) diabetes mellitus in Pima Indians. Rare mutations in exon 8 of LMNA underlie Dunnigan-Type familial partial lipodystrophy, a disease characterized by regional adipocyte degeneration and frequently accompanied by insulin resistance, glucose intolerance, and diabetes. A more common variant in exon 10 (3408C/T) has recently been associated with obesity in non-diabetic aboriginal Canadian subjects. Because obesity is a strongly predisposing factor for Type II diabetes, we hypothesized that the LMNA 3408C/T variant could be associated with diabetes and body mass index in Pima Indians. Methods. To determine whether the LMNA 3408C/T variant contributes to Type II diabetes susceptibility, we genotyped the polymorphism in 1338 Pimas using allelic discrimination technology. The locus was screened for additional variants in 20 diabetic Pima Indians and non-diabetic Pima Indians using denaturing high performance liquid chromatography and dideoxy sequencing. Results. We found no evidence for association of 3408C/T with diabetes, body mass index, total cholesterol, HDL cholesterol, triglycerides, leptin concentrations, or indices of insulin sensitivity and secretion. Subsequent screening of the remaining LMNA exons and flanking sequences revealed only rare variants in intron 4 and the 3'UTR, showing no frequency differences between diabetic and non-diabetic Pima Indians. We reassessed the linkage with diabetes following adjustment for the LMNA 3408C/T variant; adjustment for the effects of LMNA did not substantially modify the evidence for linkage. Conclusion/interpretation. We conclude that the LMNA 3408C/T variant probably does not play a role in susceptibility to diabetes or obesity in Pima Indians. [Diabetologia (2001) 44: 779–782] [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a kind of hematologic malignancy occurring in plasma cells. Cytogenetic technique plays an important role in risk stratification of MM. 1q21 amplification is one of the common chromosomal abnormalities in MM. Studies have shown that 1q21 amplification is associated with poor prognosis in MM patients. At present, with the development of new drugs, cellular immunotherapy, and improvement of hematopoietic stem cell transplantation technology, the remission depth and survival time of MM significantly increased. Rapid and accurate identification of high-risk patients and individualized treatment according to the patient's condition is the key to improve the therapeutic effect of MM. This article reviews the mechanism of 1q21 amplification in MM and the efficacy of new drugs in the treatment of MM with 1q21 chromosome amplification.

Introduction: Multiple myeloma (MM) remains an incurable disease with a median overall survival of approximately 5 years. Gain or amplification of 1q21 (1q21+) occurs in around 40% of patients with MM and generally portends a poor prognosis. Patients with MM who harbor 1q21+ are at increased risk of drug resistance, disease progression, and death. New pharmacotherapies with novel modes of action are required to overcome the negative prognostic impact of 1q21+. Areas covered: This review discusses the detection, biology, prognosis, and therapeutic targeting of 1q21+ in newly diagnosed and relapsed MM. Patients with MM and 1q21+ tend to present with higher tumor burden, greater end-organ damage, and more co-occurring high-risk cytogenetic abnormalities than patients without 1q21+. The chromosomal rearrangements associated with 1q21+ result in dysregulation of genes involved in oncogenesis. Identification and characterization of the 1q21+ molecular targets are needed to inform on prognosis and treatment strategy. Clinical trial data are emerging that addition of isatuximab to combination therapies may improve outcomes in patients with 1q21+ MM. Expert opinion: In the next 5 years, the results of ongoing research and trials are likely to focus on the therapeutic impact and treatment decisions associated with 1q21+ in MM.

Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) in the bone marrow (BM). The amplification of 1q21 is one of the most common cytogenetic abnormalities occurring in around 40% of de novo patients and 70% of relapsed/refractory MM. Patients with this unfavorable cytogenetic abnormality are considered to be high risk with a poor response to standard therapies. The gene(s) driving amplification of the 1q21 amplicon has not been fully studied. A number of clear candidates are under investigation, and some of them (IL6R, ILF2, MCL-1, CKS1B and BCL9) have been recently proposed to be potential drivers of this region. However, much remains to be learned about the biology of the genes driving the disease progression in MM patients with 1q21 amp. Understanding the mechanisms of these genes is important for the development of effective targeted therapeutic approaches to treat these patients for whom effective therapies are currently lacking. In this paper, we review the current knowledge about the pathological features, the mechanism of 1q21 amplification, and the signal pathway of the most relevant candidate genes that have been suggested as possible therapeutic targets for the 1q21 amplicon. [ABSTRACT FROM AUTHOR]

Terminal differentiation of keratinocytes involves the sequential expression of several major proteins which can be identified in distinct cellular layers within the mammalian epidermis and are characteristic for the maturation state of the keratinocyte. Many of the corresponding genes are clustered in one specific human chromosomal region 1q21. It is rare in the genome to find in such close proximity the genes belonging to at least three structurally different families, yet sharing spatial and temporal expression specificity, as well as interdependent functional features. This DNA segment, termed the epidermal differentiation complex, contains 27 genes, 14 of which are specifically expressed during calcium-dependent terminal differentiation of keratinocytes (the majority being structural protein precursors of the cornified envelope) and the other 13 belong to the S100 family of calcium binding proteins with possible signal transduction roles in the differentiation of epidermis and other tissues. In order to provide a bacterial clone resource that will enable further studies of genomic structure, transcriptional regulation, function and evolution of the epidermal differentiation complex, as well as the identification of novel genes, we have constructed a single 2.45 Mbp long continuum of genomic DNA cloned as 45 p1 artificial chromosomes, three bacterial artificial chromosomes, and 34 cosmid clones. The map encompasses all of the 27 genes so far assigned to the epidermal differentiation complex, and integrates the physical localization of these genes at a high resolution on a complete NotI and SalI, and a partial EcoRI restriction map. This map will be the starting resource for the large-scale genomic sequencing of this region by The Sanger Center, Hinxton, U.K. [ABSTRACT FROM AUTHOR]

A cDNA for a putative new member for phosphatidylinositol kinase family was cloned from an adult human whole brain cDNA library. The predicted translation product was composed of 961 amino acid residues and contained a sequence feature characteristic for lipid/protein kinases. The messenger RNA was ubiquitously expressed in various tissues, while relatively higher expression was observed in heart, skeletal muscle and testis. The chromosomal location of the gene was determined by fluorescence in situ hybridization and PCR-based analyses with both a human/rodent monochromosomal hybrid cell panel and a radiation hybrid mapping panel. [ABSTRACT FROM PUBLISHER]

Simple Summary: Multiple myeloma (MM), a plasma cell neoplasm, is an incurable hematological malignancy. Gain/amplification of chromosome arm 1q21 (1q21+) is the most common adverse genomic abnormality associated with disease progression and drug resistance. While possible mechanisms of 1q21+ occurrence and candidate genes in the 1q21 amplicon have been suggested, the precise pathogenesis of MM with 1q21+ is unknown. Herein, we review the current knowledge about the clinicopathological features of 1q21+ MM, which can assist in effective therapeutic approaches for MM patients with 1q21+. Multiple myeloma (MM), a plasma cell neoplasm, is an incurable hematological malignancy characterized by complex genetic and prognostic heterogeneity. Gain or amplification of chromosome arm 1q21 (1q21+) is the most frequent adverse chromosomal aberration in MM, occurring in 40% of patients at diagnosis. It occurs in a subclone of the tumor as a secondary genomic event and is more amplified as the tumor progresses and a risk factor for the progression from smoldering multiple myeloma to MM. It can be divided into either 1q21 gain (3 copies) or 1q21 amplification (≥4 copies), and it has been suggested that the prognosis is worse in cases of amplification than gain. Trisomy of chromosome 1, jumping whole-arm translocations of chromosome1q, and tandem duplications lead to 1q21+ suggesting that its occurrence is not consistent at the genomic level. Many studies have reported that genes associated with the malignant phenotype of MM are situated on the 1q21 amplicon, including CKS1B, PSMD4, MCL1, ANP32E, and others. In this paper, we review the current knowledge regarding the clinical features, prognostic implications, and the speculated pathology of 1q21+ in MM, which can provide clues for an effective treatment approach to MM patients with 1q21+. [ABSTRACT FROM AUTHOR]

Robin sequence (RS) has been reported in association with single gene disorders and chromosomal abnormalities; however, it has not previously been described in connection with chromosome 1q21 microduplication. We present the first known case of a neonate diagnosed with chromosome 1q21.1 microduplication syndrome and RS requiring surgical airway intervention. This case demonstrates the value of genetic testing in cases of RS presenting with other congenital anomalies.