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Waldenström Macroglobulinemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The most common structural abnormality in patients with WM is the deletion of chromosome 6q detected in approximately 50% of the patients, followed by chromosome 5 trisomy, and chromosome 8 monosomy [14]. Fluorescent in situ hybridization (FISH) confirmed the 6q deletion in 55% of WM patients, but in none of the patients with IgM MGUS [15]. A genome-wide study of copy number abnormalities (CNA) and loss of heterozygosity (LOH) in patients with IgM MGUS and WM identified 6q deletion and +18q(22.1) as the most common structural abnormalities in this patient population. Genomic imbalances typically observed in WM (del6q, +18q, trisomy 4, and trisomy 12) were rarely seen in IgM MGUS patients. The frequency of CNA progressively increased from IgM MGUS (36%) to smoldering (73%) and symptomatic WM (82%) [16]. Similar results were seen when a targeted NGS panel was used to evaluate the presence of somatic mutations in patients with IgM MGUS and WM. A significantly higher number of mutations were detected in patients with WM compared to patients with IgM MGUS, supporting the hypothesis that multiple genetic hits are needed for the progression from IgM MGUS to WM [17]. While somatic driver mutations have not been identified, mutations in MYD88, CXCR4, and KMT2D were more frequently seen in WM than in IgM MGUS suggesting that these are potential early events in the transformation of IgM MGUS to WM [17].
Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
NGS studies have shown that the GCB cell DLBCL is often associated with aberrations in genes involved in epigenetic pathways (MFHAS1, XP01, MYC, CDKN2A/B, FOXO1, TP53, GNA13 and BCL2), and the apoptosis/cell cycle pathway (EZH2, KMT2D, EP300, MEF2B and CREBBP); in contrast, the ABC subtype is often characterized by the preferential aberrant activation of the NF-κb pathway (TNFAIP3, MYD88, PIM1, CARD11, IRF4 and PRDM1), whilst both the ABC subtype and PMBL are associated with the JAK/STAT pathway (JAK1, JAK3, STAT3, STAT5B, STAT6 and SOCS1), apoptosis/cell cycle and the immune modulatory pathway (CIITA, B2M, TNFRSF14 and CD58). The presence of CD274 (PD-L1) and PDCD1LG2 (PD-L2) locus as a recurrent translocation partner for IGH, PIM1 and TP63 in the non-GCB DLBCL subtypes, suggestive of the potential use of immune checkpoint inhibitors in the treatment of these poor-risk patients, has also been shown. Other important signalling pathways for both B-cell and T-cell lymphomas include NOTCH (NOTCH1, NOTCH2 and UBR5), MAPK (BRAF), BCR (CD79A/B, ITPKB, TCF3 and ID3), PI3K/MTOR and the focal adhesion pathway (GNA13, RHOA) (Figure 11.11).
Non-Hodgkin Lymphoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Piers Blombery, David C. Linch
An important insight into the pathogenesis of DLBCL was the classification according to normal cell counterpart by gene expression profiling (GEP) studies.16 By using this approach, patients can be characterized into two major subgroups, one group with an expression profile similar to normal germinal center B-cells (GCB) and one with a similar gene expression profile to post-germinal center activated B-cells (ABC). The GCB-DLBCL and ABC-DLBCL subtypes have different mechanisms of lymphomagenesis, immunohistochemical characteristics, prognosis, and contain different suites of genetic lesions. GCB-DLBCL is characterized by increased BCL2 expression (e.g., by translocation of the BCL2 locus to the immunoglobulin heavy chain locus), epigenetic dysregulation (by activating mutations in EZH2 and inactivating mutations of KMT2D), and increased BCL6 expression. ABC-DLBCL is characterized by genetic lesions that converge to cause constitutive activation of the NF-kB pathway. More recently, large cohorts of patients have been assessed with a mixture of whole-exome sequencing and whole-transcriptome sequencing which have revealed a very high degree of genomic heterogeneity in this disease that further subdivides GCB- and ABC-DLBCL into multiple new subgroups characterized by more specific constellations of genomic lesions.17,18 This newly discovered degree of genomic complexity of DLBCL likely explains to a significant degree the failure of targeted therapies to improve outcomes in DLBCL given these therapies have been used in patients selected based on relatively broad molecular classifications (i.e., GCB vs. ABC).
Malignant teratoid intraocular ciliary body medulloepithelioma in a 5-year-old male with corresponding somatic copy number alteration profile of aqueous humor cell-free DNA
Published in Ophthalmic Genetics, 2022
Sarah Pike, Rahul Iyengar, Chen-Ching Peng, Patricia Chevez-Barrios, Brianne Brown, Rachana Shah, Jaclyn Biegel, Venkata Yellapantula, Aaron Nagiel, Bibiana Jin Reiser, Liya Xu, Jesse L. Berry
Genetic analysis of the tumor specimen did not reveal DICER1, KMT2D, or RB1 gene mutations. Testing for these mutations contributes to diagnosis of CBME and Rb, respectively. Approximately 5% of CBME cases have been associated with Pleuropulmonary Blastoma Family Tumor and Dysplasia Syndrome from a DICER1 gene mutation (2,16). Sahm et al. (23) found both DICER1 and KMT2D gene mutations in a series of sporadic CBME samples. DICER1 encodes for an endoribonuclease that produces miRNAs important for development (24). KMT2D is a histone methyltransferase that regulates DNA accessibility (25). Mutations in both genes have been associated with various cancer subtypes (23). Most cases of Rb are caused by inactivation of the RB1 tumor suppressor gene from sporadic or germline mutation (26). Ultimately, histopathology diagnosed malignant teratoid CBME. Diagnostic RB1 testing of peripheral blood and AH cfDNA was therefore not completed.
Ultra-Deep Sequencing of Plasma-Circulating DNA for the Detection of Tumor- Derived Mutations in Patients with Nonmetastatic Colorectal Cancer
Published in Cancer Investigation, 2022
Huu-Thinh Nguyen, Bac An Luong, Duc-Huy Tran, Trong-Hieu Nguyen, Quoc Dat Ngo, Linh Gia Hoang Le, Quoc Chuong Ho, Hue-Hanh Thi Nguyen, Cao Minh Nguyen, Vu Uyen Tran, Truong Vinh Ngoc Pham, Minh Triet Le, Ngoc An Trinh Le, Trung Kien Le, Thanh Luan Nguyen, Hong-Anh Thi Pham, Hong Thuy Le, Hong Diep Thi Duong, Anh Vu Hoang, Hoang Bac Nguyen, Kiet Truong Dinh, Minh-Duy Phan, Hoai-Nghia Nguyen, Thanh-Thuy Thi Do, Hoa Giang, Le Son Tran, Diep Tuan Tran
Background mutations from healthy subjects could lead to the misinterpretation of TDMs (12,18,30). However, this challenge has not been well addressed in previous studies. Here, we profiled mutations in plasma samples of 96 healthy control subjects who underwent colonoscopy but had no lesions. We detected the overlapping spectrum between TDMs and mutations from healthy subjects, confounding the distinction of cancerous mutations from background mutations. After filtering potential background mutations, we detected 33 TDMs, highly likely of tumor origin, in 56% (28/50) of CRC patients, comparable to the detection rates of ctDNA mutations reported by previous studies for early CRC stages (5,12). Moreover, like others (5,12), we also found that higher-stage disease correlated with greater numbers of tumor-matching ctDNA-unique mutations. Those TDMs were mapped to 10 of 20 CRC genes, with APC and TP53 accounting for those most frequently mutated. The majority of identified TDMs had low occurrences, demonstrating the interindividual heterogeneity of early-stage tumors. Noticeably, we identified one TDM, a silent mutation mapped to KMT2D, that was recurrently detected in 15 CRC patients. Despite being a nonsynonymous mutation, this TDMis located at the end of exon 40 of KMT2D, suggesting that it possibly alters splicing regulatory sites, mRNA stability and miRNA binding sites, thus might be related to tumorigenesis (39). Thus, future studies, using larger sample sizes, might be required to confirm the tumor origin, as well as the functional role(s) of this potential “hotspot” TDM.
Ocular manifestations in kabuki syndrome: A report of 10 cases and literature review
Published in Ophthalmic Genetics, 2021
Chong Kun Cheon, Hee Young Choi, Su Hwan Park, Jae Ho Jung, Su Jin Kim
Genetic testing was performed by whole-exome sequencing in 10 patients suspected of having KS. Mutations in the KMT2D gene were identified in all of the 10 patients with KS. All mutations detected in the KMT2D gene were de novo mutations. These 10 mutations included four small deletions or insertions causing frameshifts (Patients 3 (P3), 5, 8, and 10), three nonsense mutations (P2, 6, and 7), one missense mutation (P1), and a novel splice-site mutation (P4). A novel deletion or duplication mutation was identified in two patients (P5 and 9). However, no deletion or point mutation was found in the KDM6A gene.