Molecular Subtypes and the Role of TP53 in Diffuse Large B-Cell Lymphoma and Richter Syndrome.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and a heterogeneous entity comprised of several biologically distinct subtypes. Recently, novel genetic classifications of DLBCL have been resolved based on common mutational patterns indicative of distinct pathways of transformation. However, the complicated and costly nature of the novel classifiers has precluded their inclusion into routine practice. In view of this, the status of the TP53 gene, which is mutated or deleted in 20-30% of the cases, has emerged as an important prognostic factor for DLBCL patients, setting itself apart from other predictors. TP53 genetic lesions are particularly enriched in a genetic subtype of DLBCL that shares genomic features with Richter Syndrome, highlighting the possibility of a subset of DLBCL arising from the transformation of an occult chronic lymphocytic leukemia-like malignancy, such as monoclonal B-cell lymphocytosis. Patients with TP53-mutated DLBCL, including those with Richter Syndrome, have a particularly poor prognosis and display inferior responses to standard chemoimmunotherapy regimens. The data presented in this manuscript argue for the need for improved and more practical risk-stratification models for patients with DLBCL and show the potential for the use of TP53 mutational status for prognostication and, in prospect, treatment stratification in DLBCL.

Refining PRRSV-2 genetic classification based on global ORF5 sequences and investigation of their geographic distributions and temporal changes.

IMPORTANCE: In this study, comprehensive analysis of 82,237 global porcine reproductive and respiratory syndrome virus type 2 (PRRSV-2) open reading frame 5 sequences spanning from 1989 to 2021 refined PRRSV-2 genetic classification system, which defines 11 lineages and 21 sublineages and provides flexibility for growth if additional lineages, sublineages, or more granular classifications are needed in the future. Geographic distribution and temporal changes of PRRSV-2 were investigated in detail. This is a thorough study describing the molecular epidemiology of global PRRSV-2. In addition, the reference sequences based on the refined genetic classification system are made available to the public for future epidemiological and diagnostic applications worldwide. The data from this study will facilitate global standardization and application of PRRSV-2 genetic classification.

Genetic, Phenotypic, and Clinical Heterogeneity of NPM1-Mutant Acute Myeloid Leukemias.

The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. AML with mutated nucleophosmin 1 (NPM1-mut) is the largest of the genetically defined groups, involving about 30% of adult AMLs and is currently recognized as a distinct entity in the actual AML classifications. NPM1-mut AML usually occurs in de novo AML and is associated predominantly with a normal karyotype and relatively favorable prognosis. However, NPM1-mut AMLs are genetically, transcriptionally, and phenotypically heterogeneous. Furthermore, NPM1-mut is a clinically heterogenous group. Recent studies have in part clarified the consistent heterogeneities of these AMLs and have strongly supported the need for an additional stratification aiming to improve the therapeutic response of the different subgroups of NPM1-mut AML patients.

Genome-wide analysis suggests multiple domestication events of Chinese local pigs.

Chinese local pigs have abundant phenotypes as a result of different cultures and habits of Chinese populations, geographic constraints and the long history of pig domestication. A comprehensive investigation of local Chinese pigs will benefit biodiversity research and future breeding practices. However, their classification and demographic history are not yet clear. We studied 91 Chinese local pigs from 14 breeds and 15 Chinese wild boars to reveal the dispersal of Chinese pigs, genetic groups and the demographic history. Based on spatial feature analyses, we believe that the geographic landscape played an important role in the dispersal of local pigs. According to genetic studies, Chinese pigs are divided into three groups where each group appears to have a distinct background. The nucleotide diversity, observed heterozygosity, runs of homozygosity and inbreeding coefficient varied among the groups and widespread migration also existed between the groups. Furthermore, demographic models have been constructed to explain the evolutionary relationship between the groups using the approximate Bayesian computation approach. These suggested that Chinese local pigs are inherited from an extinct Sus scrofa population from ~22 000 years ago. Then, the three groups diverged from ancestors ~16 000, ~11 000 and ~8700 years ago respectively. This study advances our understanding of the genetic variation and demographic history of Chinese local pigs.

Genetic subtype classification using a simplified algorithm and mutational characteristics of diffuse large B-cell lymphoma in a Japanese cohort.

Recent large-scale genetic studies have proposed a new genetic classification of diffuse large B-cell lymphoma (DLBCL), which is clinically and biologically heterogeneous. However, the classification methods were complicated to be introduced into clinical practice. Here we retrospectively evaluated the mutational status and copy number changes of 144 genes in 177 Japanese patients with DLBCL, using targeted DNA sequencing. We developed a simplified algorithm for classifying four genetic subtypes-MYD88, NOTCH2, BCL2, and SGK1-by assessing alterations in 18 representative genes and BCL2 and BCL6 rearrangement status, integrating the significant genes from previous studies. In our cohort and another validation cohort from published data, the classification results in our algorithm showed close agreement with the other established algorithm. A differential prognosis among the four groups was observed. The NOTCH2 group showed a particularly poorer outcome than similar groups in previous reports. Furthermore, our study revealed unreported genetic features in the DLBCL subtypes that are mainly reported in Japanese patients, such as CD5-positive DLBCL and methotrexate-associated lymphoproliferative disorders. These results indicate the utility of our simplified method for DLBCL genetic subtype classification, which can facilitate the optimisation of treatment strategies. In addition, our study highlights the genetic features of Japanese patients with DLBCL.

Prognostic Implications of MRI Melanin Quantification and Cytogenetic Abnormalities in Liver Metastases of Uveal Melanoma.

To evaluate the prognostic implications of melanin quantification assessed by magnetic resonance imaging (MRI) with respect to the clinical, pathological, and genetic features of liver metastases of uveal melanoma (LMUM). This single-center retrospective cohort study included 63 patients eligible for margin-free resection of LMUM between 2007 and 2018. Comparative genomic hybridization of resected liver metastases on microarrays was performed for genetic risk classification. Metastases exhibiting monosomy 3 with any type of gain of chromosome 8 (M3/8g) were considered high-genetic-risk. MRI melanin quantification using the mean T1 signal (mT1s) in liver metastases was assessed quantitatively on preoperative imaging examination and compared to that of gross pathological evaluation. The association between MRI melanin quantification and overall survival (OS) was assessed by multivariate analysis using the Cox proportional hazards model. Gross pathological assessment of melanin content and MRI melanin quantification were strongly correlated (r = 0.8, p < 0.001). Independent prognostic factors associated with OS were disease-free interval ≤ 24 months (HR = 3.1; 95% CI, 1.6-6.0; p < 0.001), high-genetic-risk (HR = 2.2; 95% CI, 1.1-4.8; p = 0.04), mT1s > 1.1 (HR = 2.3; 95% CI, 1.2-4.7; p = 0.019), and complete hepatic resection (HR = 0.3; 95% CI, 0.2-0.7; p = 0.004). In patients with high-genetic-risk, mT1s showed a significant association with OS (HR = 3.7; 95% CI, 1.5-9.3; p = 0.006). The median OS was 17.5 months vs. 27 months for >1.1 and ≤1.1 mT1s tumors, respectively (p = 0.003). We showed that the level of pigmentation in M3/8g LMUM identified two subsets that were correlated with distinct clinical outcomes.

[Triple-negative breast cancer. Modern molecular genetic concepts and their clinical significance]. / Troinoi negativnyi rak molochnoi zhelezy. Sovremennye molekulyarno-geneticheskie predstavleniya i ikh klinicheskoe znachenie.

Triple negative breast cancer (BC) is a heterogeneous group of carcinomas that substantially differ in clinical, morphological, and molecular genetic characteristics, tumor response to chemotherapy, and prognosis. These features define triple negative BC today as a special clinical problem that has not yet been completely solved. The review is devoted to the description and systematization of the currently available literature data concerning molecular and genetic features and differences in a fairly significant group of breast carcinomas with a severe, aggressive course and an extremely poor prognosis. The review presents the existing molecular genetic classification of triple negative BC based on the results of studies conducted by M.D. Burstein (2015) and B.D. Lehmann (2016), which determines the presence of 4 tumor-specific subtypes: basal-like type (type 1 and type 2), mesenchymal, and luminal androgen receptor types. The paper reflects the main stages of transformation of the proposed classification over the past decade and an attempt has been make to describe the molecular characteristics of each subtype of these carcinomas.

Urinary shedding of leptospires in palearctic bats.

Leptospirosis is a bacterial zoonotic infection of worldwide occurrence. Bats, like other mammalian reservoirs, may be long-term carriers that maintain endemicity of infection and shed viable leptospires in urine. Direct and/or indirect contact with these Leptospira shedders is the main risk factor as regards public health concern. However, knowledge about bat leptospirosis in the Palearctic Region, and in Europe in particular, is poor. We collected urine from 176 specimens of 11 bat species in the Czech Republic, Poland, Republic of Armenia and the Altai Region of Russia between 2014 and 2019. We extracted DNA from the urine samples to detect Leptospira spp. shedders using PCR amplification of the 16S rRNA and LipL32 genes. Four bat species (Barbastella barbastellus n = 1, Myotis bechsteinii n = 1, Myotis myotis n = 24 and Myotis nattereri n = 1) tested positive for Leptospira spp., with detected amplicons showing 100% genetic identity with pathogenic Leptospira interrogans. The site- and species-specific prevalence range was 0%-24.1% and 0%-20%, respectively. All bats sampled in the Republic of Armenia and Russia were negative. Given the circulation of pathogenic leptospires in strictly protected Palearctic bat species and their populations, non-invasive and non-lethal sampling of urine for molecular Leptospira spp. detection is recommended as a suitable surveillance and monitoring strategy. Moreover, our results should raise awareness of this potential disease risk among health professionals, veterinarians, chiropterologists and wildlife rescue workers handling bats, as well as speleologists and persons cleaning premises following bat infestation.

New agents and regimens for diffuse large B cell lymphoma.

As a widely recognized standard regimen, R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is able to cure two-thirds patients with diffuse large B cell lymphoma (DLBCL), and the remaining patients suffer from refractory or relapsed disease due to resistance to R-CHOP and fare poorly. Unsatisfied outcomes for those relapsed/refractory patients prompted efforts to discover new treatment approaches for DLBCL, including chimeric antigen receptor T cells, bispecific T cell engagers, immunomodulatory drugs, immune checkpoint inhibitors, monoclonal antibodies, antibody-drug conjugates, molecular pathway inhibitors, and epigenetic-modifying drugs. Herein, up-to-date data about the most promising treatment approaches for DLBCL are recapitulated, and novel genetic classification systems are introduced to guide individualized treatment for DLBCL.

Automated apparent diffusion coefficient analysis for genotype prediction in lower grade glioma: association with the T2-FLAIR mismatch sign.

PURPOSE: The prognosis of lower grade glioma (LGG) patients depends (in large part) on both isocitrate dehydrogenase (IDH) gene mutation and chromosome 1p/19q codeletion status. IDH-mutant LGG without 1p/19q codeletion (IDHmut-Noncodel) often exhibit a unique imaging appearance that includes high apparent diffusion coefficient (ADC) values not observed in other subtypes. The purpose of this study was to develop an ADC analysis-based approach that can automatically identify IDHmut-Noncodel LGG. METHODS: Whole-tumor ADC metrics, including fractional tumor volume with ADC > 1.5 × 10-3mm2/s (VADC>1.5), were used to identify IDHmut-Noncodel LGG in a cohort of N = 134 patients. Optimal threshold values determined in this dataset were then validated using an external dataset containing N = 93 cases collected from The Cancer Imaging Archive. Classifications were also compared with radiologist-identified T2-FLAIR mismatch sign and evaluated concurrently to identify added value from a combined approach. RESULTS: VADC>1.5 classified IDHmut-Noncodel LGG in the internal cohort with an area under the curve (AUC) of 0.80. An optimal threshold value of 0.35 led to sensitivity/specificity = 0.57/0.93. Classification performance was similar in the validation cohort, with VADC>1.5 ≥ 0.35 achieving sensitivity/specificity = 0.57/0.91 (AUC = 0.81). Across both groups, 37 cases exhibited positive T2-FLAIR mismatch sign-all of which were IDHmut-Noncodel. Of these, 32/37 (86%) also exhibited VADC>1.5 ≥ 0.35, as did 23 additional IDHmut-Noncodel cases which were negative for T2-FLAIR mismatch sign. CONCLUSION: Tumor subregions with high ADC were a robust indicator of IDHmut-Noncodel LGG, with VADC>1.5 achieving > 90% classification specificity in both internal and validation cohorts. VADC>1.5 exhibited strong concordance with the T2-FLAIR mismatch sign and the combination of both parameters improved sensitivity in detecting IDHmut-Noncodel LGG.

Increased intratumoral infiltration in IDH wild-type lower-grade gliomas observed with diffusion tensor imaging.

PURPOSE: Diffuse lower grade gliomas (LGG) with isocitrate dehydrogenase (IDH) gene mutations (IDHMUT) have a distinct survival advantage compared with IDH wild-type (IDHWT) cases but the mechanism underlying this disparity is not well understood. Diffusion Tensor Imaging (DTI) has identified infiltrated non-enhancing tumor regions that are characterized by low isotropic (p) and high anisotropic (q) diffusion tensor components that associate with poor survival in glioblastoma. We hypothesized that similar regions are more prevalent in IDHWT (vs. IDHMUT) LGG. METHODS: p and q maps were reconstructed from preoperative DTI scans in N = 41 LGG patients with known IDH mutation and 1p/19q codeletion status. Enhancing and non-enhancing tumor volumes were autosegmented from standard (non-DTI) MRI scans. Percentage non-enhancing tumor volumes exhibiting low p and high q (Vinf) were then determined using threshold values (p = 2 × 10-3mm2/s, q = 3 × 10-4 mm2/s) and compared between IDHWT and IDHMUT LGG, and between IDHMUT LGG with and without 1p/19q codeletion. RESULTS: Vinf volumes were significantly larger in IDHWT LGG than in IDHMUT LGG (35.4 ± 18.3% vs. 15.9 ± 7.6%, P < 0.001). Vinf volumes did not significantly differ between IDHMUT LGG with and without 1p/19q codeletion (17.1 ± 9.5% vs. 14.8 ± 5.8%, P = 1.0). CONCLUSION: IDHWT LGG exhibited larger volumes with suppressed isotropic diffusion (p) and high anisotropic diffusion (q) which reflects regions with increased cell density but non-disrupted neuronal structures. This may indicate a greater prevalence of infiltrative tumor in IDHWT LGG.

Molecular genetic classification in Prader-Willi syndrome: a multisite cohort study.

BACKGROUND: Prader-Willi syndrome (PWS) is due to errors in genomic imprinting. PWS is recognised as the most common known genetic cause of life-threatening obesity. This report summarises the frequency and further characterises the PWS molecular classes and maternal age effects. METHODS: High-resolution microarrays, comprehensive chromosome 15 genotyping and methylation-specific multiplex ligation probe amplification were used to describe and further characterise molecular classes of maternal disomy 15 (UPD15) considering maternal age. RESULTS: We summarised genetic data from 510 individuals with PWS and 303 (60%) had the 15q11-q13 deletion; 185 (36%) with UPD15 and 22 (4%) with imprinting defects. We further characterised UPD15 findings into subclasses based on the presence (size, location) or absence of loss of heterozygosity (LOH). Additionally, significantly older mothers (mean age=32.5 years vs 27.7 years) were found in the UPD15 group (n=145) compared with the deletion subtype (n=200). CONCLUSIONS: We report on molecular classes in PWS using advanced genomic technology in the largest cohort to date. LOH patterns in UPD15 may impact the risk of having a second genetic condition if the mother carries a recessive mutant allele in the isodisomic region on chromosome 15. The risk of UPD15 may also increase with maternal age.

Genetic classification of Aegilops columnaris Zhuk. (2n=4x=28, UcUcXcXc) chromosomes based on FISH analysis and substitution patterns in common wheat × Ae. columnaris introgressive lines.

Aegilops columnaris is a tetraploid species originated from Ae. umbellulata (2n=2x=14, UU) and a yet unknown diploid grass species. Although Ae. columnaris possesses some agronomically valuable traits, such as heat and drought tolerance and resistance to pests, it has never been used in wheat breeding because of difficulties in producing hybrids and a lack of information on the relationships between Ae. columnaris and common wheat chromosomes. In this paper, we report the development of 57 wheat - Ae. columnaris introgressive lines covering 8 of the14 chromosomes of Aegilops. Based on substitution spectra of hybrids and the results of FISH analysis of the parental Ae. columnaris line with seven DNA probes, we have developed the genetic nomenclature of the Uc and Xc chromosomes. Genetic groups and genome affinities were established for 11 of 14 chromosomes; the classification of the remaining three chromosomes remains unsolved. Each Ae. columnaris chromosome was characterized on the basis of C-banding pattern and the distribution of seven DNA sequences. Introgression processes were shown to depend on the parental wheat genotype and the level of divergence of homoeologous chromosomes. We found that lines carrying chromosome 5Xc are resistant to leaf rust; therefore, this chromosome could possess novel resistance genes that have never been utilized in wheat breeding.

Malignant mesenchymal tumors of the uterus - time to advocate a genetic classification.

INTRODUCTION: Sarcomas are rare uterine tumors with leiomyosarcomas and endometrial stromal sarcomas constituting the predominant entities often making their first appearance in young and middle-aged women. By histology combined with immunostaining alone some of these tumors can offer diagnostic challenges e.g. for the differential diagnosis between leiomyosarcomas and smooth muscle tumors of uncertain malignant potential (STUMP). Areas covered: Recent advances in the genetic classification and subclassification, respectively, have shown that genetic markers can offer a valuable adjunct to conventional diagnostic tools. Herein, we will review these recent data from the literature also referring to genetic alterations found in STUMP, endometrial stromal nodules, and leiomyomas including their variants. Expert commentary: For the future, we consider genetic classification as a necessary step in the clinical management of these tumors which will help not only to improve the diagnosis but also the therapy of these malignancies often associated with a worse prognosis.

Hyperhaploid uterine mesenchymal tumors-a novel genetic subgroup?

Hyperhaploid karyotypes have been described to occur in subsets of various solid tumors and leukemias. In these cases, monosomy is noted for most of the chromosomes while a few chromosomes still remain disomic. Evidence has emerged that at least in some tumor entities these remaining chromosomes are non-randomly selected. In addition, structural alterations can accompany the reduced chromosome number and secondary duplication of the chromosome complement is also a frequent finding. In this report, we describe hyperhaploidy in a case of an endometrial stromal nodule of a 50 year old woman who underwent hysterectomy because of symptomatic uterine fibroids. In addition, we review two other recently described cases of uterine mesenchymal tumors with that type of genetic alteration. Despite some histologic differences, striking similarities between these three cases exist with respect to the chromosomes were retained as disomic. Thus, the question arises if hyperhaploidy defines a novel genetic subgroup of uterine mesenchymal tumors.

Neuroendocrine Tumors of the Urinary Bladder According to the 2016 World Health Organization Classification: Molecular and Clinical Characteristics.

Neuroendocrine neoplasms of the urinary bladder are a rare type of tumor that account for a small percentage of urinary bladder neoplasms. These tumors of the urinary bladder range from well-differentiated neuroendocrine neoplasms (carcinoids) to the more aggressive subtypes such as small cell carcinoma. Despite the rarity of the neuroendocrine tumors of the bladder, there has been substantial investigation into the underlying genomic, molecular, and the cellular alterations within this group of neoplasms. Accordingly, these findings are increasingly incorporated into the understanding of clinical aspects of these neoplasms. In this review, we provide an overview of recent literature related to the 2016 World Health Organization Classification of Neuroendocrine Tumors of the Urinary Bladder. Particular emphasis is placed on molecular alterations and recently described gene expression. The neuroendocrine tumors of the urinary bladder are subdivided into four subtypes. Similar to their pulmonary and other extrapulmonary site counterparts, these have different degrees of neuroendocrine differentiation and morphological features. The clinical aspects of four subtypes of neuroendocrine tumor are discussed with emphasis of the most recent developments in diagnosis, treatment, and prognosis. An understanding of molecular basis of neuroendocrine tumors will provide a base of knowledge for future investigations into this group of unusual bladder neoplasms.

Significance of rat mammary tumors for human risk assessment.

We have previously indicated that the ideal animal tumor model should mimic the human disease. This means that the investigator should be able to ascertain the influence of host factors on the initiation of tumorigenesis, mimic the susceptibility of tumor response based on age and reproductive history, and determine the response of the tumors induced to chemotherapy. The utilization of experimental models of mammary carcinogenesis in risk assessment requires that the influence of ovarian, pituitary, and placental hormones, among others, as well as overall reproductive events are taken into consideration, since they are important modifiers of the susceptibility of the organ to neoplastic development. Several species, such as rodents, dogs, cats, and monkeys, have been evaluated for these purposes; however, none of them fulfills all the criteria specified previously. Rodents, however, are the most widely used models; therefore, this work will concentrate on discussing the rat rodent model of mammary carcinogenesis.

Phylogenetic characterization of VP6 gene (inner capsid) of porcine rotavirus C collected in Japan.

Porcine rotavirus C (RVC) has been often detected in sporadic cases or outbreaks of diarrhea in suckling and weaned pigs. Previous surveillance studies using both enzyme-linked immunosorbent assays and reverse-transcription polymerase chain reaction in some countries including Japan and the United States have demonstrated a high prevalence of porcine RVCs. In order to understand the phylogenetic relatedness of RVCs, we performed genetic analysis of VP6 gene encoding inner capsid protein by using 22 porcine RVC strains collected in Japan from 2002 to 2010. Comparative analyses of the VP6 nucleotide and amino acid sequences from these porcine RVCs exhibited lower sequence identities than those from human and bovine RVCs. The phylogenetic analysis of VP6 gene of RVC indicated the presence of seven clusters (tentatively assigned I1-I7) according to host species with cut-off values of 87% at the nucleotide level, and VP6 genes of porcine RVCs were divided into five genotypes. These findings indicate that multiple porcine RVC strains with distinctive genotypes are broadly spreading and circulating among farms in Japan. Our data may provide important insights in understanding evolutionary dynamics of RVCs.

The neuronal ceroid-lipofuscinoses: a historical introduction.

The neuronal ceroid-lipofuscinoses (Batten disease) collectively constitute one of the most common groups of inherited childhood onset neurodegenerative disorders, and have also been identified in many domestic and laboratory animals. The group of human neuronal ceroid-lipofuscinoses currently comprises 14 genetically distinct disorders, mostly characterised by progressive mental, motor and visual deterioration with onset in childhood or adolescence. Abnormal autofluorescent, electron-dense granules accumulate in the cytoplasm of nerve cells, and this storage process is associated with selective destruction and loss of neurons in the brain and retina. The present paper outlines nearly 200 years of clinical, neuropathological, biochemical and molecular genetic research, gradually leading, since 1995, to the identification of 13 different genes and over 360 mutations that underlie these devastating brain disorders and form the basis of a new classification system. These genes are evidently of vital importance for the normal development and maintenance of cerebral neurons. Elucidation of their functions and interactions in health and disease is a prerequisite for the identification of possible therapeutic targets, but may also further our understanding of the basic mechanisms of neurodegeneration and ageing. An account is also given of the development of international cooperation and free access electronic resources facilitating NCL research. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.