FaMMily Affairs: Dissecting inherited contributions to multiple myeloma risk.

Etiological links to multiple myeloma (MM) remain poorly understood, though emerging evidence suggests a significant hereditary component. This review integrates current literature on inherited factors contributing to MM risk, synthesizing both epidemiologic and genomic data. We examine familial clustering patterns, assess genome-wide association studies (GWAS) that reveal common genetic variants linked to MM, and explore rare, high-penetrance variants in key susceptibility genes.

An imbalance between proliferation and differentiation underlies the development of microRNA-defective pineoblastoma.

Mutations in the microRNA processing genes and drive several cancers that resemble embryonic progenitors. To understand how microRNAs regulate tumorigenesis, we ablated or in the developing pineal gland to emulate the pathogenesis of pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. Accordingly, these mice develop pineal tumors marked by loss of microRNAs, including the let-7/miR-98-5p family, and de-repression of microRNA target genes.

Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics.

Recent studies show that rare, deleterious variants (RDVs) in certain genes are critical determinants of heritable cancer risk. To more comprehensively understand RDVs, we performed the largest-to-date germline variant calling analysis in a case-control setting for a multi-cancer association study from whole-exome sequencing data of 20,789 participants, split into discovery and validation cohorts. We confirm and extend known associations between cancer risk and germline RDVs in specific gene-sets, including DNA repair (OR = 1.

Biallelic TET2 mutations confer sensitivity to 5'-azacitidine in acute myeloid leukemia.

Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza.

Inherited cancer predisposing mutations in patients with therapy-related myeloid neoplasms.

Some patients with therapy-related myeloid neoplasms (t-MN) may have unsuspected inherited cancer predisposition syndrome (CPS). We propose a set of clinical criteria to identify t-MN patients with high risk of CPS (HR-CPS). Among 225 t-MN patients with an antecedent non-myeloid malignancy, our clinical criteria identified 52 (23%) HR-CPS patients.

Prediction of breast cancer risk based on flow variant analysis of circulating peripheral blood mononuclear cells.

Identifying women at high risk for developing breast cancer is potentially lifesaving. Patients with pathogenic genetic variants can embark on a program of surveillance for early detection, chemoprevention, and/or prophylactic surgery. Newly diagnosed cancer patients can also use the results of gene panel sequencing to make decisions about surgery; therefore, rapid turnaround time for results is critical.

Patient similarity network of newly diagnosed multiple myeloma identifies patient subgroups with distinct genetic features and clinical implications.

The remarkable genetic heterogeneity of multiple myeloma poses a substantial challenge for proper prognostication and clinical management of patients. Here, we introduce MM-PSN, the first multiomics patient similarity network of myeloma. MM-PSN enabled accurate dissection of the genetic and molecular landscape of the disease and determined 12 distinct subgroups defined by five data types generated from genomic and transcriptomic profiling of 655 patients.

Novel genetic variants associated with mortality after unrelated donor allogeneic hematopoietic cell transplantation.

Background: Identification of non-human leukocyte antigen (HLA) genetic risk factors could improve survival after allogeneic blood or marrow transplant (BMT) through matching at additional loci or individualizing risk prediction. We hypothesized that non-HLA loci contributed significantly to 1-year overall survival (OS), disease related mortality (DRM) or transplant related mortality (TRM) after unrelated donor (URD)BMT.

Methods: We performed a genome-wide association study (GWAS) in 2,887 acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and their ≥8/8 HLA-matched URDs comprising two independent cohorts treated from 2000-2011.

Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56CD57 natural killer (NK) cells and exhausted CD8 T cells.

The Functional Hallmarks of Cancer Predisposition Genes.

The canonical model for hereditary cancer predisposition is a cancer predisposition gene (CPG) that drives either one or both of two fundamental hallmarks of cancer, defective genomic integrity and deregulated cell proliferation, ultimately resulting in the accumulation of mutations within cells. Thus, the genes most commonly associated with cancer-predisposing genetic syndromes are tumor suppressor genes that regulate DNA repair (eg, genes) and/or cell cycle (eg, ). In recent years, however, the spectrum of high-penetrance CPGs has expanded considerably to include genes in non-canonical pathways such as oncogenic signaling, metabolism, and protein translation.

Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study.

Bilirubin, an endogenous antioxidant, may play a protective role in cancer development. We applied two-sample Mendelian randomization to investigate whether genetically raised bilirubin levels are causally associated with the risk of ten cancers (pancreas, kidney, endometrium, ovary, breast, prostate, lung, Hodgkin's lymphoma, melanoma, and neuroblastoma). The number of cases and their matched controls of European descent ranged from 122,977 and 105,974 for breast cancer to 1200 and 6417 for Hodgkin's lymphoma, respectively.

Functional Common and Rare Germline Variants Cooperate in Familial and Sporadic Cancer Susceptibility.

We investigated a Spanish and Catalan family in which multiple cancer types tracked across three generations, but for which no genetic etiology had been identified. Whole-exome sequencing of germline DNA from multiple affected family members was performed to identify candidate variants to explain this occurrence of familial cancer. We discovered in all cancer-affected family members a single rare heterozygous germline variant (I654V, rs1801201) in , which is located in a transmembrane glycine zipper motif critical for ERBB2-mediated signaling and in complete linkage disequilibrium (' = 1) with a common polymorphism (I655V, rs1136201) previously reported in some populations as associated with cancer risk.

Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).

Initially, children were thought to be spared from disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a month into the epidemic, a novel multisystem inflammatory syndrome in children (MIS-C) emerged. Herein, we report on the immune profiles of nine MIS-C cases.

Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and multiple organ involvement in individuals under 21 years following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To identify genes, pathways and cell types driving MIS-C, we sequenced the blood transcriptomes of MIS-C cases, pediatric cases of coronavirus disease 2019, and healthy controls. We define a MIS-C transcriptional signature partially shared with the transcriptional response to SARS-CoV-2 infection and with the signature of Kawasaki disease, a clinically similar condition.

Inherited Rare, Deleterious Variants in ATM Increase Lung Adenocarcinoma Risk.

Introduction: Lung cancer is the leading cause of cancer deaths in the world, and lung adenocarcinoma (LUAD) is its most prevalent subtype. Symptoms are often found in advanced disease in which treatment options are limited. Identifying genetic risk factors will enable better identification of high-risk individuals.

Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).

Initially, the global outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spared children from severe disease. However, after the initial wave of infections, clusters of a novel hyperinflammatory disease have been reported in regions with ongoing SARS-CoV-2 epidemics. While the characteristic clinical features are becoming clear, the pathophysiology remains unknown.

Precision oncology: lessons learned and challenges for the future.

The decreasing cost of and increasing capacity of DNA sequencing has led to vastly increased opportunities for population-level genomic studies to discover novel genomic alterations associated with both Mendelian and complex phenotypes. To translate genomic findings clinically, a number of health care institutions have worked collaboratively or individually to initiate precision medicine programs. These precision medicine programs involve designing patient enrollment systems, tracking electronic health records, building biobank repositories, and returning results with actionable matched therapies.