Annual Review of Cancer Biology - Volume 3, 2019

Disease recurrence following cancer therapy remains an intractable clinical problem and represents a major impediment to reducing the mortality attributable to malignant tumors. While research has traditionally focused on the cell-intrinsic mechanisms and mutations that render tumors refractory to both classical chemotherapeutics and targeted therapies, recent studies have begun to uncover myriad roles for the tumor microenvironment (TME) in modulating therapeutic efficacy. This work suggests that drug resistance is as much ecological as it is evolutionary. Specifically, cancers resident in organs throughout the body do not develop in isolation. Instead, tumor cells arise in the context of nonmalignant cellular components of a tissue. While the roles of these cell-extrinsic factors in cancer initiation and progression are well established, our understanding of the TME's influence on therapeutic outcome is in its infancy. Here, we focus on mechanisms by which neoplastic cells co-opt preexisting or treatment-induced signaling networks to survive chemotherapy.

Genomic analyses of diffuse large B cell lymphoma (DLBCL) are revealing the genetic and phenotypic heterogeneity of these aggressive lymphomas. In part, this heterogeneity reflects the existence of distinct genetic subtypes that acquire characteristic constellations of somatic genetic alterations to converge on the DLBCL phenotype. In parallel, functional genomic screens and proteomic analyses have identified multiprotein assemblies that coordinate oncogenic survival signaling in DLBCL. In this review, we merge these recent insights into a unified conceptual framework with implications for the design of precision medicine trials in DLBCL.

Fanconi anemia (FA) is a complex genetic disorder characterized by bone marrow failure (BMF), congenital defects, inability to repair DNA interstrand cross-links (ICLs), and cancer predisposition. FA presents two seemingly opposite characteristics: (a) massive cell death of the hematopoietic stem and progenitor cell (HSPC) compartment due to extensive genomic instability, leading to BMF, and (b) uncontrolled cell proliferation leading to FA-associated malignancies. The canonical function of the FA proteins is to collaborate with several other DNA repair proteins to eliminate clastogenic (chromosome-breaking) effects of DNA ICLs. Recent discoveries reveal that the FA pathway functions in a critical tumor-suppressor network to preserve genomic integrity by stabilizing replication forks, mitigating replication stress, and regulating cytokinesis. Homozygous germline mutations (biallelic) in 22 FANC genes cause FA, whereas heterozygous germline mutations in some of the FANC genes (monoallelic), such as BRCA1 and BRCA2, do not cause FA but significantly increase cancer susceptibility sporadically in the general population. In this review, we discuss our current understanding of the functions of the FA pathway in the maintenance of genomic stability, and we present an overview of the prevalence and clinical relevance of somatic mutations in FA genes.