Identification and Validation of a Previously Missed Mutational Signature in Colorectal Cancer.

Mutational signature analysis has greatly enhanced our understanding of the mutagenic processes found in cancer and normal tissues. As part of a recent study, we analyzed 802 treatment-naïve, microsatellite-stable colorectal cancers (CRC) and identified a signature, SBS_D, which was conservatively decomposed into SBS18, a signature associated with reactive oxygen species. Here, we re-evaluate this decomposition and provide evidence that SBS_D represents a distinct mutational process from that of SBS18.

The long-term effects of chemotherapy on normal blood cells.

Several chemotherapeutic agents act by increasing DNA damage in cancer cells, triggering cell death. However, there is limited understanding of the extent and long-term consequences of collateral DNA damage in normal tissues. To investigate the impact of chemotherapy on mutation burdens and the cell population structure of normal tissue, we sequenced blood cell genomes from 23 individuals aged 3-80 years who were treated with a range of chemotherapy regimens.

High resolution clonal architecture of hypomutated Wilms tumours.

A paradigm of childhood cancers is that they have a low mutation burden, with some ostensibly bearing fewer mutations than the normal tissues from which they derive. We set out to resolve this paradox by examining paediatric renal cancers with exceptionally few mutations using high resolution, high depth sequencing approaches. We find that apparent hypomutation is the result of unusual clonal architecture due to a normal tissue-like mode of tumour evolution, raising the possibility that the mutation burden of some cancers has been systematically misjudged.

Geographic and age variations in mutational processes in colorectal cancer.

Incidence rates of colorectal cancer vary geographically and have changed over time. Notably, in the past two decades, the incidence of early-onset colorectal cancer, which affects individuals below 50 years of age, has doubled in many countries. The reasons for this increase are unknown.

Horizontal transfer of nuclear DNA in transmissible cancer.

Horizontal transfer of nuclear DNA between cells of host and cancer is a potential source of adaptive variation in cancer cells. An understanding of the frequency and significance of this process in naturally occurring tumors is, however, lacking. We screened for this phenomenon in the transmissible cancers of dogs and Tasmanian devils and found an instance in the canine transmissible venereal tumor (CTVT).

The complexity of tobacco smoke-induced mutagenesis in head and neck cancer.

Tobacco smoke, alone or combined with alcohol, is the predominant cause of head and neck cancer (HNC). We explore how tobacco exposure contributes to cancer development by mutational signature analysis of 265 whole-genome sequenced HNC samples from eight countries. Six tobacco-associated mutational signatures were detected, including some not previously reported.

The somatic mutation landscape of normal gastric epithelium.

The landscapes of somatic mutation in normal cells inform us about the processes of mutation and selection operative throughout life, providing insight into normal ageing and the earliest stages of cancer development. Here, by whole-genome sequencing of 238 microdissections from 30 individuals, including 18 with gastric cancer, we elucidate the developmental trajectories of normal and malignant gastric epithelium. We find that gastric glands are units of monoclonal cell populations that accrue roughly 28 somatic single-nucleotide variants per year, predominantly attributable to endogenous mutational processes.

Geographic and age-related variations in mutational processes in colorectal cancer.

Colorectal cancer incidence rates vary geographically and have changed over time. Notably, in the past two decades, the incidence of early-onset colorectal cancer, affecting individuals under the age of 50 years, has doubled in many countries. The reasons for this increase are unknown.

Prolonged persistence of mutagenic DNA lesions in somatic cells.

DNA is subject to continual damage, leaving each cell with thousands of individual DNA lesions at any given moment. The efficiency of DNA repair means that most known classes of lesion have a half-life of minutes to hours, but the extent to which DNA damage can persist for longer durations remains unknown. Here, using high-resolution phylogenetic trees from 89 donors, we identified mutations arising from 818 DNA lesions that persisted across multiple cell cycles in normal human stem cells from blood, liver and bronchial epithelium.

Implementing Mutational Epidemiology on a Global Scale: Lessons from Mutographs.

The Mutographs Cancer Grand Challenge team aimed to discover unknown causes of cancer through mutational epidemiology, an alliance of cancer epidemiology and somatic genomics. By generating whole-genome sequences from thousands of cancers and normal tissues from more than 30 countries on five continents, it discovered unsuspected mutagenic exposures affecting millions of people, raised the possibility that some carcinogens act by altering forces of selection in tissue microenvironments rather than by mutagenesis, and demonstrated changes to the direction of somatic evolution in normal cells of the human body in response to exogenous exposures and noncancer diseases. See related article by Bressan et al.

The genomic and clinical consequences of replacing procarbazine with dacarbazine in escalated BEACOPP for Hodgkin lymphoma: a retrospective, observational study.

Background: Procarbazine-containing chemotherapy regimens are associated with cytopenias and infertility, suggesting stem-cell toxicity. When treating Hodgkin lymphoma, procarbazine in escalated-dose bleomycin-etoposide-doxorubicin-cyclophosphamide-vincristine-procarbazine-prednisolone (eBEACOPP) is increasingly replaced with dacarbazine (eBEACOPDac) to reduce toxicity. We aimed to investigate the impact of this drug substitution on the mutation burden in stem cells, patient survival, and toxicity.

Geographical variation in the incidence of colorectal cancer and urinary tract cancer is associated with population exposure to colibactin-producing Escherichia coli.

Biomedical research has implicated the bacterial metabolite colibactin as a causal risk factor for several cancer types, in particular, colorectal cancer. Colibactin has been known to drive tumorigenesis by inducing double-strand breaks in the DNA of epithelial cells exposed to colibactin-producing bacteria. Some phylogroup B2 Escherichia coli secrete colibactin during interbacterial warfare, concomitantly exposing the host to an increasing risk of DNA damage.

Protocol for a non-surgical model of perineural invasion for assessing neural drivers of cancer aggressiveness in mice.

Perineural invasion (PNI) is a significant risk factor for cancer recurrence and metastasis; however, its mechanisms relating to cancer aggressiveness remain poorly understood. Here, we present a protocol for a non-surgical model of PNI in mice using a neurotropic melanoma cell line that migrates from the skin to the sciatic nerve. We describe the steps for cell culture and injection, tumor burden measurements, mouse euthanasia, and tissue dissection.

A case report of successful bedside needle decompression in the management of tension pneumoperitoneum secondary to colonic perforated colonic Pseudo-obstruction.

Introduction And Importance: Pneumoperitoneum is a well-known consequence of gastrointestinal perforations but can also be a consequence of medical diseases such as asthma exacerbations or interventions such as mechanical ventilation. Tension pneumoperitoneum is a rare, life-threatening form of large volume pneumoperitoneum that can cause cardiovascular and respiratory compromise due to increased intra-abdominal pressure.

Case Presentation: We present a case report where an 86-year-old male was diagnosed with large volume pneumoperitoneum with compression of the inferior vena cava and intra-abdominal hollow and solid organs due to a suspected splenic flexure perforation in the setting of an acute colonic pseudo-obstruction that was able to be successfully managed solely with bedside needle decompression.

Extracorporeal Cardiopulmonary Resuscitation: CME Review.

Extracorporeal cardiopulmonary resuscitation (eCPR) is increasingly being used for refractory cardiac arrest for both in-hospital and out-of-hospital cardiac arrests. The term eCPR refers to cannulating a patient to an extracorporeal membrane oxygenation (ECMO) circuit to provide perfusion after cardiac arrest refractory to standard cardiopulmonary resuscitation. Extracorporeal cardiopulmonary resuscitation has been shown to offer increased survival benefit among a select group of adult and pediatric patients experiencing refractory cardiac arrests, both in hospital and out of hospital.

The Complexity of Tobacco Smoke-Induced Mutagenesis in Head and Neck Cancer.

Tobacco smoke, alone or combined with alcohol, is the predominant cause of head and neck cancer (HNC). Here, we further explore how tobacco exposure contributes to cancer development by mutational signature analysis of 265 whole-genome sequenced HNC from eight countries. Six tobacco-associated mutational signatures were detected, including some not previously reported.

Geographic variation of mutagenic exposures in kidney cancer genomes.

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations.

Bias between capnometry and venous carbon dioxide during initial assessment of pediatric emergency department patients: A video-based study.

Objective: The bias of capnometry (ETCO) and venous carbon dioxide (vpCO) among pediatric emergency department (PED) patients triaged to critical care areas is unknown. We aimed to explore correlations and bias between ETCO and vpCO¸and identify predictors of bias.

Methods: This was an observational, video-based, retrospective study comparing ETCO and vpCO.

Reconstructing phylogenetic trees from genome-wide somatic mutations in clonal samples.

Phylogenetic trees are a powerful means to display the evolutionary history of species, pathogens and, more recently, individual cells of the human body. Whole-genome sequencing of laser capture microdissections or expanded stem cells has allowed the discovery of somatic mutations in clones, which can be used as natural barcodes to reconstruct the developmental history of individual cells. Here we describe Sequoia, our pipeline to reconstruct lineage trees from clones of normal cells.

The Mutographs biorepository: A unique genomic resource to study cancer around the world.

Large-scale biorepositories and databases are essential to generate equitable, effective, and sustainable advances in cancer prevention, early detection, cancer therapy, cancer care, and surveillance. The Mutographs project has created a large genomic dataset and biorepository of over 7,800 cancer cases from 30 countries across five continents with extensive demographic, lifestyle, environmental, and clinical information. Whole-genome sequencing is being finalized for over 4,000 cases, with the primary goal of understanding the causes of cancer at eight anatomic sites.

Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment.

Motivation: Analysis of mutational signatures is a powerful approach for understanding the mutagenic processes that have shaped the evolution of a cancer genome. To evaluate the mutational signatures operative in a cancer genome, one first needs to quantify their activities by estimating the number of mutations imprinted by each signature.

Results: Here we present SigProfilerAssignment, a desktop and an online computational framework for assigning all types of mutational signatures to individual samples.

Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment.

Analysis of mutational signatures is a powerful approach for understanding the mutagenic processes that have shaped the evolution of a cancer genome. Here we present SigProfilerAssignment, a desktop and an online computational framework for assigning all types of mutational signatures to individual samples. SigProfilerAssignment is the first tool that allows both analysis of copy-number signatures and probabilistic assignment of signatures to individual somatic mutations.