A massive undertaking involving more than 1,300 scientists from 37 countries reported in 23 papers shows the results of analyzing 47 million genetic changes in 2,600 genomes of 38 different tumor types. The Pan-Cancer Analysis of Whole Genomes (PCAWG) presented what the researchers called “the most comprehensive study of whole cancer genomes to date.”

Taking advantage of the latest sequencing and computational informatics technologies, the researchers, divided into 16 working groups, opened doors to the genetic complexities and commonalities in cancer, and offered insights that could spur further discoveries and eventual treatments.

PCAWG analyzed whole genomes rather than the more common approach of sequencing only protein-coding regions. They produced 1,188 tumor transcriptomes to link RNA and DNA alterations and explored genetic drivers, tumor signatures, and virus DNA found in cancers. These analyses generated more than 800 terabytes of data, roughly equivalent to the storage required for 200,000 movies.

PCAWG found cancer-driver mutations for 95% of cases, and that on average each cancer genome has four or five drivers. Sizable minorities of cancers showed signs of chromoplexy (17.8%) or chromothripsis (22.3%), reflecting complex and chaotic rearrangement processes. The researchers found that genetic changes leading to cancer occur early on—sometimes decades in advance of diagnosis.

The investigation also uncovered genetic drivers in noncoding DNA, like noncoding regions of the tumor-suppressor gene TP53 and of the telomerase gene TERT. Another PCAWG team characterized mutational signatures using more than 84 million somatic mutations from 4,645 whole-genome and 19,184 exome sequences to describe 81 signatures including single- doublet- and clustered-base-substitutions as well as small insertion-and-deletion signatures, many not previously identified. In a first, another team identified 16 structural variants involving large rearrangements.

An analysis of viruses associated with cancer highlighted the prevalence of Epstein–Barr virus, hepatitis B virus, and human papillomavirus.

All the PCAWG papers, published in Nature and related journals, are open access at nature.com/collections/afdejfafdb. The researchers’ raw genome sequencing data and other resources also are available to researchers.

Opioid Poisonings Worsening in Children, Adolescents

About one-quarter of opioid poisonings occur in children and adolescents, and poisoning incidents have become more severe in recent years, according to an abstract presented at the Society of Critical Care Medicine's annual congress. The retrospective study of more than 750,000 opioid poisoning cases reported to the National Poison Data System from 2005 to 2018 found that 27.5% (207,543) of cases occurred in patients younger than age 19.

Trend analysis over three eras (2005–2009, 2010–2014, and 2015–2018) showed that the percentage of patients admitted to critical care units and deaths increased over time; 6.6%, 8.5%, and 9.6% and 0.18%, 0.20%, and 0.28%, respectively. The probability of having a moderate or major effect also rose, by 0.55% and 0.11%, respectively.

Opioid poisonings with the intent of committing suicide increased over the three time periods, from 13.9% to 21.2%.

In a separate published report, the researchers said they observed two peak age distributions for opioid poisonings, in children from newborns to age 4 and in teenagers from 15 to almost 19.

Emergency Departments Over-test for Suspected Pulmonary Embolism

Computed tomographic pulmonary angiography (CTPA) is overused in the diagnostic workup of pulmonary embolism (PE), underscoring “the urgent need for dissemination and implementation of protocols to reduce low-yield CTPA scanning,” including D-dimer testing, according to the authors of a study examining emergency department (ED) practices involving PE-related testing (Circ Cardiovasc Qual Outcomes 2020;13:e005753).

The study, a cross-sectional analysis of electronic health record and billing data from 16 EDs in Indiana and 11 hospitals in the Dallas-Fort Worth area, identified ED patients who underwent any of the following, including D-dimer testing, CTPA, scintillation ventilation perfusion lung scanning, or pulmonary angiography. Out of 1.83 million patient encounters, 5.3% had a diagnostic test for PE. Nearly 60% of all patients who had tests for PE underwent CTPA without D-dimer testing. About 21% of CTPA took place in women younger than age 45, who are at greater risk of cancer from CTPA radiation exposure, according to the authors.

The pooled diagnostic yield of CTPA for PE was 3.1%, with a 1.3% rate in Indiana EDs, and a 4.8% rate in Dallas-Fort Worth facilities.

Patients in Indiana were less likely than those in Dallas-Fort Worth to receive D-dimer testing before CTPA (30% versus 52%, respectively), possibly reflecting the impact of a targeted quality improvement initiative that had taken place in Dallas-Fort Worth to increase use of D-dimer testing in low-risk patients.

The data imply that “D-dimer ordering correlates with an increased yield rate of PE on CTPA,” wrote the investigators. “This relationship suggests but does not prove a positive cause-effect relationship between rate of D-dimer ordering and PE yield.”