Articles in 2021

Half of all colorectal cancers bear KRAS-activating mutations that affect the metabolic dependencies of cancer cells and drive resistance to commonly used drugs. A new study provides insights into KRAS-driven metabolic rewiring and identifies a new therapeutic target for KRAS-mutant cancers.

Whole-genome sequencing of monozygotic twins, along with their parents, spouses and children, identifies postzygotic mutations present in the somatic tissue of one twin, but not the other, and characterizes differences in the number and timing of these mutations.

Analysis of copy number alterations in 1,451 patient-derived xenografts (PDXs) and matched patient tumor samples shows strong conservation from patient tumors through late-passage PDXs and a lack of systematic copy number evolution driven by the mouse host.

Colorectal tumors with mutated KRAS and APC require the amino acid transporter SLC7A5 to drive tumorigenesis. Mechanistically, SLC7A5 drives transcriptional and metabolic reprogramming by maintaining intracellular amino acid levels, leading to enhanced protein synthesis.

GLIMPSE is a new method for haplotype phasing and genotype imputation of low-coverage sequencing datasets from large reference panels. GLIMPSE shows remarkable performance across different coverages and human populations.

A large-scale genome-wide meta-analysis conducted across different platforms identifies genetic loci regulating levels of circulating metabolites.

Genomic structural equation modeling of genome-wide association data for educational attainment and cognitive test performance is used to estimate the genetic component of variation in educational attainment that is independent of cognitive ability. The study finds that noncognitive skills account for 57% of genetic variation in educational attainment.

Here, we argue that, in line with the dramatic increase in the collection, storage and curation of human genomic data for biomedical research, genomic data repositories and consortia have adopted governance frameworks to both enable wide access and protect against possible harms. However, the merits and limitations of different governance frameworks in achieving these twin aims are a matter of ongoing debate in the scientific community; indeed, best practices and points for consideration are notably absent in devising governance frameworks for genomic databases. According to our collective experience in devising and assessing governance frameworks, we identify five key functions of ‘good governance’ (or ‘better governance’) and three areas in which trade-offs should be considered when specifying policies within those functions. We apply these functions as a benchmark to describe, as an example, the governance frameworks of six large-scale international genomic projects.

A high tumor mutational burden (TMB) is associated with improved immunotherapy response in many tumor types. This analysis of 10,233 individuals shows that, in contrast, high TMB is associated with poorer survival in patients that have not been treated with immune checkpoint inhibitors.

A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.

A genetic screen designed to capture modulators of single-cell state variability identifies a new mode of altering resistance to BRAF inhibition in melanoma that pushes cells toward a more differentiated state. Modulating cellular plasticity may provide a new avenue to overcome drug resistance.