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The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer

Discovery: The Rosetta team in Nature Genetics have demonstrated that the amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer (CRC). SLC7A5 mediates the transmembrane trafficking of glutamine in exchange for essential amino acids that sustain cell growth, also referred to as an antiporter* in the paper, and has been shown to be critical for tumour development in early and late-stage mouse models of CRC.

Methods: This was achieved using a combination of approaches, including 3D cell culture (organoids), the generation of genetically engineered mouse models (GEMMs) [early and late stage carcinoma] and the analysis of human CRC samples. 

*An antiporter (also called exchanger or counter-transporter) is a cotransporter and integral membrane protein involved in secondary active transport of two or more different molecules or ions across a phospholipid membrane such as the plasma membrane in opposite directions, one into the cell and one out of the cell.

Team Rosetta
Journal Nature Genetics
Authors Owen Swansom et al
DATE 07 January 2021
Contralateral breast cancer risk in patients with ductal carcinoma in situ and invasive breast cancer

We aimed to assess contralateral breast cancer (CBC) risk in patients with ductal carcinoma in situ (DCIS) compared with invasive breast cancer (BC). Women diagnosed with DCIS (N = 28,003) or stage I–III BC (N = 275,836) between 1989 and 2017 were identified from the nationwide Netherlands Cancer Registry. Cumulative incidences were estimated, accounting for competing risks, and hazard ratios (HRs) for metachronous invasive CBC. To evaluate effects of adjuvant systemic therapy and screening, separate analyses were performed for stage I BC without adjuvant systemic therapy and by mode of first BC detection. Multivariable models including clinico-pathological and treatment data were created to assess CBC risk prediction performance in DCIS patients. The 10-year cumulative incidence of invasive CBC was 4.8% for DCIS patients (CBC = 1334). Invasive CBC risk was higher in DCIS patients compared with invasive BC overall (HR = 1.10, 95% confidence interval (CI) = 1.04–1.17), and lower compared with stage I BC without adjuvant systemic therapy (HR = 0.87; 95% CI = 0.82–0.92). In patients diagnosed ≥2011, the HR for invasive CBC was 1.38 (95% CI = 1.35–1.68) after screen-detected DCIS compared with screen-detected invasive BC, and was 2.14 (95% CI = 1.46–3.13) when not screen-detected. The C-index was 0.52 (95% CI = 0.50–0.54) for invasive CBC prediction in DCIS patients. In conclusion, CBC risks are low overall. DCIS patients had a slightly higher risk of invasive CBC compared with invasive BC, likely explained by the risk-reducing effect of (neo)adjuvant systemic therapy among BC patients. For support of clinical decision making more information is needed to differentiate CBC risks among DCIS patients.

Team PRECISION
Journal npj Breast Cancer
Authors Daniele Giardiello et al
DATE 03 November 2020
The critical roles of somatic mutations and environmental tumor-promoting agents in cancer risk

Cancer is driven by genomic mutations in ‘cancer driver’ genes, which have essential roles in tumor development. These mutations may be caused by exposure to mutagens in the environment or by endogenous DNA-replication errors in tissue stem cells. Recent observations of abundant mutations, including cancer driver mutations, in histologically normal human tissues suggest that mutations alone are not sufficient for tumor development, thus prompting the question of how single mutant cells give rise to neoplasia. In a concept supported by decades-old data from mouse tumor models, non-mutagenic tumor-promoting agents have been posited to activate the proliferation of dormant mutated cells, thus generating actively growing lesions, with the promotion stage as the rate-limiting step in tumor formation. Non-mutagenic promoting agents, either endogenous or environmental, may therefore have a more important role in human cancer etiology than previously thought.

Team Mutographs
Journal Nature Genetics
Authors Allan Balmain
DATE 26 October 2020
Generating realistic null hypothesis of cancer mutational landscapes using SigProfilerSimulator

Background

Performing a statistical test requires a null hypothesis. In cancer genomics, a key challenge is the fast generation of accurate somatic mutational landscapes that can be used as a realistic null hypothesis for making biological discoveries.

Results

Here we present SigProfilerSimulator, a powerful tool that is capable of simulating the mutational landscapes of thousands of cancer genomes at different resolutions within seconds. Applying SigProfilerSimulator to 2144 whole-genome sequenced cancers reveals: (i) that most doublet base substitutions are not due to two adjacent single base substitutions but likely occur as single genomic events; (ii) that an extended sequencing context of ± 2 bp is required to more completely capture the patterns of substitution mutational signatures in human cancer; (iii) information on false-positive discovery rate of commonly used bioinformatics tools for detecting driver genes.

Conclusions

SigProfilerSimulator’s breadth of features allows one to construct a tailored null hypothesis and use it for evaluating the accuracy of other bioinformatics tools or for downstream statistical analysis for biological discoveries.

Team Mutographs
Journal BMC Informatics
Authors Erik N. Bergstrom, Mark Barnes, Iñigo Martincorena, Ludmil B. Alexandrov
DATE 07 October 2020
Smoking status at diagnosis and colorectal cancer prognosis according to tumor lymphocytic reaction

Background

Smoking has been associated with worse colorectal cancer patient survival and may potentially suppress the immune response in the tumor microenvironment. We hypothesized that the prognostic association of smoking behavior at colorectal cancer diagnosis might differ by lymphocytic reaction patterns in cancer tissue.

Methods

Using 1474 colon and rectal cancer patients within 2 large prospective cohort studies (Nurses’ Health Study and Health Professionals Follow-up Study), we characterized 4 patterns of histopathologic lymphocytic reaction, including tumor-infiltrating lymphocytes (TILs), intratumoral periglandular reaction, peritumoral lymphocytic reaction, and Crohn’s-like lymphoid reaction. Using covariate data of 4420 incident colorectal cancer patients in total, an inverse probability weighted multivariable Cox proportional hazards regression model was conducted to adjust for selection bias due to tissue availability and potential confounders, including tumor differentiation, disease stage, microsatellite instability status, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, and KRASBRAF, and PIK3CA mutations.

Results

The prognostic association of smoking status at diagnosis differed by TIL status. Compared with never smokers, the multivariable-adjusted colorectal cancer–specific mortality hazard ratio for current smokers was 1.50 (95% confidence interval = 1.10 to 2.06) in tumors with negative or low TIL and 0.43 (95% confidence interval = 0.16 to 1.12) in tumors with intermediate or high TIL (2-sided Pinteraction = .009). No statistically significant interactions were observed in the other patterns of lymphocytic reaction.

Conclusions

The association of smoking status at diagnosis with colorectal cancer mortality may be stronger for carcinomas with negative or low TIL, suggesting a potential interplay of smoking and lymphocytic reaction in the colorectal cancer microenvironment.

Team OPTIMISTICC
Journal JNCI Cancer Spectrum
Authors Kenji Fujiyoshi et al
DATE October 2020