Travis Zack

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies. The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies. This contribution from The Cancer Genome Atlas (TCGA) project describes the molecular evaluation of 295 primary gastric adenocarcinomas. Based on the results, the authors propose a novel classification separating gastric cancers into four subtypes according to: Epstein–Barr virus positive status, microsatellite instability, chromosomal instability or genomic stability. Given the histologic and etiologic heterogeneity of gastric cancer identification of these subtypes, using a schema that can readily be applied to patient samples should help with patient stratification and trials of targeted therapies.

Rameen Beroukhim and colleagues analyzed somatic structural alterations in 12 tumor types. Whole-genome doubling was found in over a third of all cancers, associated with TP53 mutation. Fifteen new significantly mutated candidate driver genes were found associated with recurrently amplified or deleted regions. Determining how somatic copy number alterations (SCNAs) promote cancer is an important goal. We characterized SCNA patterns in 4,934 cancers from The Cancer Genome Atlas Pan-Cancer data set. Whole-genome doubling, observed in 37% of cancers, was associated with higher rates of every other type of SCNA, TP53 mutations, CCNE1 amplifications and alterations of the PPP2R complex. SCNAs that were internal to chromosomes tended to be shorter than telomere-bounded SCNAs, suggesting different mechanisms underlying their generation. Significantly recurrent focal SCNAs were observed in 140 regions, including 102 without known oncogene or tumor suppressor gene targets and 50 with significantly mutated genes. Amplified regions without known oncogenes were enriched for genes involved in epigenetic regulation. When levels of genomic disruption were accounted for, 7% of region pairs were anticorrelated, and these regions tended to encompass genes whose proteins physically interact, suggesting related functions. These results provide insights into mechanisms of generation and functional consequences of cancer-related SCNAs.

BACKGROUND: Large language models (LLMs) such as GPT-4 hold great promise as transformative tools in health care, ranging from automating administrative tasks to augmenting clinical decision making. However, these models also pose a danger of perpetuating biases and delivering incorrect medical diagnoses, which can have a direct, harmful impact on medical care. We aimed to assess whether GPT-4 encodes racial and gender biases that impact its use in health care. METHODS: Using the Azure OpenAI application interface, this model evaluation study tested whether GPT-4 encodes racial and gender biases and examined the impact of such biases on four potential applications of LLMs in the clinical domain-namely, medical education, diagnostic reasoning, clinical plan generation, and subjective patient assessment. We conducted experiments with prompts designed to resemble typical use of GPT-4 within clinical and medical education applications. We used clinical vignettes from NEJM Healer and from published research on implicit bias in health care. GPT-4 estimates of the demographic distribution of medical conditions were compared with true US prevalence estimates. Differential diagnosis and treatment planning were evaluated across demographic groups using standard statistical tests for significance between groups. FINDINGS: We found that GPT-4 did not appropriately model the demographic diversity of medical conditions, consistently producing clinical vignettes that stereotype demographic presentations. The differential diagnoses created by GPT-4 for standardised clinical vignettes were more likely to include diagnoses that stereotype certain races, ethnicities, and genders. Assessment and plans created by the model showed significant association between demographic attributes and recommendations for more expensive procedures as well as differences in patient perception. INTERPRETATION: Our findings highlight the urgent need for comprehensive and transparent bias assessments of LLM tools such as GPT-4 for intended use cases before they are integrated into clinical care. We discuss the potential sources of these biases and potential mitigation strategies before clinical implementation. FUNDING: Priscilla Chan and Mark Zuckerberg.