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Systematic analysis of cancer-associated mutations in the blood cells of healthy individuals. Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma-associated genes, and nine were recurrently mutated ( DNMT3A , TET2 , JAK2 , ASXL1 , TP53 , GNAS , PPM1D , BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5–6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion.

The Cancer Genome Atlas consortium analyzed 293 lower-grade gliomas obtained from adult patients. The integration of genomic and clinical data shows that genetic status correlates better with biology and survival than does histologic status. Diffuse low-grade and intermediate-grade gliomas (World Health Organization [WHO] grades II and III, hereafter called lower-grade gliomas) (see the Glossary) are infiltrative neoplasms that arise most often in the cerebral hemispheres of adults and include astrocytomas, oligodendrogliomas, and oligoastrocytomas. 1 , 2 Because of their highly invasive nature, complete neurosurgical resection is impossible, and the presence of residual tumor results in recurrence and malignant progression, albeit at highly variable intervals. A subset of these gliomas will progress to glioblastoma (WHO grade IV gliomas) within months, whereas others remain stable for years. Similarly, survival ranges widely, from 1 to 15 years, and some . . .

Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C , PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes ( ATM , BAP1 , BRCA1/2 , BRIP1 , FANCM , PALB2 and RAD51C/D ). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine. Published sequencing data sets of cancer samples could be used to identify genetic variants associated with the risk of developing cancer. Here, Lu et al . analyse over 4,000 tumour-normal pairs to reveal variable frequencies of inherited susceptibilities across 12 cancer types and find enrichment of functionally validated missense variants of unknown significance.

Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. We analyzed blood-derived sequence data from 2,728 individuals within The Cancer Genome Atlas, and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia/lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5–6% of people older than 70 years) contain mutations that may represent premalignant, initiating events that cause clonal hematopoietic expansion.

Background The All of Us Research Program (AoURP, “the program”) is an initiative, sponsored by the National Institutes of Health (NIH), that aims to enroll one million people (or more) across the USA. Through repeated engagement of participants, a research resource is being created to enable a variety of future observational and interventional studies. The program has also committed to genomic data generation and returning important health-related information to participants. Methods Whole-genome sequencing (WGS), variant calling processes, data interpretation, and return-of-results procedures had to be created and receive an Investigational Device Exemption (IDE) from the United States Food and Drug Administration (FDA). The performance of the entire workflow was assessed through the largest known cross-center, WGS-based, validation activity that was refined iteratively through interactions with the FDA over many months. Results The accuracy and precision of the WGS process as a device for the return of certain health-related genomic results was determined to be sufficient, and an IDE was granted. Conclusions We present here both the process of navigating the IDE application process with the FDA and the results of the validation study as a guide to future projects which may need to follow a similar path. Changes to the program in the future will be covered in supplementary submissions to the IDE and will support additional variant classes, sample types, and any expansion to the reportable regions.

Clear cell sarcoma (CCS) is a rare malignancy that occurs around tendons or aponeuroses of the extremities. In about 90% of cases, CCS is driven by a chromosomal translocation between chromosomes 22 and 12 that generates a fusion gene between EWSR1 and ATF1. The translated EWSR1-ATF1 (EA1) oncoprotein functions as a nucleus-localized factor to epigenetically reprogram transcription into a cancerous state. However, the precise roles of EA1 in driving CCS are largely unknown. The utilization of robust mouse models and next-generation sequencing revealed the functional genomic landscape of CCS and the epigenomic profile of the EA1 oncoprotein. Copy number alterations, including amplifications of chromosomes 7 and 8, were identified in human CCS tumors. Secondary genetic alterations, such as MYC hyperactivation, were recapitulated in the mouse model to demonstrate they can impact tumor growth and phenotype. Lastly, epigenomic profiling revealed previously uncharacterized functions of EA1 and epigenetic regulatory regions shared between human and mouse CCS. Sarcoma subtypes driven by a chromosomal translocation are understudied and preferentially affect pediatric populations. Understanding the genomic landscape and the fusion oncoprotein functions that drive these cancers are crucial to improve therapies.