MuSiC: Identifying mutational significance in cancer genomes

104

155

Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data for mutations in enzymes involved in dNTP metabolism. We found that sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), a deoxyribonucleoside triphosphate triphosphohydrolase that decreases dNTP pools, is frequently mutated in colon cancers, that these mutations negatively affect SAMHD1 activity, and that several SAMHD1 mutations are found in tumors with defective mismatch repair. We show that minor changes in dNTP pools in combination with inactivated mismatch repair dramatically increase mutation rates. Determination of dNTP pools in mouse embryos revealed that inactivation of one SAMHD1 allele is sufficient to elevate dNTP pools. These observations suggest that heterozygous cancer-associated SAMHD1 mutations increase mutation rates in cancer cells.

Section: Samhd1mentioning

confidence: 99%

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Rentoft

Lindell

Tran

et al. 2016

104

155

“…In contrast, somatic mutations are often neither specific nor sensitive for a particular type of cancer. Even within commonly mutated genes, individual mutations may be found across tens or hundreds of kilobases, limiting the utility of targeted sequencing of molecular markers (10,13,14).…”

mentioning

confidence: 99%

DNA methylation markers for diagnosis and prognosis of common cancers

Hao

Luo

Krawczyk

et al. 2017

382

278

The ability to identify a specific cancer using minimally invasive biopsy holds great promise for improving the diagnosis, treatment selection, and prediction of prognosis in cancer. Using whole-genome methylation data from The Cancer Genome Atlas (TCGA) and machine learning methods, we evaluated the utility of DNA methylation for differentiating tumor tissue and normal tissue for four common cancers (breast, colon, liver, and lung). We identified cancer markers in a training cohort of 1,619 tumor samples and 173 matched adjacent normal tissue samples. We replicated our findings in a separate TCGA cohort of 791 tumor samples and 93 matched adjacent normal tissue samples, as well as an independent Chinese cohort of 394 tumor samples and 324 matched adjacent normal tissue samples. The DNA methylation analysis could predict cancer versus normal tissue with more than 95% accuracy in these three cohorts, demonstrating accuracy comparable to typical diagnostic methods. This analysis also correctly identified 29 of 30 colorectal cancer metastases to the liver and 32 of 34 colorectal cancer metastases to the lung. We also found that methylation patterns can predict prognosis and survival. We correlated differential methylation of CpG sites predictive of cancer with expression of associated genes known to be important in cancer biology, showing decreased expression with increased methylation, as expected. We verified gene expression profiles in a mouse model of hepatocellular carcinoma. Taken together, these findings demonstrate the utility of methylation biomarkers for the molecular characterization of cancer, with implications for diagnosis and prognosis.

“…However, although variations in the observed frequency of SNPs will arise from the positive/negative selection of somatic mutations, they may also be intrinsic (germline-derived), making their functional significance at different sites difficult to assess (19,20) (Fig. S1).…”

mentioning

confidence: 99%

Deep sequencing as a probe of normal stem cell fate and preneoplasia in human epidermis

Simons

2015

Using deep sequencing technology, methods based on the sporadic acquisition of somatic DNA mutations in human tissues have been used to trace the clonal evolution of progenitor cells in diseased states. However, the potential of these approaches to explore cell fate behavior of normal tissues and the initiation of preneoplasia remain underexploited. Focusing on the results of a recent deep sequencing study of eyelid epidermis, we show that the quantitative analysis of mutant clone size provides a general method to resolve the pattern of normal stem cell fate and to detect and characterize the mutational signature of rare field transformations in human tissues, with implications for the early detection of preneoplasia.stem cells | DNA sequencing | epidermis | cancer A dvances in genetic lineage tracing in transgenic animal models have provided important insights into the proliferative potential and fate behavior of stem and progenitor cell populations in normal tissues (1, 2). As well as providing constraints on the mechanisms that regulate stem cell self-renewal, these approaches have established a quantitative framework to address tumor initiation and progression (3-6). However, studies based on the clonal activation of oncogenes in animal models can fail to recapitulate the natural processes that lead to neoplasia in human tissues. In recent years, there has been increasing emphasis on the characterization of cancer genomes in human tissues and their potential to elucidate the pathways involved in tumor progression (7)(8)(9)(10)(11)(12)(13)(14). Although these studies have revealed a range of cancer genes (15), the heterogeneity and evolutionary diversity of the tumor environment make the separation of driver and passenger mutations challenging.Against the trend to focus on human tumor samples, a recent study has used ultradeep exome sequencing to determine the mutational profile of normal human eyelid epidermis (16). In the course of DNA replication, all dividing cells are subject to random SNPs. If the mutation rate is sufficiently low that their acquisition at a given locus in a cell subpopulation is typically associated with a single event, they confer a potentially unique hereditary label on cells, allowing the fate of their progeny to be traced over time. By resolving the mutant allele fraction in a biopsy using deep sequencing, the relative size of mutant clones can be inferred. A similar approach based on the spontaneous acquisition of mitochondrial DNA mutation has been used to address progenitor cell fate in human airways and intestinal epithelia (17,18). To assess the selective growth advantage of different mutations in normal epidermis, Martincorena et al. (16) compared the dN/dS ratio and average size of clones derived from mutations in genes associated with cancer drivers with those associated with synonymous mutations in nondriver genes. Their analysis showed a significant increase in the abundance and average size of clones that bear mutations in NOTCH1 and tumor protein p53 (TP53) compared wit...