Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation

Tomasetti, Cristian; Vogelstein, Bert; Parmigiani, Giovanni

doi:10.1073/pnas.1221068110

Cited by 374 publications

(400 citation statements)

References 25 publications

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“…Colonic stem cells divide very frequently-every 30 h by some estimates (35)-and would therefore be expected to accumulate large numbers of founder mutations over the years, with total mutational burden increasing with age. Recent studies show a correlation between age at diagnosis and total number of somatic mutations in acute myeloid leukemia (36) and colorectal cancer (20,37). We tested this correlation in our data after excluding MSI cases, as a distinct mutational mechanism is operational in these tumors.…”

Section: Resultsmentioning

confidence: 95%

Hypermutable DNA chronicles the evolution of human colon cancer

Naxerova

Brachtel

Salk

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Intratumor genetic heterogeneity reflects the evolutionary history of a cancer and is thought to influence treatment outcomes. Here we report that a simple PCR-based assay interrogating somatic variation in hypermutable polyguanine (poly-G) repeats can provide a rapid and reliable assessment of mitotic history and clonal architecture in human cancer. We use poly-G repeat genotyping to study the evolution of colon carcinoma. In a cohort of 22 patients, we detect poly-G variants in 91% of tumors. Patient age is positively correlated with somatic mutation frequency, suggesting that some poly-G variants accumulate before the onset of carcinogenesis during normal division in colonic stem cells. Poorly differentiated tumors have fewer mutations than well-differentiated tumors, possibly indicating a shorter mitotic history of the founder cell in these cancers. We generate poly-G mutation profiles of spatially separated samples from primary carcinomas and matched metastases to build well-supported phylogenetic trees that illuminate individual patients' path of metastatic progression. Our results show varying degrees of intratumor heterogeneity among patients. Finally, we show that poly-G mutations can be found in other cancers than colon carcinoma. Our approach can generate reliable maps of intratumor heterogeneity in large numbers of patients with minimal time and cost expenditure.lineage tracing | microsatellites | tumor phylogenetics H uman cancers are composed of a continually evolving population of genetically and phenotypically divergent cells (1). This reservoir of diversity feeds the natural selection process that fundamentally drives disease progression through acquisition of metastatic properties and emergence of therapy-resistant clones (2-4). In recent years, characterization of intratumor heterogeneity has received increased attention as advanced sequencing technologies have enabled more detailed analysis of tumor cell populations (5-8).Depending on the context, the term "intratumor heterogeneity" refers either to differences between cells that coexist in one localized tumor region or to variation in clonal composition between spatially separated parts, most notably between a primary tumor and its metastases (in the latter case, "intracancer heterogeneity" is a more appropriate terminology). The extent of genetic divergence between primary and metastatic tumors (and the history of dissemination encoded therein) is beginning to be investigated, but relatively few patient data are currently available. The canonical "linear progression" model of metastasis states that a genetically advanced cell metastasizes late in primary tumor development (9-11). This aggressive clone generates new metastases in a so-called "metastasis shower" (12). Linear progression predicts that metastases will be genetically similar to the primary tumor and to each other. The alternative "parallel progression" model (9) posits that metastasis occurs early in tumor evolution and consequently expects metastases to be substantially differe...

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Section: Resultsmentioning

confidence: 95%

Hypermutable DNA chronicles the evolution of human colon cancer

Naxerova

Brachtel

Salk

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent work has shown that a very large proportion of mutations may have appeared before tumour initiation and that the number of somatic mutations in tumours of self-renewing tissues are positively correlated with the age of the patient at diagnosis 11,12 . In support of that, we see a trend that younger patients below the age of 55 (N ¼ 15/49) in our cohort tend to have much smaller number of mutations (2.16 vs 3.88 mutations per Mb; P ¼ 0.018).…”

Section: Resultsmentioning

confidence: 99%

Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing

et al. 2014

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Gastric cancer (GC) is the second most common cause of cancer-related deaths. It is known to be a heterogeneous disease with several molecular and histological subtypes. Here we perform whole-genome sequencing of 49 GCs with diffuse (N ¼ 31) and intestinal (N ¼ 18) histological subtypes and identify three mutational signatures, impacting TpT, CpG and TpCp[A/T] nucleotides. The diffuse-type GCs show significantly lower clonality and smaller numbers of somatic and structural variants compared with intestinal subtype. We further divide the diffuse subtype into one with infrequent genetic changes/low clonality and another with relatively higher clonality and mutations impacting TpT dinucleotide. Notably, we discover frequent and exclusive mutations in Ephrins and SLIT/ROBO signalling pathway genes. Overall, this study delivers new insights into the mutational heterogeneity underlying distinct histologic subtypes of GC that could have important implications for future research in the diagnosis and treatment of GC.

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“…Finally, next-generation DNA and RNA sequencing efforts (eg, The Cancer Genome Atlas) have demonstrated that very few common mutations unite particular solid tumor types; rather, patient tumors have a spectrum of mutations that collectively drive tumor growth. 11,33,34 In the face of this rapidly emerging and previously unappreciated complexity, it is not surprising that therapeutics developed using overly simplistic paradigms and models have been only modestly successful at impacting survival. The development of personalized medicine and its efficient implementation will likely leverage PDX models, the CSC paradigm and next-generation DNA and RNA sequencing to improve our collective understanding of tumor pathobiology, beginning with the more precise identification of patient subtypes and the identity of CSC in each of these respective tumor subtypes.…”

Section: Addressing Tumor Heterogeneitymentioning

confidence: 99%

“…As previously discussed, the Cancer Genome Atlas project has demonstrated that the spectrum of driver mutations differs significantly among patients, thus the relevance of particular GEMMs to patients in the clinic is increasingly questionable. 33,34 Notwithstanding the above criticisms, GEMMs may have advantages over xenograft models in their cellular composition and/or sensitivity to therapeutic agents. 48 Specifically, GEMM tumors contain stromal and hematopoietic components not possible in a human tumor xenograft setting, and thus these tumors may respond more appropriately to small molecules, immunomodulatory, and/or biological agents that cross-react with mouse antigens.…”

Section: Traditional Models Have Not Predicted Clinical Successmentioning

confidence: 99%

“…30,32,85 The exact relationship between CSC, normal stem cell populations, and the 'cell of origin' in cancer remains something of a mystery. 32,86 To be clear, although a tumor's initial CSC (ie, cell of origin) likely evolves from normal stem cells as a result of accumulating mutations that confer oncogenic properties over time, 33 the cell of origin in cancer and the predominant CSC present in an evolved tumor may possess differing phenotypes and properties depending on the point in time the tumor is being studied. More specifically, the CSC identity in disease may evolve an identity different from the cell of origin.…”

Section: Pdx Models and The Resurrection Of Tumor Stem Cellsmentioning

confidence: 99%

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Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century

Williams

Anderson

Santaguida

et al. 2013

Laboratory Investigation

170

166

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Cancer is a heterogeneous disease manifest in many forms. Tumor histopathology can differ significantly among patients and cellular heterogeneity within tumors is common. A primary goal of cancer biologists is to better understand tumorigenesis and cancer progression; however, the complex nature of tumors has posed a substantial challenge to unlocking cancer's secrets. The cancer stem cell (CSC) paradigm for the pathobiology of solid tumors appropriately acknowledges phenotypic and functional tumor cell heterogeneity observed in solid tumors and accounts for the disconnect between drug approval based on response and the general inability of approved therapies to meaningfully impact survival due to their failure to eradicate these most important of cellular targets. First proposed to exist decades ago, CSC have only recently begun to be precisely identified due to technical advancements that facilitate identification, isolation, and interrogation of distinct tumor cell subpopulations with differing ability to form and perpetuate tumors. Precise identification of CSC populations and the complete hierarchy of cells within solid tumors will facilitate more accurate characterization of patient subtypes and ultimately contribute to more personalized and effective therapies. Rapid advancement in the understanding of tumor biology as it exists in patients requires cooperation among institutions, surgeons, pathologists, cancer biologists and patients alike, primarily because this translational research is best done with patient-derived tissue grown in the xenograft setting as patient-derived xenografts. This review calls for a broader change in the approaches taken to study cancer pathobiology, highlights what implications the CSC paradigm has for pathologists and cancer biologists alike, and calls for greater collaboration between institutions, physicians and scientists in order to more rapidly advance our collective understanding of cancer.

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Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation

Cited by 374 publications

References 25 publications

Hypermutable DNA chronicles the evolution of human colon cancer

Hypermutable DNA chronicles the evolution of human colon cancer

Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing

Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century

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