title: Hypermutable DNA chronicles the evolution of human colon cancer.
abstract: 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.
authors.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors.forename: Kamila
authors.initials: K
authors.lastname: Naxerova
authors.forename: Elena
authors.initials: E
authors.lastname: Brachtel
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Salk
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Seese
authors.forename: Karen
authors.initials: K
authors.lastname: Power
authors.forename: Bardia
authors.initials: B
authors.lastname: Abbasi
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.forename: Sarah
authors.initials: S
authors.lastname: Chiang
authors.forename: Simon
authors.initials: S
authors.lastname: Kasif
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics*; D018740:Genetic Heterogeneity; D006801:Humans; D018895:Microsatellite Repeats; D008875:Middle Aged; D008938:Mitosis / Q000235:genetics; D009154:Mutation; D010802:Phylogeny; D011068:Poly G / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D011068:Poly G
keywords: lineage tracing; microsatellites; tumor phylogenetics
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