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: Kamila Naxerova, Elena Brachtel, Jesse J Salk, Aaron M Seese, Karen Power, Bardia Abbasi, Matija Snuderl, Sarah Chiang, Simon Kasif, Rakesh K Jain
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 18 Pg. E1889-98 (May 06 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24753616 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• DNA, Neoplasm
• Poly G

Topics

• Adenocarcinoma (etiology, genetics, secondary)
• Adult
• Aged
• Aged, 80 and over
• Carcinogenesis (genetics)
• Cell Differentiation (genetics)
• Cohort Studies
• Colonic Neoplasms (etiology, genetics, pathology)
• DNA, Neoplasm (genetics)
• Genetic Heterogeneity
• Humans
• Microsatellite Repeats
• Middle Aged
• Mitosis (genetics)
• Mutation
• Phylogeny
• Poly G (genetics)