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Published online on October 28, 2005, 10.1073/pnas.0507904102
PNAS | November 8, 2005 | vol. 102 | no. 45 | 16368-16373


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MEDICAL SCIENCES
Detection and quantification of mutations in the plasma of patients with colorectal tumors

Frank Diehl *, Meng Li *, Devin Dressman *, Yiping He *, Dong Shen *, Steve Szabo *, Luis A. Diaz, Jr *, Steven N. Goodman *, Kerstin A. David {dagger}, Hartmut Juhl {dagger}, Kenneth W. Kinzler *, and Bert Vogelstein *, {ddagger}

*Howard Hughes Medical Institute and The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, 1650 Orleans Street, Baltimore, MD 21231; and {dagger}Indivumed, Center for Cancer Research at Israelitic Hospital, Orchideenstieg 14, 22297 Hamburg, Germany

Contributed by Bert Vogelstein, September 16, 2005

The early detection of cancers through analysis of circulating DNA could have a substantial impact on morbidity and mortality. To achieve this goal, it is essential to determine the number of mutant molecules present in the circulation of cancer patients and to develop methods that are sufficiently sensitive to detect these mutations. Using a modified version of a recently developed assay for this purpose, we found that patients with advanced colorectal cancers consistently contained mutant adenomatous polyposis coli (APC) DNA molecules in their plasma. The median number of APC DNA fragments in such patients was 47,800 per ml of plasma, of which 8% were mutant. Mutant APC molecules were also detected in >60% of patients with early, presumably curable colorectal cancers, at levels ranging from 0.01% to 1.7% of the total APC molecules. These results have implications for the mechanisms through which tumor DNA is released into the circulation and for diagnostic tests based on this phenomenon.

colorectal cancer | plasma DNA | tumor suppressor gene | circulating DNA | diagnosis

Author contributions: F.D., K.A.D., H.J., K.W.K., and B.V. designed research; F.D., M.L., and S.S. performed research; D.D., Y.H., D.S., K.A.D., and H.J. contributed new reagents/analytic tools; F.D., L.A.D., S.N.G., K.W.K., and B.V. analyzed data; and F.D., S.N.G., H.J., K.W.K., and B.V. wrote the paper.

Conflict of interest statement: Under a licensing agreement between EXACT Sciences and The Johns Hopkins University, K.W.K. and B.V. are entitled to a share of royalties received by the university on sales of products related to digital PCR. Under a licensing agreement between Agencourt Biosciences Corporation and The Johns Hopkins University, D.D., K.W.K., and B.V. are entitled to a share of royalties received by the university on sales of products related to the use of BEAMing for preparing templates for DNA sequencing. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

Abbreviations: APC, adenomatous polyposis coli; PE, phycoerythrin.

{ddagger} To whom correspondence should be addressed. E-mail: vogelbe{at}jhmi.edu.

© 2005 by The National Academy of Sciences of the USA


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