Clinical relevance of alterations in quantity and quality of plasma DNA in colorectal cancer patients: based on the mutation spectra detected in primary tumors.
BACKGROUND
While circulating plasma DNA (cpDNA) likely originates in tumors, its utility is limited without knowledge of tumor mutations. This study assessed mutational spectra in primary tumors and clarified the utility of quantitative and qualitative cpDNA alterations in colorectal cancer (CRC) patients.


METHODS
Between 2005 and 2006, 191 surgical colorectal cancer patients at Taipei Veterans General Hospital were enrolled in a study of mutational spectra of 155 mutations in 74 genes. Concentrations of cpDNA in 133 patients were measured by Taqman qPCR. The measured endpoint was overall survival (OS) after surgery. The prognostic value was determined using the log-rank test and Cox regression analysis.


RESULTS
Of 191 tumors, 208 mutations in 17 genes were found in 137 tumors (71.7 %). Mutation frequencies were 38.7 % in KRAS, followed by APC (23.0 %), TP53 (19.9 %), PIK3CA (7.3 %), and BRAF (4.2 %). The median cpDNA in stage I, II, and III patients was 4,300, 4,800, and 5,600 copies/mL, respectively, increasing to 13,000 copies/mL in stage IV disease (p = .003). From 90 primary tumors with mutations, the sensitivity of cpDNA mutations were 24.0, 45.0, and 27.3 % in the stage I, II, and III disease, respectively, increasing to 87.5 % in stage IV. The 5-year OS of CRC patients with low cpDNA was significantly better than that of patients with high cpDNA (p = .001). Stepwise elimination showed cpDNA to be a strong prognostic factor for OS.


CONCLUSIONS
Plasma DNA alteration is a useful tool for clinical surveillance of colorectal cancer patients and might be an independent prognosticator.
Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
Jen-Kou
JK
Lin
Pei-Ching
PC
Lin
Chien-Hsing
CH
Lin
Jeng-Kai
JK
Jiang
Shung-Haur
SH
Yang
Wen-Yi
WY
Liang
Wei-Shone
WS
Chen
Shih-Ching
SC
Chang
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000097:blood*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D060888:Real-Time Polymerase Chain Reaction; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins