Molecular detection of neoplastic cells in lymph nodes of metastatic colorectal cancer patients predicts recurrence

Montserrat Sanchez-Cespedes, Manel Esteller, Kenji Hibi, Frederick O. Cope, William H. Westra, Steven Piantadosi, James G. Herman, Jin Jen, David Sidransky

Research output: Contribution to journalArticle

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Abstract

Disseminated disease, especially to the liver, constitutes the major risk of recurrence for colorectal cancer patients. However, successful resection can still be achieved in 2535% of colorectal cancer patients with isolated metastases. To evaluate the clinical value of occult micrometastatic disease detection in lymph nodes, we tested genetic (K-ras and p53 gene mutations) and epigenetic (p16 promoter hypermethylation) molecular markers in the perihepatic lymph nodes from colorectal cancer patients with isolated liver metastases. DNA was extracted from 21 paraffin-embedded liver metastases and 80 lymph nodes from 21 colorectal cancer patients. K-ras and p53 gene mutations were identified in DNA from liver metastases by PCR amplification followed by cycle sequencing. A sensitive oligonucleotide- mediated mismatch ligation assay was used to search for the presence of K-ras and p53 mutations to detect occult disease in 68 lymph nodes from tumors positive for these gene mutations. Promoter hypermethylation at the p16 tumor suppressor gene was examined in both liver lesions and lymph nodes by methylation-specific PCR. Sixteen of the 21 (76 %) liver metastases harbored either gene point mutations or p16 promoter hypermethylation. Twelve of the 68 lymph nodes were positive for tumor cells by molecular evaluation and negative for tumor cells by histopathology and cytokeratin immunohistochemistry, whereas none were positive for tumor cells by histopathology or negative for tumor cells by molecular analysis (P = 0.0005, McNemar's test). Moreover, in three patients with lymph nodes that were histologically negative at all sites, molecular screening detected tumor DNA at one or more lymph nodes. Survival analysis showed a median survival of 1056 days for patients without evidence of lymph node involvement by molecular analysis and 165 days for patients with positive lymph nodes by this approach (P = 0.0005). These results indicate that lymph node metastasis screening in colorectal cancer patients by molecular-based techniques increases the sensitivity of tumor cell detection and can be a good predictor of recurrence in colorectal cancer patients with resectable liver metastases.

Original languageEnglish (US)
Pages (from-to)2450-2454
Number of pages5
JournalClinical Cancer Research
Volume5
Issue number9
StatePublished - Sep 1999
Externally publishedYes

Fingerprint

Colorectal Neoplasms
Lymph Nodes
Recurrence
Neoplasm Metastasis
Liver
Neoplasms
Mutation
ras Genes
p53 Genes
DNA
Polymerase Chain Reaction
Survival Analysis
Keratins
Tumor Suppressor Genes
Point Mutation
Epigenomics
Oligonucleotides
Paraffin
Methylation
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sanchez-Cespedes, M., Esteller, M., Hibi, K., Cope, F. O., Westra, W. H., Piantadosi, S., ... Sidransky, D. (1999). Molecular detection of neoplastic cells in lymph nodes of metastatic colorectal cancer patients predicts recurrence. Clinical Cancer Research, 5(9), 2450-2454.

Molecular detection of neoplastic cells in lymph nodes of metastatic colorectal cancer patients predicts recurrence. / Sanchez-Cespedes, Montserrat; Esteller, Manel; Hibi, Kenji; Cope, Frederick O.; Westra, William H.; Piantadosi, Steven; Herman, James G.; Jen, Jin; Sidransky, David.

In: Clinical Cancer Research, Vol. 5, No. 9, 09.1999, p. 2450-2454.

Research output: Contribution to journalArticle

Sanchez-Cespedes, M, Esteller, M, Hibi, K, Cope, FO, Westra, WH, Piantadosi, S, Herman, JG, Jen, J & Sidransky, D 1999, 'Molecular detection of neoplastic cells in lymph nodes of metastatic colorectal cancer patients predicts recurrence', Clinical Cancer Research, vol. 5, no. 9, pp. 2450-2454.
Sanchez-Cespedes M, Esteller M, Hibi K, Cope FO, Westra WH, Piantadosi S et al. Molecular detection of neoplastic cells in lymph nodes of metastatic colorectal cancer patients predicts recurrence. Clinical Cancer Research. 1999 Sep;5(9):2450-2454.
Sanchez-Cespedes, Montserrat ; Esteller, Manel ; Hibi, Kenji ; Cope, Frederick O. ; Westra, William H. ; Piantadosi, Steven ; Herman, James G. ; Jen, Jin ; Sidransky, David. / Molecular detection of neoplastic cells in lymph nodes of metastatic colorectal cancer patients predicts recurrence. In: Clinical Cancer Research. 1999 ; Vol. 5, No. 9. pp. 2450-2454.
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abstract = "Disseminated disease, especially to the liver, constitutes the major risk of recurrence for colorectal cancer patients. However, successful resection can still be achieved in 2535{\%} of colorectal cancer patients with isolated metastases. To evaluate the clinical value of occult micrometastatic disease detection in lymph nodes, we tested genetic (K-ras and p53 gene mutations) and epigenetic (p16 promoter hypermethylation) molecular markers in the perihepatic lymph nodes from colorectal cancer patients with isolated liver metastases. DNA was extracted from 21 paraffin-embedded liver metastases and 80 lymph nodes from 21 colorectal cancer patients. K-ras and p53 gene mutations were identified in DNA from liver metastases by PCR amplification followed by cycle sequencing. A sensitive oligonucleotide- mediated mismatch ligation assay was used to search for the presence of K-ras and p53 mutations to detect occult disease in 68 lymph nodes from tumors positive for these gene mutations. Promoter hypermethylation at the p16 tumor suppressor gene was examined in both liver lesions and lymph nodes by methylation-specific PCR. Sixteen of the 21 (76 {\%}) liver metastases harbored either gene point mutations or p16 promoter hypermethylation. Twelve of the 68 lymph nodes were positive for tumor cells by molecular evaluation and negative for tumor cells by histopathology and cytokeratin immunohistochemistry, whereas none were positive for tumor cells by histopathology or negative for tumor cells by molecular analysis (P = 0.0005, McNemar's test). Moreover, in three patients with lymph nodes that were histologically negative at all sites, molecular screening detected tumor DNA at one or more lymph nodes. Survival analysis showed a median survival of 1056 days for patients without evidence of lymph node involvement by molecular analysis and 165 days for patients with positive lymph nodes by this approach (P = 0.0005). These results indicate that lymph node metastasis screening in colorectal cancer patients by molecular-based techniques increases the sensitivity of tumor cell detection and can be a good predictor of recurrence in colorectal cancer patients with resectable liver metastases.",
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