Aberrant expression of pRb and p16INK4a
as an indicator of outcome after resection in colorectal carcinoma
The authors conducted a study to identify potential abnormalities of retinoblastoma protein and p16INK4a expression in resectable colorectal carcinomas and to assess their prognostic significance in patients with colorectal carcinomas. From July 1990 through December 1993, 117 consecutive patients with colorectal carcinomas (CRC) underwent curative resection with radical lymphadenectomy. The resected specimens were examined immunohistochemically using monoclonal antibodies to identify abnormalities of retinoblastoma protein (pRb) and p16INK4a (P16) expression. The association of pRb and p16 expression status with clinicopathologic features was analyzed retrospectively. The Cox proportional hazards model was used to identify factors independently affecting survival after resection. The median followup period was 62 months. Aberrant expression of pRb and p16 was identified in 82 (70 percent) and 87 (74 percent) patients, respectively. Coincident abnormalities of these proteins occurred in 61 (52 percent) patients. Loss of pRb expression correlated with tumor site (P=0.0119), whereas p16 overexpression correlated with tumor size (P=0.0034). Coincident abnormalities of pRb and p16 were associated with TNM tumor stage (P=0.011). The outcome after resection was worse in patients with aberrant expression of pRb or p16, or both, than in patients with normally expressed pRb and p16 (for pRb, P=0.0151; for p16, P=0.0247). Coincident abnormalities of pRb and p16 independently affected postresection survival (relative risk=6.312, P<0.001; relative risk=5.994, P<0.0001, respectively). Most CRCs demonstrate aberrant expression of pRb or p16, or both, at resectable stages. The authors concluded that aberrant expression of pRb and p16, alone and in combination, heralds poor prognosis in patients with CRC.
Cui X, Shirai Y, Wakai T, et al. Aberrant expression of pRb and p16INK4a, alone or in combination, indicates poor outcome after resection in patients with colorectal carcinoma. Hum Pathol. 2004;35:1189-1195.
Reprints: Dr. Xing Cui, Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan
The authors analyzed the prognostic significance of six molecular biomarkers in stage I non-small-cell lung cancer (NSCLC) patients. They were death-associated protein kinase (DAPK) promoter methylation, interleukin-10 (IL-10) protein expression, cyclooxygenase-2 (COX-2) mRNA expression, human telomerase reverse transcriptase catalytic subunit (hTERT) mRNA expression, retinoic acid receptor-beta (RAR-β) mRNA expression, and K-ras mutational status. Biomarker analyses were performed on tumors from 94 patients with stage I NSCLC who underwent surgical resection at the authors' institution. A minimum followup period of five years was required. DAPK methylation was assessed by methylation-specific polymerase chain reaction (PCR). RAR-β, COX-2, and hTERT mRNA levels were determined by in situ hybridization with digoxigenin-labeled antisense riboprobes. K-ras mutation status was determined by the PCR-primer introduced restriction with enrichment for mutant alleles method. IL-10 protein expression was analyzed by immunohistochemistry using a polyclonal antihuman IL-10 antibody. Cancer-specific survival was analyzed with a Cox proportional hazards model. To identify independent prognostic factors, a stepwise selection method was used. DAPK methylation, IL-10 lack of expression, COX-2 expression, hTERT expression, RAR-β expression, and K-ras mutations were observed in 46.8 percent, 29.8 percent, 59.6 percent, 34 percent, 23.4 percent, and 34 percent of patients, respectively. In the final model, DAPK methylation and IL-10 lack of expression were significant negative prognostic factors for cancer-specific survival, whereas COX-2 expression was of borderline significance. The authors concluded that in this cohort of resected stage I NSCLC patients, molecular markers that independently predict cancer-specific survival have been identified. The prognostic roles of DAPK methylation, IL-10, and other biomarkers in NSCLC merit further investigation.
Lu C, Soria JC, Tang X, et al. Prognostic factors in resected stage I non-small-cell lung cancer: a multivariate analysis of six molecular markers. J Clin Oncol. 2004; 22(22):4575-4583.
Reprints: Dr. Charles Lu, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 432, Houston, TX 77030-4009; firstname.lastname@example.org
The survival rate for patients with head and neck squamous cell carcinoma remains unchanged despite recent therapeutic advances. To reverse this trend, reliable and clinically applicable markers of tumor aggressiveness must be identified. One such marker may be tumor-associated macrophage content. The authors hypothesized that tumor-associated macrophages contribute to head and neck squamous cell carcinoma (HNSCC) aggressiveness. They conducted a study to prove this hypothesis using mRNA expression analysis and a large cohort of clinical specimens. Oligonucleotide microarray analysis was performed on a prospective cohort of 20 patients with previously untreated oral cavity or oropharynx squamous cell carcinoma (OC/OP SCCA) and on normal oropharyngeal mucosa from four patients. After determining whether macrophage chemoattractants were produced by tumors, conditioned media from three HNSCC cell lines were used to quantify macrophage migration in an in vitro assay. A high-density tissue microarray of 102 patients with previously untreated OC/OP SCCA was stained immunohistochemically for CD68 to identify tissue macrophages, and the results were correlated with clinicopathologic data and survival. The authors found that monocyte chemoattractant protein 1 was upregulated significantly in tumors compared with normal mucosa (P=0.0025; fold change=1.89). All University of Michigan SCC tumor cell line-conditioned media caused a significant increase in macrophage migration (P<0.05). Tissue microarray data revealed that the macrophage content of the primary tumor was strongly associated with lymph node metastasis (P<0.0001), extracapsular lymph node spread (P=0.0001), and advanced clinical disease stage (P=0.0002). When it was evaluated with other clinicopathologic data, macrophage content was found to be an independent predictor of lymph node metastasis (P<0.0001). The authors concluded that primary tumor macrophage content is a strong predictor of tumor aggressiveness in HNSCC.
Marcus B, Arenberg D, Lee J, et al. Prognostic factors in oral cavity and oropharyngeal squamous cell carcinoma: the impact of tumor-associated macrophages. Cancer. 2004;101:2779-2787.
Reprints: Dr. Theodoros N. Teknos, Dept. of Otolaryngology-Head and Neck Surgery, University of Michigan Medical Center, 1500 E. Medical Center Dr., 1904 Taubman Center, Ann Arbor, MI 48103; email@example.com