Search

Epidermal growth factor receptor 1 (EGFR) and erb-b2 receptor tyrosine kinase 2 (ERBB2/HER2) are frequently dysregulated in human cancers. We analyzed EGFR and ERBB2 status in 105 gastric and gastroesophageal junction carcinoma and their clinicopathologic features. For EGFR, 92 (88%) tumors were scored as 0, 2 (2%) as 1+, 7 (7%) as 2+, and 4 (3%) as 3+ by immunohistochemistry (IHC) and 4 (4%) tumors showed EGFR amplification by fluorescence in situ hybridization (FISH). For ERBB2, 90 (86%) tumors were scored as 0, 4 (4%) as 1+, 6 (6%) as 2+, and 5 (5%) as 3+ by IHC and 12 (12%) showed ERBB2 amplification by FISH. The concordance rate between IHC and FISH of EGFR was 98.1% (P<0.001) and of ERBB2 was 93.3% (P<0.001). Most tumors with ERBB2 amplification were tubular adenocarcinoma (N=11, P=0.02) and Lauren intestinal type (N=12, P=0.016). There was no statistically significant difference between EGFR amplification and tumor classification. EGFR amplification had significant impact on overall survival in certain subgroups: early stages (stages I and II) (P<0.001), well to moderately differentiated tumors (P=0.001), and fewer regional lymph node metastasis (pN1) (P=0.001). ERBB2 status had little predictive value on overall survival. In conclusion, this study showed ERBB2 amplification was significantly observed in tubular adenocarcinoma and Lauren intestinal-type carcinoma. The IHC scoring criteria for ERBB2 can be applied to EGFR. EGFR amplification had associated with poor prognosis in early, well to moderately differentiated carcinoma.

This study examined the incidence rates, histologic and stage distribution, and long-term survival rates of patients with cervical cancer in Korea. A total of 44,182 patients diagnosed with cervical cancer between 1993 and 2002 were reported to the Korea Central Cancer Registry and the Gynecologic Oncology Committee of Korean Society of Obstetrics and Gynecology. The age-standardized incidence rates were 19.0, 17.8, and 15.1 per 100,000 women in 1993-1995, 1996-1998, and 1999-2002, respectively. The incidence rates of adenocarcinoma (AC) have been in the range between 1.2 in 1993-1995 and 1.4 in 1999-2002, while those of squamous cell carcinoma declined from 15.1 in 1993-1995 to 12.2 in 1999-2002. The 5-year relative survival rate was 79.2%. Relative survival rates, according to stage by the FIGO, at 5 years were 94.2%, 69.7%, 38.9%, and 21.1% for stages I, II, III, and IV respectively. Relative survivals improved between 1993 and 1997, probably due to the introduction of cervical cancer screening and effective treatment. The incidence rates of AC have been constant despite decreased cervical cancer in Korea. Introduction of cervical cancer screening and effective treatment may have contributed to the improved relative survival.

In a previous study, we demonstrated that elevation of COX-2 is significantly associated with lymph node metastasis in squamous cell carcinoma (SCC) of cervix. The main objective of this study is to characterize the relationship between elevation of COX-2 and its possible clinical role in adenocarcinoma (AC) of cervix. Using immunohistochemistry, we examined COX-2 expression levels in 84 patients with AC of uterine cervix [71 ACs, 13 adenosquamous carcinomas (ASCs)]. Elevation of COX-2 was correlated with clinicopathological variables and p53 expression, as detected by immunohistochemistry. Elevation of COX-2 was detected in 13.0% (11 of 84) of the tumors. Elevation of COX-2 was significantly correlated with histologic type (AC 8.5% vs. ASC 38.5%, P=0.011). Both tumor stage and lymph node metastasis were correlated with elevation of COX-2 with a borderline significance (P=0.062 and 0.068, respectively). Elevation of p53 was not associated with elevation of COX-2. The association between lymph node metastasis and elevation of COX-2 was stronger in cases of AC than in cases of ASC (28.4 vs. 4.3%, P=0.023). According to the results of univariate analysis, elevation of COX-2 was significantly associated with decreased overall survival (P=0.003, log-rank test). However, multivariate analyses revealed that only tumor stage was independently associated with overall survival, suggesting that elevation of COX-2 itself may not be an independent prognostic factor. The present study shows that elevation of COX-2 may contribute to lymph node metastasis in AC of uterine cervix. This suggests that the potential therapeutic role of COX-2 inhibitors should be validated, not only in SCC, but also in AC of uterine cervix.

The incidence of cervical adenocarcinoma (CA) is rising, whereas the incidence of cervical squamous cell carcinoma (CSCC) continues to decrease. However, it is still unclear whether different molecular characteristics underlie these 2 types of cervical carcinoma. To better understand the epigenetic characteristics of cervical carcinoma, we investigated the DNA promoter hypermethylation profiles in CA and CSCC. In addition, we investigated whether DNA hypermethylation patterns might be used for the molecular diagnosis of CA and endometrial adenocarcinoma (EA). Using the bisulfite-modification technique and methylation-specific PCR, we examined the aberrant promoter hypermethylation patterns of 9 tumor suppressor genes (APC, DAPK, CDH1, HLTF, hMLH1, p16, RASSF1A, THBS1 and TIMP3) in 62 CSCCs, 30 CAs and 21 EAs. After Bonferroni correction adjustment (statistically significant at p < 0.0055), we found that the aberrant hypermethylations of CDH1 and DAPK were more frequent in CSCCs than in CAs (80.6% vs. 43.3%, p = 0.001; 77.4% vs. 46.7%, p = 0.005), whereas HLTF and TIMP3 were more frequently methylated in CAs (3.2% vs. 43.3%, p < 0.001; 8.1% vs. 53.3%, p = 0.001). The hypermethylations of RASSF1A and APC were more frequent in CAs than in CSCCs, but this was not significant (9.7% vs. 33.3%, p = 0.008; and 14.5% vs. 40.0%, respectively, p = 0.009). In addition, RASSF1A hypermethylation was significantly more frequent in EAs than in CAs (81.0% vs. 33.3%, p = 0.001). In conclusion, the existence of these unique methylation patterns in these cancers suggests that their tumorigenesis may involve different epigenetic mechanisms., (2005 Wiley-Liss, Inc.)

We examined whether Epstein-Barr virus (EBV) infection plays a role in cervical carcinogenesis in Korean women. EBV infection was examined using polymerase chain reaction (PCR) with two different primer pairs flanking the BamHI "W" fragment of EBV and by EBV-encoded small RNAs (EBER) in situ hybridization in various histologic types of cervical cancer, including 17 cases of squamous cell carcinoma, 36 cases of adenocarcinoma, and 3 cases of small-cell carcinoma. We also evaluated 20 cases of cervical intraepithelial neoplasia and 20 cases of normal uterine cervix. One case of squamous cell carcinoma and three cases of cervical intraepithelial neoplasia were positive for EBV DNA using PCR, but EBER in situ hybridization analysis showed that none of the PCR-positive cases expressed EBER. EBV DNA was not found using PCR in any of the 20 normal uterine cervices. From our results, EBV infection does not seem to play a role in cervical carcinogenesis in Korean women.

There is increasing evidence for the role of heterocyclic and other arylamines in carcinogenesis, including lung carcinogenesis. Chinese women have a high rate of lung cancer despite a low smoking prevalence, and studies in this population may provide useful information on risk factors other than smoking. Hepatic CYP1A2 and NAT2 are involved in the metabolism of carcinogenic arylamines, and NAT2 also catalyzes the detoxification pathway for these compounds. In this study, we examined the effect of CYP1A2 activity using a urinary caffeine metabolic ratio assay for 54 Chinese women with newly diagnosed lung cancer (including 28 adenocarcinomas) and 174 hospital controls. Among them, NAT2 genotype was available for 47 cases and 98 controls. There was no effect of CYP1A2 activity on overall risk of lung cancer in the study population [odds ratio (OR) 0.8, 95% confidence interval (CI) 0.4-1.6, adjusted for age at diagnosis, smoking and cruciferous vegetable intake]. For adenocarcinomas, the OR was 1.5, 95% CI 0.6-3.4. After further adjustment for NAT2 acetylator genotype, the OR for adenocarcinoma was 1.8 (95% CI 0.7-4.8). When the combined NAT2/CYP1A2 status was examined, women with slow NAT2 and rapid CYP1A2 activity were at highest risk (adjusted OR 6.9, 95% CI 1.3-37.6) relative to women with rapid NAT2 and slow CYP1A2 activity, for lung adenocarcinoma. While larger studies are needed to confirm or refute these results, they are consistent with a role for heterocyclic arylamines in lung carcinogenesis in this primarily non-smoking population.

Chinese women are recognized to have a high incidence of lung cancer despite a low smoking prevalence. Several studies have implicated domestic exposure to cooking fumes as a possible risk factor, although the exact carcinogens have yet to be identified. Heterocyclic amines are known carcinogens, which have been identified in cooked meat, and also in fumes generated during frying or grilling of meats. We conducted a case-control study of 303 Chinese women with pathologically confirmed, primary carcinomas of the lung and 765 controls to examine the association between exposure to meat cooking and lung cancer risk. Data on demographic background, smoking status, and domestic cooking exposure, including stir-frying of meat, were obtained by in-person interview while in hospital. The response rates among eligible cases and controls were 95.0 and 96.9%, respectively. The proportion of smokers (current or ex-smokers) among cases and controls was 41.7 and 13.1%, respectively. Adenocarcinomas comprised 31.5% of cancers among smokers and 71.6% among nonsmokers. When cases were compared with controls, the odds ratio (OR) for lung cancer (all subtypes) among ex-smokers was 4.3 [95% confidence interval (CI) 2.7-6.8] and that among current smokers was 5.0 (95% CI, 3.4-7.3). Among smokers, women who reported that they stir-fried daily in the past had a significantly increased risk of lung cancer (adjusted OR, 2.0; 95% CI, 1.0-3.8) and among these women, risk was enhanced for those who stir-fried meat daily (OR, 2.7; 95% CI, 1.3-5.5). Women who stir-fried daily but cooked meat less often than daily did not show an elevated risk (OR, 1.0. 95% CI, 0.5-2.4). Risk was further increased among women stir-frying meat daily who reported that their kitchen was filled with oily fumes during cooking (OR, 3.7; 95% CI, 1.8-7.5). These cooking practices on their own did not increase risk among nonsmokers in our study population. Our results suggest that inhalation of carcinogens, such as heterocyclic amines generated during frying of meat, may increase the risk of lung cancer among smokers. Further studies in different settings are warranted to examine this possibility, which may also help to explain the higher risk observed among women smokers compared with men.

Among non-smokers, the factors resulting in lung carcinogenesis are poorly understood. We conducted a hospital-based case-control analysis of 294 Chinese women, of whom 217 were non-smokers, to evaluate the role of polymorphic N-acetyltransferase (NAT2) as a susceptibility factor for the disease. The proportion of slow acetylator genotypes among non-smoking cases (n = 92) and controls (n = 125) was 38.0 and 24.0%, respectively [odds ratio (OR) 2.0, 95% confidence interval (CI) 1.1-3.7]. No effect of NAT2 genotype was seen among smokers. Among non-smokers, the effect was marked for adenocarcinomas (OR 2.1, 95% CI 1.1-4.0). As NAT2 activity is known to modify risk of arylamine-induced carcinogenesis, our results suggest that exposure to arylamines in the environment may play a role in risk of lung cancer among non-smokers.

The present study describes mutations of the tumour suppressor gene p53 in a local collection of colorectal and hepatocellular carcinomas (HCCs). Tumour DNA was extracted from both fresh and paraffin-embedded tissues and exons 5-8 of the p53 gene were amplified by polymerase chain reaction (PCR). Mutations were detected by single-strand conformation polymorphism (SSCP) analysis followed by direct DNA sequencing. Of the 38 colorectal carcinomas and 42 HCCs examined, 15 (39%) and 13 (31%), respectively, showed p53 mutations. Two-thirds (10/15) of the mutations in colorectal carcinomas were base transitions with a predominance at CpG dinucleotide sites--a pattern characteristic to an endogenous process in cancer development. Three mutational hotspots at codons 175, 248 and 282 were also identified. Mutations did not correlate with histological grade, Dukes stage, or metastasis. However, tumours at the distal site of the colorectum showed a higher proportion of mutations than the proximal site. In the case of HCCs, majority (9/13) of the mutations were base transitions and no mutations were observed at codon 249. This is in contrast to results from other high-incidence areas such as Africa and China, where aflatoxin is believed to be a major aetiologic factor for liver cancers. The results therefore suggest that other risk factors, rather than dietary exposure to aflatoxin, may contribute to the high HCC incidence in Singapore.

Purpose: Pelvic radiation is standard treatment for women with stage IIb to IVa cervical cancer, but treatment results are disappointing, particularly for women with bulky tumors. We investigated the role of primary chemotherapy followed by pelvic radiotherapy in a randomized trial., Patients and Methods: Two hundred sixty patients with stage IIb and IVa cervical cancer received either standard pelvic radiotherapy or primary chemotherapy with cisplatin 60 mg/m2 and epirubicin 110 mg/m2 administered at 3-week intervals for three cycles, followed by pelvic radiotherapy., Results: Ninety-nine patients have relapsed with a median follow-up duration of 1.3 years; in 62 patients, the first site of progressive disease was the pelvis. Patients who received primary chemotherapy had a significantly higher pelvic failure rate than those who received radiotherapy alone (P < .003). Seventy-six patients have died, and those who received primary chemotherapy had significantly inferior survival compared with those who received radiotherapy alone (P = .02). Tumor response following chemotherapy was observed in 63%. After radiotherapy, tumor response occurred in 72% of those who received combined modality treatment, compared with 92% of those who received radiotherapy alone., Conclusion: Primary chemotherapy with epirubicin and cisplatin, although resulting in tumor response in a significant proportion of patients, is accompanied by an inferior local control rate and survival compared with standard pelvic radiotherapy alone.