Earlier onset and multiple primaries in familial as opposed to sporadic esophageal cancer

AIM: To study the differences in onset age and multiple primary cancers between familial and sporadic esophageal squamous cell carcinoma(ESCC).METHODS: The differences in onset age and multiple primary cancers were analyzed between ESCC patients with(n = 766) and without(n = 1776) a family history of the cancer. The cases analyzed constituted all consecutive patients who had undergone cure-intent surgery at the Department of Thoracic Surgery of the 4th Hospital of Hebei Medical University from January 1 1975 to December 31 1989. Because we also originally aimed to examine the difference in survival time, only older subjects with a long follow-up period were selected.RESULTS: Overall, patients with ESCC and a positive family history of the cancer had a significantly younger age at onset and more multiple primary cancers than those without a positive family history(51.83 ± 8.39 vs 53.49 ± 8.23 years old, P = 0.000; 5.50% vs 1.70%, P = 0.000). Both of these differences were evident in subgroup analyses, however, no correlations were observed. While age at onset differed significantly by family history in males, smokers, and drinkers, the difference in multiple primary cancers by family history was significant in nonsmoking, nondrinking, and younger onset patients. In multivariate analysis, age over 50 years, tobacco smoking, and multiple primary cancers were found to be significant predictors of familial cancer: the corresponding OR(95%CI) and P-value were 0.974(0.963-0.985) and 0.000; 1.271(1.053-1.535) and 0.012; and 4.265(2.535-7.176) and 0.000, respectively.CONCLUSION: Patients with ESCC and a positive family history of the cancer had a significantly younger onset age and more multiple primary cancers than those without a positive family history. Sub-group analyses indicated that younger onset age may be due to the interaction of genetic predisposition and environmental hazards, and multiple primary cancers may only be due to genetic predisposition.

Expression of FANCD2 in Sporadic Breast Cancer and Clinicopathological Analysis

FANCD2 is involved in DNA damage repair and maintenance of chromosome stability.The purpose of this study was to investigate the expression of FANCD2 in sporadic breast cancer tissues and its association with clinicopathological features.A total of 162 Chinese women with invasive breast carcinoma who had no family history in first-degree relatives and 12 normal breast tissues were examined.The expression of FANCD2 was detected by immunohistochemical staining based on a tissue microarray technique.SAS system was used to analyze the data.Twenty-one out of the 162 invasive breast cancers(13%) were negative for FANCD2.The mean percentage of FANCD2 positive cells was significantly lower in breast cancers than in controls(P0.05).It was suggested that FANCD2 may play a critical role in breast carcinogenesis.It may become a valuable and independent marker for identifying women with sporadic breast cancer and evaluating the prognosis.

Clinical characteristics of patients in their forties who underwent surgical resection for colorectal cancer in Korea

BACKGROUND The proportion of young patients with colorectal cancer(CRC),especially in their 40s,is increasing worldwide.AIM To confirm the clinical characteristics of such patients,we planned a study comparing them to patients in their 30s and 50s.METHODS Patients undergoing primary resection for CRC,patients in their 30s,40s and 50s were included in the study.Patient and tumor characteristics,and perioperative and oncologic outcomes were compared.RESULTS Most clinical characteristics of 451(10.5%)patients in their 40s were more similar to those of patients in their 30s than those in their 50s.On pathology data,there were more metastatic lesions(30s vs 40s vs 50s;17.5%vs 21.1%vs 14.9%,P=0.012)in patients in their 40s.There was a trend toward less frequent K-ras mutations among patients in their 40s(48.5%vs 33.3%vs 44.5%,P=0.064).The proportion of patients receiving postoperative chemotherapy was also significantly greater among patients in their 40s(58.3%vs 63.9%vs 56.3%,P=0.032).Five-year overall survival(OS)and disease-free survival(DFS)did not differ between the three groups(5-year OS,92.2%vs 89.8%vs 92.2%,P=0.804;5-year total DFS,98.6%vs 95.7%vs 96.1%,P=0.754;5-year local DFS,98.6%vs 94.3%vs 94.9%,P=0.579;5-year systemic DFS,86.4%vs 87.9%vs 86.4%,P=0.908).CONCLUSION Patients with CRC in their 40s showed significantly more numerous metastatic lesions.The oncologic outcome of stage 1-3 patients in their 40s was not inferior compared to that of those in their 30s and 50s.

MutL homolog 1 methylation and microsatellite instability in sporadic colorectal tumors among Filipinos

BACKGROUND Colorectal cancer(CRC)ranks third in terms of incidence and second in mortality worldwide.In CRC,the silencing of mismatch repair genes,including the mutL homolog 1(hMLH1)has been linked to microsatellite instability(MSI),the lengthening or shortening of microsatellite repeats.Very limited data have been presented so far on the link of hMLH1 methylation and MSI in Southeast Asia populations with sporadic CRC,and on its clinical significance.AIM To investigate the significance of the MSI status and hMLH1 methylation in CRC Filipino patients.METHODS Fifty-four sporadic CRC patients with complete clinical data were included in this study.Genomic DNA from CRC tumor biopsies and their normal tissue counterparts were profiled for MSI by high resolution melting(HRM)analysis using the Bethesda Panel of Markers(BAT25,BAT26,D2S123,D5S346,and D17S250).hMLH1 methylation screening was performed using bisulfite conversion and methylation specific polymerase chain reaction.Statistical analysis was conducted to calculate their associations to clinicopathological characteristics and survival relevance(Kaplan-Meier curves and the log-rank test).RESULTS hMLH1 methylation was observed in 9%and 35%of CRC and normal samples,respectively.Higher incidence of consistently methylated hMLH1 found in both normal and CRC was noticed for relation to location of tumor(P<0.05).As for MSI status,D2S123 the most common unstable microsatellite and MSI-high(MSIH)was the most common MSI profile,counted for 46%and 50%of normal and CRC tissues,respectively.The presence of MSI-low(MSI-L)and microsatellite stable(MSS)was 43%and 11%for normal,and 31%and 19%for CRC samples.The mean month of patients’survival was shorter in patients whose normal and tumor tissues had methylated compared to those with unmethylated hMLH1 and with MSI-H compared to those with MSI-L/MSS(P<0.05).This was supported by significant difference in Kaplan-Meier with log-rank analysis.This data indicated that hMLH1 methylation and high MSI status have prognostic value.CONCLUSION This study showed the clinical significance of hMLH1 methylation and MSI status in sporadic CRC Filipino patients,especially in the normal part of the tumor.

Screening of tumor suppressor genes on 1q31.1-32.1 in Chinese patients with sporadic colorectal cancer

Background As a model for both multistep and multipathway carcinogenesis, colorectal neoplastic progression provides paradigms for researching both oncogenes and tumor suppressor genes （TSGs）. However, the mechanism of colorectal cancer （CRC） is not completely understood, and many genes may be involved in the colorectal carcinogenesis. The purpose of this study was to screen for the potential TSGs on chromosome 1q31.1-32.1 in Chinese patients with sporadic colorectal cancer, to explore whether colorectal cancer in the Chinese population has unique genetic alterations and determine whether other putative TSGs exist and contribute to colon carcinogenesis. Methods Six polymorphic microsatellite markers, at a density of approximately one marker in every 1.6 cM, were chosen for refined loss of heterozygosity （LOH） mapping of 1q31.1-32.1. Eighty-three colorectal cancer patients＇ tumor and normal DNA were analyzed via polymerase chain reaction （PCR） for these microsatellite markers. PCR products were eletrophoresed on an ABI 377 DNA sequencer. Genescan 3.1 and Genotype 2.1 software were used for LOH scanning and analysis. On the basis of refined LOH mapping results, we undertook a microarray-based expression screening to identify tumor association genes in 19 of the CRC cases. Results The average LOH frequency of 1q31.1-32.1 was 24.41%, with the highest frequency of 36.73% （18/49） at D1S2622, and the lowest of 16.42% （11/67） at D1S412. A minimal region of frequent deletion was located within a 2 cM genomic segment at D1S413-D1S2622. There was no significant association between LOH of any marker in the studied regions and the clinicopathological data （patient sex, age, tumor size, growth pattern, or Dukes stage）. On the basis of refined mapping results, we chose 25 genes located in the D1S413-D1S2622 （1q31.3-32.1） region and presented a microarray-based high throughput screening approach in 19 sporadic CRC cases to identify candidate CRC related tumor suppressor genes. This study found 4 significantly down-expressed genes, including CSRP1, LMOD1, PPP1R12B and CFHL3. There was no significant association between expression levels of CFHL3, CSRP1, LMOD1, PPP1R12B and the clinicopathological data. By database searching, CSRP1 was hypothesized to be a colorectal cancer related tumor suppressor gene. Conclusions Through detailed deletion mapping, we found that the 1q31.3-32.1 region might harbor one or more colorectal cancer related tumor suppressor gene（s）. And by microarray-based high-throughput screening of candidate genes located in this region and by subsequent database searching, we present the first evidence that CSRP1 might be involved in the progression of CRC.

Heterogeneity of germline variants in high risk breast and ovarian cancer susceptibility genes in India

Breast and ovarian cancers now account for one in three cancers in Indian women and their incidence is rising.Major differences in the clinical presentation of breast and ovarian cancers exist between India and the United Kingdom.For example,Indian patients with breast cancer typically present a decade earlier than in the UK.Reasons for this could be multifactorial,including differences in underlying biology,environmental risks,and other systematic factors including access to screening.One possible explanation lies in variable incidence or penetrance of germline mutations in genes such as BRCA1 and BRCA2.We performed a methodical database and literature review to investigate the prevalence and spectrum of high-risk cancer susceptibility genes in Indian patients with breast and ovarian cancers.We identified 148 articles,but most studies were small,with inconsistent inclusion criteria and based on heterogeneous technologies,so that mutation frequency could not be reliably ascertained.Data were also often lacking on penetrance,histopathology,and survival outcomes.After filtering out unsuitable studies,only 13 remained,comprising 1028 patients.Large-scale research studies are urgently needed to determine mutation prevalence,spectra,and clinico-pathological features,and hence derive guidelines for screening,treatment,and prevention specific to the Indian population.