Haixin Li

The hOGG1 Ser326Cys Polymorphism and Lung Cancer Risk: A Meta-analysis

The potentially functional polymorphism Ser326Cys in the human 8-oxoguanine DNA glycosylase (hOGG1) gene has been implicated in lung cancer risk, but published studies have mixed findings. To summarize published data, we did a comprehensive meta-analysis. Two investigators extracted data independently from 17 case control studies published in the PubMed using the search phrases “hOGG1/OGG1/OGG and polymorphism/genetic variation and lung cancer.” The meta-analysis included 6,375 cancer cases and 6,406 control subjects. The results showed that individuals carrying the hOGG1 Cys/Cys genotype did not have significantly increased risk of lung cancer [odds ratios (OR), 1.15; 95% (confidence interval) CI, 0.94-1.41] compared with those with the Ser/Ser genotype; similarly, no significant association with lung cancer risk was found either in the recessive (OR, 1.09; 95% CI, 0.90-1.32 for Cys/Cys versus Ser/Cys+Ser/Ser) or dominant model of the Ser326 allele (OR, 1.06; 95% CI, 0.93-1.21 for Cys/Cys+Ser/Cys versus Ser/Ser). However, significantly increased risks were found among Asian subjects (OR, 1.18; 95% CI, 1.01-1.38 for Cys/Cys+Ser/Cys versus Ser/Ser) in a dominant model. In stratified analyses by control source, compared with the Ser/Ser genotype, lung cancer risk associated with the hOGG1 Cys/Cys genotype was significantly increased in population-based studies (OR, 1.32; 95% CI, 1.04-1.67) but not in hospital-based studies (OR, 1.18; 95% CI, 0.98-1.42); in stratified analyses by the smoking status, however, the increased risk was observed only among nonsmokers in a dominant model (OR, 1.32; 95% CI, 1.04-1.67). The meta-analysis suggested that a careful matching should be considered in future larger genetic association studies including multiple ethnic groups. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1739–45)

Deletion of the WWOX gene and frequent loss of its protein expression in human osteosarcoma

To evaluate the role of WWOX gene in human osteosarcoma, array comparative genomic hybridization on 10 frozen osteosarcoma specimens and immunohistochemical staining of 55 formalin-fixed and paraffin-embedded tissues for WWOX was performed. Deletion of the WWOX gene was observed in 3 of 10 samples and the WWOX protein was undetectable in 34 of 55 osteosarcomas. This is the first investigation of the role of WWOX gene in human osteosarcoma. The WWOX gene deletion, loss of its protein expression, and lack of correlation of WWOX expression with patient survival suggest loss of WWOX expression is an early event in the pathogenesis of osteosarcoma and the phenotypic results of its deletion do not imminently result in patient death.

Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy.

Significance We have identified a lethal subtype of gastric cancer (GC) that is characterized by high levels of clonal heterogeneity and TP53 (tumor protein P53) mutation. We have also uncovered key novel mutations in the targetable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair and identified BRCA2 (breast cancer 2, early onset) mutations as new genetic markers to predict better survival for GC. Our study represents a novel approach for GC personalized medicine and identified novel clinical actionable therapies for GC therapy. Gastric cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with three primary tumors and two matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC). The HiC subtype of intratumoral heterogeneity was associated with older age, TP53 (tumor protein P53) mutation, enriched C > G transition, and significantly shorter survival, whereas the LoC subtype was associated with younger age, ARID1A (AT rich interactive domain 1A) mutation, and significantly longer survival. Phylogenetic tree analysis of whole-genome sequencing data from multiple samples of two patients supported the clonal evolution of GC metastasis and revealed the accumulation of genetic defects that necessitate combination therapeutics. The most recurrently mutated genes, which were validated in a separate cohort of 216 cases by targeted sequencing, were members of the homologous recombination DNA repair, Wnt, and PI3K-ERBB pathways. Notably, the drugable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair were mutated in 10% of GC cases. Mutations of the BRCA2 (breast cancer 2, early onset) gene, found in 8% of our cohort and validated in The Cancer Genome Atlas GC cohort, were associated with significantly longer survivals. These data define distinct clinicogenetic forms of GC in the Chinese population that are characterized by specific mutation sets that can be investigated for efficacy of single and combination therapies.

Clonality Analysis for Multicentric Origin and Intrahepatic Metastasis in Recurrent and Primary Hepatocellular Carcinoma

AimsTo clarify the incidence of multicentric occurrence (MO) and intrahepatic metastasis (IM) for hepatocellular carcinoma (HCC) related to hepatitis B virus in China and to identify the differences between them.MethodsHistopathologic and genetic features of primary and recurrent tumors in 160 cases with HCC were analyzed. The two groups, the origin of which was definitely determinable as of multicentric occurrence or as of intrahepatic metastasis, were analyzed for their disease-free survival and clinicopathological differences.ResultsAccording to histopathological findings, 27.5% and 59.4% patients were considered to be MO and IM, respectively. By comparing the genetic information of loss of heterozygosity and microsatellite instability for 10 different markers between primary and recurrent tumor, 30.0% and 63.8% patients with recurrent HCC were considered to be MO and IM, respectively. In total, 126 cases with unanimous conclusions from the histopathological and genetic method were selected and divided into the MO group (37 cases) and the IM group (89 cases). Analysis of stepwise regression identified that recurrence time, grading, portal vein invasion, tumor number, and Child’s stage were the most important discriminating factors between MO and IM (p < 0.05). As for their prognosis, Kaplan–Meier and log rank test showed that the disease-free survival in the MO group was significantly better than in the IM group (p = 0.002).ConclusionsCombined analysis of histopathological and genetic analysis may reflect more exactly the nature of recurrent HCC. The incidence of MO in China is lower than in other countries—30% compared to up to 50% in Japan [Morimoto et al., Journal of Hepatology 39:215–221, 2003; Yamamoto et al., Hepatology 29;1446–1452, 1999]. Recurrence time, tumor grading, portal vein invasion, tumor number, and Child’s stage are the most important discriminating factors between MO and IM. The prognosis (disease-free survival) of patients with MO compared to IM is significantly better.

A cancer incidence survey in Tianjin: the third largest city in China—between 1981 and 2000

During the past three decades, the social/natural environment and lifestyle of people in China have undergone a marked transformation to westernization. However, age-standardized cancer rates have not been determined to any great extent in China. In this study, we tracked the cancer incidence between 1981 and 2000 in Tianjin, to identify the changes in incidence associated with social and economic changes. Cancer incidence data were collected by the Tianjin Cancer Registry. Sex, age, and organ site-specific incidence trends were analyzed by the “join-point regression” method. Overall crude cancer incidence increased, but the age-standardized incidence slightly decreased during the study period. The incidence of lung cancer increased between 1981 and 1996 but decreased between 1996 and 2000. The incidences of uterine, esophageal, stomach, and liver cancers decreased. However, the incidences of colorectal, pancreatic, breast, ovarian, and prostate cancers all increased during the study period. There was an aging-related increase in the overall crude cancer incidence and an alteration in the distribution of cancer types in Tianjin. The incidences of cancer types that are more prevalent in developed countries appeared to increase in China, whereas the incidences of cancer types that are more prevalent in developing countries appeared to decline.

Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women

Ovarian cancer is the leading cause of death from gynaecological malignancies worldwide. Here we perform a three-stage genome-wide association study (GWAS) in Han Chinese women to identify risk genetic variants for epithelial ovarian cancer (EOC). We scan 900,015 single-nucleotide polymorphisms (SNPs) in 1,057 EOC cases and 1,191 controls in stage I, and replicate 41 SNPs (P(meta)<10(-4)) in 960 EOC cases and 1,799 controls (stage II), and an additional 492 EOC cases and 1,004 controls (stage III). Finally, we identify two EOC susceptibility loci at 9q22.33 (rs1413299 in COL15A1, P(meta) = 1.88 × 10(-8)) and 10p11.21 (rs1192691 near ANKRD30A, P(meta) = 2.62 × 10(-8)), and two consistently replicated loci at 12q14.2 (rs11175194 in SRGAP1, P(meta) = 1.14 × 10(-7)) and 9q34.2 (rs633862 near ABO and SURF6, P(meta) = 8.57 × 10(-7)) (P<0.05 in all three stages). These results may advance our understanding of genetic susceptibility to EOC.

APEX1 gene amplification and its protein overexpression in osteosarcoma: Correlation with recurrence, metastasis, and survival

The expression of apurinic/apyrimidinic exonuclease 1 (APEX1) in tumors has been linked with chemoresistance, radioresistance, and shorter patient survival times. We sought to gain insight into the role of APEX1 in human osteosarcoma by evaluation of gene copy number alterations and its protein expression in osteosarcoma patients treated at the Sarcoma Center of Tianjin Cancer Hospital (Tianjin, China). To evaluate the gene copy number alterations of APEX1, we acquired 10 fresh tissue samples from 9 patients and performed whole-genome array-based comparative genomic hybridization (aCGH). We next acquired formalin-fixed and paraffin embedded tissues from 57 well-annotated osteosarcoma cases and performed immunohistochemical analyses for APEX1. APEX1 gene amplification was observed in 50% (5/10) of the osteosarcoma samples. The overexpression of APEX1 protein was detected in 64.9% (37/57) of the osteosarcomas ranging from negative (35.1%, 20/57), weakly positive (35.1%, 20/57), moderate (14%, 8/57) and strongly positive (15.8%, 9/57). The APEX1 expression had significant correlation with osteosarcoma local recurrence and/or metastasis. Moreover, multivariate analysis showed that APEX1 expression was an independent molecular predictor for disease-free survival of patients with osteosarcomas. Our study for the first time showed that APEX1 gene was amplified in osteosarcomas and that APEX1 expression was an independent predictor of the osteosarcoma local recurrence and/or metastasis. Thus, APEX1 may serve as a prognostic marker and potential therapeutic target for osteosarcoma.

Clinicopathologic features between multicentric occurence and intrahepatic metastasis of multiple hepatocellular carcinomas related to HBV.

AIMS To clarify the incidence of multicentric occurrence (MO) and intrahepatic metastasis (IM) for hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) in China and to identify the differences between them. PATIENTS AND METHODS Histopathologic features of multiple tumors in 82 cases with HCC were analyzed. The two groups, the origin was determinable as of multicentric occurrence or as of intrahepatic metastasis, were analyzed for their survival rate, disease-free survival and clinicopathologic differences. RESULTS According to histological findings, 19.5% and 69.5% patients were considered to be MO and IM, respectively. In total 73 cases from the histopathological method were selected and divided into group MO (16 cases) and the group IM (57 cases). Analysis of stepwise regression identified that: Childs stage, cholinesterase (host factors), tumor size, histological grade and positive portal vein invasion (tumor factors) were the most important discriminating factors between MO and IM (p<0.05). As for their prognosis, Kaplan-Meier and Log rank test showed the survival rate in group MO was significantly better than that in the group IM (p=0.003). No statistical significance was found between the disease-free survival in group MO and that in group IM (p=0.141). The analysis of Coxs proportional hazards model showed that tumor type (MO or IM) and Childs stage were the important prognostic factors (p=0.002 and 0.014, respectively). CONCLUSIONS The incidence of MO in patients with multiple HCCs related to HBV is only about 20%, which is lower than that of Japan. Childs stage, cholinesterase (host factors), tumor size, histological grade and positive portal vein invasion (tumor factors) are the most important discriminating factors between MO and IM. The prognosis of patients with MO compared to IM is significantly better and tumor type (MO or IM) and Childs stage are important prognostic factors.

Trends in head and neck cancer incidence in Tianjin, China, between 1981 and 2002.

Head and neck cancer is 1 of the major global health issues but received limited attention, and its incidence has rarely been systematically studied in China.

Gene-Environment Interactions for Breast Cancer Risk Among Chinese Women: A Report From the Shanghai Breast Cancer Genetics Study

Genome-wide association studies have identified approximately 20 susceptibility loci for breast cancer. A cumulative genetic risk score (GRS) was constructed from 10 variants with replicated associations among participants of the Shanghai Breast Cancer Genetics Study (Shanghai, China, 1996-1998 and 2002-2005). Interactions between the GRS and 11 breast cancer risk factors were evaluated. Among the 6,408 study participants, no evidence of effect modification was found with the GRS for age at menarche, age at menopause, age at first live birth/parity, total months of breastfeeding, family history of breast cancer, history of benign breast disease, hormone replacement therapy, body mass index, waist/hip ratio, or regular physical activity. The effect of the GRS was least homogeneous by duration of menstruation; further analysis indicated a nominally significant interaction with one genetic variant. The mitochondrial ribosomal protein S30 gene (MRPS30) rs10941679 was associated with breast cancer risk only among women with more than 30 years of menstruation (odds ratio = 1.15, 95% confidence interval: 1.05, 1.26). Although this multiplicative interaction reached a nominal significance level (P = 0.037), it did not withstand correction for multiple comparisons. In conclusion, this study revealed no apparent interactions between genome-wide association study-identified genetic variants and breast cancer risk factors in the etiology of this common cancer.