LAPTM4B Polymorphisms is Associated with Ovarian Cancer Susceptibility and Its Prognosis

Japanese Journal of Clinical Oncology Advance Access published March 12, 2012 Jpn J Clin Oncol 2012 doi:10.1093/jjco/hys026 Original Article LAPTM4...
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Japanese Journal of Clinical Oncology Advance Access published March 12, 2012

Jpn J Clin Oncol 2012 doi:10.1093/jjco/hys026

Original Article

LAPTM4B Polymorphisms is Associated with Ovarian Cancer Susceptibility and Its Prognosis Ye Xu 1, Yunduo Liu 1, Rouli Zhou 2, Fanling Meng 1, Ying Gao 1, Shanshan Yang 1, Xueting Li 1, Meng Yang 1 and Ge Lou 1,* 1

*For reprints and all correspondence: Ge Lou, Department of Gynecology, The Affiliated Tumor Hospital, Harbin Medical University, Harbin 150081, China. E-mail: dr_loug[email protected] Received December 16, 2011; accepted February 12, 2012

Objective: Lysosome-associated protein transmembrane 4 beta (LAPTM4B) is an important novel gene associated with the proliferation and differentiation of cells. Recent studies have shown that it was overexpressed in many cancer tissues. This study investigated the association between different LAPTM4B polymorphisms and the susceptibility and prognosis of ovarian cancer. Methods: A case – control study was performed in 282 patients with ovarian cancer and 365 control subjects. Genomic DNA was extracted from peripheral blood lymphocytes in all participants. LAPTM4B genotypes were determined using polymerase chain reaction. Results: There was a significantly higher LAPTM4B*2 allele frequency in ovarian cancer cases than controls (P , 0.05). Using the LAPTM4B*1/1 genotype as the reference, we found that the LAPTM4B*1/2 and LAPTM4B*2/2 genotypes were positively associated with ovarian cancer. Additionally, we found a negative correlation between the tumor grade and LAPTM4B allele genotype, which indicates strongly that LAPTM4B*2 could affect the survival of patients. Conclusions: These findings indicate that the LAPTM4B*2 allele may be a risk factor for ovarian cancer and may play an important role in genetic susceptibility to ovarian cancer. Key words: ovarian cancer – LAPTM4B – polymorphism – susceptibility – prognosis

INTRODUCTION Ovarian cancer is the second most common female reproductive malignancy, but its 47% mortality rate accounts for more deaths than any other reproductive cancers. Because of a lack of effective measures for early detection and diagnosis, the majority of patients with ovarian cancer present with significant intraperitoneal and/or lymph node metastatic disease at diagnosis (1). Consequently, the long-term survival rate is only 30 – 40%. Therefore, it is important to explore the etiology of ovarian cancer and block its progression. With the completion of the Human Genome Project and recent breakthroughs in basic cancer research, understanding the pathogenesis of ovarian cancer at a molecular

level and improving early diagnosis are promising areas of research. Lysosome-associated protein transmembrane-4 beta (LAPTM4B), a novel tumor-associated gene, has been successfully cloned in hepatocellular carcinomas (HCCs) (2,3). It is expressed at fairly low levels in normal adult liver but is significantly overexpressed in most HCCs. Furthermore, expression levels are closely related to differentiation status in HCCs (2 – 5). LAPTM4B was mapped to 8q22 and contains seven exons, separated by six introns. The full length of the messenger RNA (mRNA) is 2245 bp, which encodes a lysosome-associated protein with four transmembrane regions.

# The Author 2012. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

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Department of Gynecology, The Affiliated Tumor Hospital, Harbin Medical University, Harbin and 2Department of Cell Biology, The School of Basic Medical Sciences, Peking University, Beijing, China

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LAPTM4B polymorphisms and ovarian cancer

Figure 1. Schematic diagram representation of exon 1 of lysosomeassociated protein transmembrane 4 beta (LAPTM4B) alleles. Allele *1 contains one copy of the 19-bp sequence (shaded box) and allele *2 contains two copies of the 19-bp sequences that are tandemly arranged (two shaded boxes). The DNA sequences in the shaded boxes are shown in the lower panels.




Cases consisted of 282 patients with ovarian cancer who were first diagnosed and treated at the Affiliated Tumor Hospital at Harbin Medical University from January 2003 to December 2006. The diagnoses were confirmed by pathology reports that were obtained after operation. All patients had no chemotherapy treatment before operation. Histological typing was carried out according to World Health Organization classification standards (13). Tumor staging and grading were based on the criteria from the International Federation of Gynecology and Obstetrics (FIGO) staging system (14). Controls were healthy individuals recruited from the same hospital for regular gynecological examinations during the period when women with ovarian cancer were enrolled. To be eligible, control subjects had to present




Genomic DNA from human peripheral white blood cells was isolated using standard methods (Axygen, USA) from the 282 patients with ovarian cancer and 365 healthy female controls. For each sample, genotyping of LAPTM4B was determined by polymerase chain reaction (PCR) using the specific primers F (forward) 5 0 -GCCGACTAGGGGAC TGGCGGA-3 0 (nt 72 – 92) and R (reverse) 5 0 -CGAGAG CTCCGAGCTTCTGCC-30 (nt 255 – 275) (3) and separated on a 3% agarose gel. The PCR reaction mixture (50 ml) contained 0.5 U of Taq DNA polymerase (TaKaRa, Japan) and 5 ml of template DNA at a final concentration of 100 ng/ml. PCR conditions were as follows: initial denaturation at 968C for 5 min, followed by 35 cycles of 30 s each at 948C, annealing for 30 s at 658C and extension for 1 min at 728C. The final extension step was performed at 728C for 5 min. The amplified products were analyzed by electrophoresis in 3% agarose and visualized with 0.5 mg/ml ethidium bromide. For the PCR-based genotyping assay, genotyping was performed without prior knowledge of the subjects’ cases and control status. Two research assistants independently read the gel pictures and performed repeated assays if they did not reach a consensus on the tested genotype. In addition, 10% of the samples were randomly selected to perform the repeated assays, and the results were 100% concordant.

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LAPTM4B exists as two allelic genes, named LAPTM4B*1 and LAPTM4B *2 (GenBank accession No.: AY219176 and AY219177, respectively). Both have the same sequence except for a 19-bp segment in the 50 untranslated region (UTR) of exon 1. Allele *1 contains only one copy of a 19-bp sequence in the 50 UTR, whereas this sequence is duplicated and tandemly arranged in allele *2 (Fig. 1) (6). Recent studies have shown that LAPTM4B is an important gene associated with proliferation and differentiation of cells. In addition, it is overexpressed in many cancers, including gastric, breast, lung, (7) colon, rectal and esophageal cancer as well as gall-bladder carcinoma (8). Our previous studies have shown that LAPTM4B is up-regulated in cervical cancer (9), endometrial cancer (10) and ovarian cancer (11) and has important roles in the development and progression of these gynecological malignancies. Moreover, we also found that LAPTM4B gene polymorphisms contributed to the risk of cervical cancer (12). However, the correlation of LAPTM4B gene polymorphisms with ovarian carcinoma is still unclear. The available information makes it plausible to postulate that there may be an association between the allelic variation of LAPTM4B and the genetic susceptibility to ovarian cancer. Therefore, we designed a case – control study to examine this hypothesis.

with no abnormal findings during the gynecological examination, have no family history of cancer, be aged within 18 – 76 years and reside in the Heilongjiang Province. A total of 365 potential participants were interviewed, and all subsequently consented. Of the 282 ovarian cancer cases, 137 (48.58%) were serous cystadenocarcinoma, 18 (6.38%) were mucinous cystadenocarcinoma, 95 (33.69%) were adenocarcinoma (65 cases of endometrioid carcinoma, 27 cases of clear cell carcinoma and 3 cases of unclassified tumor) and 32 (11.35%) were other pathological types. Fifty-six patients with ovarian cancer classified as FIGO Stage I, 39 as FIGO Stage II, 165 as FIGO Stage III and 22 as FIGO Stage IV. Based on the histological grade analysis, clear cell tumors are all regarded as high grade, 65 cases were well differentiated, 61 were moderately differentiated and 156 were poorly differentiated. Trained personnel interviewed prospective blood donors, explained the study and asked them to read the study description. If subjects agreed to participate, written informed consent was obtained, and subsequently a blood sample was collected. This study was performed with the approval of the Institutional Ethics Committee of Harbin Medical University. Three milliliters of blood was collected from the cases and the controls who consented to donate samples for genotype assays. All blood specimens were stored in a 2808C freezer at the Gynecologic Department of Affiliated Tumor Hospital of Harbin Medical University.

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To confirm the genotyping results, 30% PCR-amplified DNA samples for the LAPTM4B gene were randomly selected and examined by DNA sequencing, and the results were also 100% concordant. FOLLOW-UP EVALUATION

STATISTICAL ANALYSIS The chi-squared test or Fisher’s exact test was used to compare the genotypic frequency and other parametric distributions between cancer cases and controls. Genotypic frequencies were tested for Hardy – Weinberg equilibrium using the chi-squared test (15). Associations between genotypes and risk of ovarian cancer were estimated using odds ratios (ORs) and 95% confidence intervals (CIs), which were computed with conditional logistic regression models. OS was calculated using the Kaplan – Meier method, and differences between groups were evaluated by the log-rank test. Survival times of patients still alive at the time of the last follow-up were censored. A multivariate Cox regression model was performed for OS comprising tumor stage, tumor grade, residual tumor mass and two LAPTM4B polymorphisms. Stratified analysis was used to evaluate the potential interaction effects between LAPTM4B genotypes and selected variables. Statistical analysis was carried out using SPSS 13.0 software (SPSS, Chicago, IL, USA). P values of ,0.05 were considered to indicate statistical significance and all P values were based on two-way tests.

RESULTS We tested 282 ovarian cancer subjects and 365 normal control subjects for the 19-bp polymorphism of the LAPTM4B gene. Using the specific primers for LAPTM4B, three different genotypes were identified in the PCR products. In homozygous individuals, we consistently found a 204-bp fragment coding for LAPTM4B *1/1 and a 223-bp fragment for LAPTM4B *2/2. In LAPTM4B *1/2 heterozygous individuals, both fragments were observed. Representative LAPTM4B genotypes from 15 individuals in this study are shown in Fig. 2. There were no significant differences in age between the case and control groups (P ¼ 0.32). All patients and normal

control subjects were investigated. The distributions of the genotype frequencies of LAPTM4B in the cases and controls are illustrated in Table 1. The observed genotype frequencies for this polymorphism were in agreement with that expected under the Hardy – Weinberg equilibrium in the controls (P ¼ 0.64). The LAPTM4B*2 allelic frequency was significantly higher in cases than those in controls (36.35 vs. 21.92%, respectively; P , 0.0001). LAPTM4B*2 subjects had a significantly higher risk of ovarian cancer compared with LAPTM4B*1 subjects OR ¼ 1.83; 95% CI ¼ 1.39 – 2.40). A statistical comparison showed that there were significant differences in the distribution of LAPTM4B *2/2 and LAPTM4B *1/2 between ovarian cancer groups and controls (P , 0.0001). In adjusted multivariate logistic regression analyses, subjects with the LAPTM4B*1/2 and *2/2 genotypes had, respectively, 1.72-fold (95% CI ¼ 1.03 – 2.34) and 2.98-fold (95% CI ¼ 1.73 – 5.07) increased risk of ovarian cancer than those carrying LAPTM4B*1/1. We also investigated the relationship between tumor grade and the allele genotype. The allelic frequencies of the LAPTM4B*2 were 38.78, 37.70 and 29.23% in the poorly differentiated group, moderately differentiated group and well-differentiated group, respectively, which indicated that LAPTM4B*2 significantly increased the incidence of poorly differentiated tumor grade [P ¼ 0.002, OR ¼ 1.71 (95% CI ¼ 1.21 – 2.43)]. All 282 patients with ovarian cancer underwent standard chemotherapy treatment after surgery. To examine the impact of LAPTM4B polymorphisms on the OS, we first performed univariate analysis of clinicopathological variables for prognosis. There were no statistically significant differences in characteristics such as age, pathological category, serum CA-125 level, ascites and intraperitoneal metastases (P . 0.05). The OS was significantly associated with residual tumor size (P ¼ 0.017), lymph node metastases (P , 0.001), pathological grade (P , 0.001) and FIGO classification (P , 0.001). LAPTM4B*1/2 and LAPTM4B*2/2 were related to a poor OS for patients with ovarian cancer (Fig. 3; Table 2). To evaluate the independent impact of LAPTM4B polymorphism on prognosis, a multivariate Cox regression model adjusted for statistically significant prognostic factors was performed. The multivariate analysis showed that the LAPTM4B polymorphism was an independent prognostic marker for OS of patients with ovarian cancer

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Examination performed during the follow-up period included serum CA-125, pelvic magnetic resonance imaging, color Doppler ultrasound of the liver and kidney, X-rays every 3 months for 2 years and at 6-month intervals in 3 – 5 years thereafter and annually thereafter. All 282 patients were followed for a median of 41 months (6 – 98 months), and the average of follow-up time was 45.98 months. The end point of the study was overall survival (OS). OS was defined as the time since primary surgery until death due to ovarian cancer or the date of last contact.

Figure 2. Samples were analyzed by separation in a 3% agarose gel electrophoresis. Lane M1: DNA marker (200, 300, 400, 500, 600 and 700 bp); lanes 2, 7, 12 and 13: *1/2 genotype; lanes 1, 3, 4, 5, 8, 9, 10, 11 and 14: *1/1 genotype and lanes 6 and 15: *2/2 genotype.

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LAPTM4B polymorphisms and ovarian cancer

Table 1. Allele and genotype frequencies of LAPTM4B gene polymorphism among patients and controls and their associations with the risk of ovarian cancer Pa

Number (%)

OR (95% CI)b





122 (43.26)

231 (63.29)


115 (40.79)

108 (29.59)

1.716 (1.032–2.339)



45 (15.96)

26 (7.12)

2.977 (1.728–5.069)




1.00 (reference)





359 (63.65)

570 (78.08)


205 (36.35)

160 (21.92)

LAPTM4B *1/1

122 (43.26)

231 (63.29)


160 (56.74)

134 (36.71)

Allele frequencies

1.834 (1.392–2.400)


Recessive model 1.00 (reference) ,0.0001

2.161 (1.546–2.906)


OR indicates odds ratio; CI, confidence interval. Two-sided chi-squared test. Data were calculated by logistic regression, adjusted for age.



CI ¼ 1.22 – 7.18) increased mortality of ovarian cancer than those carrying LAPTM4B*1/1 (Table 3). In addition, we further analyzed the distribution of clinical parameters such as age, residual tumor size, pathological category, serum CA-125 level, ascites, lymph node metastasis, intraperitoneal metastasis and FIGO classification of patients with different genotypes of LAPTM4B. The relationship between the genotype distribution of LAPTM4B and these clinical parameters failed to reach statistical significance in our study (data not shown).


Figure 3. Kaplan– Meier curves of overall survival related to the LAPTM4B polymorphisms in the 282 ovarian cancer patients. Patients with LAPTM4B*1/2 and LAPTM4B*2/2 had a poorer prognosis than that of patients with LAPTM4B*1/1.

(Table 2).We noted LAPTM4B*2 had higher risk of mortality when compared with those carrying LAPTM4B*1. In adjusted multivariate logistic regression analyses, subjects with the LAPTM4B*1/2 and *2/2 genotypes had, respectively, 1.24-fold (95% CI ¼ 0.72 – 2.24) and 2.95-fold (95%

LAPTM4B is a gene associated with cell proliferation and differentiation. Overexpression will accelerate cell proliferation, encourage uncontrolled proliferation, lead to malignant transformation and enhance metastasis. Previous studies have showed a possible association between LAPTM4B gene polymorphisms and susceptibility to several cancers, such as gastric and colon cancer. Furthermore, our previous experiments have also confirmed the relationship between LAPTM4B polymorphism and cervical cancer. Unfortunately, a detailed understanding of the relationship between LAPTM4B polymorphism and ovarian cancer remains unclear. Our major finding in this study is that subjects with the LAPTM4B*2 allele show a significantly higher risk of ovarian cancer. This result is consistent with our previous findings (11), which showed through immunohistochemical and western blotting analysis that the expression of LAPTM4B protein in cancer tissues is much higher than that in normal tissues. As the process of carcinogenesis is a

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1.00 (reference) ,0.0001

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Table 2. Univariate Kaplan–Meier analysis and multivariate Cox regression model of prognostic covariates in 282 patients with ovarian cancer Prognostic variables

Overall survival Univariate Mean + SE

Age (years) 57 + 2


59 + 2

HR (95% CI)b


0.017 73 + 1 27 + 7

0.915 (0.524– 2.112)




59 + 7


72 + 3

Serum CA125



67 + 3


75 + 1 ,0.001

FIGO stage I

75 + 2


66 + 2

1.893 (0.734– 4.347)



47 + 4

2.283 (1.816– 3.291)



25 + 9

4.726 (1.738– 6.267)


Pathological category


Serous adenocarcinoma

73 + 3

Mucoid adenocarcinoma

62 + 4


55 + 4

Other pathological types

49 + 2 ,0.001

Pathological grade G1

75 + 1


59 + 3

0.982 (0.457– 1.923)



36 + 7

2.213 (1.448– 3.269)


1.837 (1.005– 2.712)


2.071 (1.467– 2.685)



Lymph node metastases Absent

69 + 2


40 + 4

Intraperitoneal metastases



57 + 2


52 + 3

LAPTM4B polymorphisms



63 + 2

LAPTM4B*1/2 and LAPTM4B*2/2

37 + 4

G1, well differentiated; G2, moderately differentiated; G3, poorly differentiated. Log rank test. Hazard ratio (95% confidence interval). c Multivariate Cox regression model.

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,2 cm 2 cm Ascites


Pa 0.862


Residual tumor size



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LAPTM4B polymorphisms and ovarian cancer

Table 3. The relationship between genotype frequencies of LAPTM4B gene and 5-year overall survival of ovarian cancer Overall survival Survival X

P Percentage



HR (95% CI)a




Genotype LAPTM4B*1/1





1.00 (reference)






1.24 (0.72– 2.24)






2.95 (1.22– 7.18)
















long-term and cooperative effect of various factors, including multiple micro-predisposing genes (16,17), our findings indicate that the LAPTM4B*2 allele is one of the risk genes contributing to ovarian cancer. In our study, we also found allele *2 predisposed to tumors containing poorly differentiated cells (P ¼ 0.002), which also suggested that LAPTM4B*2 might lead to the malignant behavior of ovarian cancer and therefore be involved in the progression of ovarian cancer. These findings were consistent with some previous studies which have shown that the frequencies of *1/2 and *2/2 genotypes in gastric, lung and colon cancer patients are significantly higher than that in corresponding controls and that the allelic frequencies of the *2 was significantly higher than those of the corresponding controls (18 – 20). These results all show that the *2 genotype is associated with the incidence of certain tumors. Our study showed similar results, with a significantly elevated risk of developing ovarian cancer in women with the *1/2 genotype and the *2/2 genotype compared with the *1/1 genotype. When analyzing 5-year prognosis, we could see that LAPTM4B*2 increased the risk of death in patients (OR ¼ 1.62, 95% CI ¼ 1.10 – 2.39, P ¼ 0.017). In addition, individuals with LAPTM4B*1/2 and LAPTM4B*2/2 had a higher risk of death compared with LAPTM4B*1/1 individuals. Therefore, we highly suspect that LAPTM4B*2 affects the survival of patients. As a member of the mammalian four transmembranespanning protein superfamily (20), LAPTM4B is localized to the membrane of late endosomes and lysosomes (21,22). LAPTM4B has a 46% homology with nucleoside transport protein LAPTM4a which is highly conserved by evolution and associated with drug resistance (21,23,24). Research has shown that the N-terminus of LAPTM4B protein sequence is the molecularly important functional region, which may play an important role in regulating cell proliferation in the signal transduction. LAPTM4B may promote the transition from G1 to S phase by the pathway of Cyclin E and accelerate cell

1.00 (reference) 0.015

1.62 (1.10– 2.39)


malignant proliferation (25). Therefore different LAPTM4B alleles may directly or indirectly cause different individual cancer susceptibility through the above means. Currently, some researchers believe that the polymorphism of LAPTM4B associated with cancer incidence is due to 19-bp repeated fragments. The *1 allele contains one copy of the 19-bp sequence in its first exon, whereas the 19-bp sequence is duplicated in tandem as a 38-bp sequence in the *2 allele. The 19-bp difference in the first exon of the LAPTM4B gene alters the open reading frame (ORF), so it may influence the structure and function of the protein encoded by it. The ORF of LAPTM4B*1 is expected to encode a 317 amino acid protein. In contrast, the LAPTM4B*2 allele is extended by the 19-bp sequence insertion and the dislocation of the terminal stop codon. Collectively, this led to an extension of 53 amino acids at the N-terminus of protein coding frame and results in a production of an enlarged 370 amino acid protein (18,19). The different protein structure and activity of LAPTM4B may lead to different transport function or activity, or alter the metabolism of carcinogenic substances. Either of these functions could induce different oncogenic susceptibility (20,24). In agreement with this hypothesis, our case – control analysis showed that individuals with the *2 allele had a higher risk of developing ovarian cancer compared with those with the *1 allele. The cases and controls in our study matched on age, ethnicity and residence and the cases were pathologically confirmed, followed by a strict quality control from genotype detection, so our results are representative and credible. However, our study still has some limitations. To collect sufficient samples to perform this analysis, we needed to collect 5 years of patient data. The long preservation time resulted in substantial degradation of some DNA samples, so the power of the present study was further reduced by the loss of some samples. Furthermore, all subjects were restricted to the Han population, so the present data should be validated in larger samples and in other ethnic groups who may have different allele frequencies. Additionally, ovarian cancer can

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Jpn J Clin Oncol 2012

Funding This study was supported by a grant from Harbin Special Funds for Technological Innovation (No. 2006RFLXS022), Harbin, Heilongjiang Province, China. The authors thank all the people and patients who had participated in this study.









15. 16.



Conflict of interest statement None declared.

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be graded into many pathological types. However, in our sample population, certain types were less common or not available for subgroup analyses. A much larger study would be needed to effectively test our conclusion across all types. Through research of gene polymorphisms and disease occurrence, we can illustrate the body’s susceptibility to disease. This comparison revealed a significant difference in allele frequencies between the cases and controls, which indicates a relationship between LAPTM4B allele *2 and susceptibility to ovarian cancer. LAPTM4B*2 may be more vulnerable to chemical and biological carcinogens in the environment than LAPTM4B*1. It may cause gene expression losing control and play a role in tumor starts or promote the tumor progression. In contrast, LAPTM4B*1 is more protective. In summary, we have identified a polymorphism of the LAPTM4B gene associated with susceptibility to ovarian cancer for the first time. LAPTM4B*2 possibly act as an indicator to screen for a susceptible and high-risk population of ovarian cancer.

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