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. 2015 Jun 16:10:70.
doi: 10.1186/s13000-015-0308-y.

Loss of heterozygosity at D8S262: an early genetic event of hepatocarcinogenesis

Qiao Zhu  1 , Li Gong  2 , Xiaoyan Liu  1 , Jun Wang  1 , Pin Ren  1 , Wendong Zhang  3 , Li Yao  1 , Xiujuan Han  1 , Shaojun Zhu  1 , Miao Lan  1 , Yanhong Li  4   5 , Wei Zhang  6
Affiliations

Loss of heterozygosity at D8S262: an early genetic event of hepatocarcinogenesis

Qiao Zhu et al. Diagn Pathol. .

Abstract

Background: Hepatocellular carcinoma (HCC) is a multi-factor, multi-step, multi-gene and complicated process resulting from the accumulation of sequential genetic and epigenetic alterations. An important change among them is from precancerous lesions to HCC. However, only few studies have been reported about the sequential genetic changes during hepatocarcinogenesis.

Methods: We observed firstly molecular karyotypes of 10 matched HCC using Affymetrix single-nucleotide polymorphism (SNP) 6.0 arrays, and found chromosomal fragments with high incidence (more than 70%) of loss of heterozygosity (LOH). Then, we selected 28 microsatellite markers at some gene spanning these chromosomal fragments, and examined the frequency of LOH of 128 matched HCC and 43 matched precancerous lesions-dysplastic nodules (DN) by a PCR-based analysis. Finally, we investigated the expression of proteins encoded by these genes in HCC, DN and the surrounding hepatic tissues.

Results: The result of Affymetrix SNP6.0 arrays demonstrated that more than 70% (7/10) cases had chromosomal fragment deletion on 4q13.3-35.1, 8p23.2-21.2, 16q11.2-24.3, and 17p13.3-12. Among 28 microsatellite markers selected, LOH frequencies at D8S262 for DN and HCC were found to be the highest, 51.2% and 72.7%, respectively. Immunohistochemically, the positive rate of its adjacent gene CSMD1 in HCC, DN, and the surrounding hepatic tissues were 27.3% (35/128), 75% (33/44), and 82% (105/128), respectively.

Conclusions: LOH at D8S262 may be associated with an early genetic event of hepatocarcinogenesis, and a predictor for the monitor and prevention of HCC.

Virtual slides: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1557074981159099 .

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Figures

Fig. 1
Fig. 1
Affymetrix SNP6.0 arrays showed that more than 70 % (7/10) cases had chromosomal deletion on 8p23.2-21.2, 4q13.3-35.1, 17p13.3-12, and 16q11.2- 24.3, respectively. Red color indicated amplification of chromosomal fragment; Blue color indicated neutral LOH without CNV
Fig. 2
Fig. 2
Representative images of PCR gels from a part of microsatellite loci for HCC. Compared with the surrounding normal liver tissues, HCC showed a reduction in fluorescence intensity of 50% or greater in 1 or more alleles. a, D4S415; b, D4S2954; c, D8S262; d, D4S3331; e, D8S1725; f, D8S261. N normal liver tissue; HCC hepatocellular carcinoma
Fig. 3
Fig. 3
Representative images of PCR gels from a part of microsatellite loci for NAH. Compared with the surrounding normal liver tissues, NAH showed a reduction in fluorescence intensity of 50 % or greater in 1 or more alleles. N normal liver tissue; T NAH. Among them, T1 had not occurred LOH
Fig. 4
Fig. 4
The expression of CSMD1 in HCC, NAH, and the surrounding normal liver tissues. a, strong positive expression in normal liver tissue (200×); b, positive expression in HCC (100×); c, negative expression in HCC (100×); d, positive expression in NAH (100×)
Fig. 5
Fig. 5
The expression of CSMD1 was stronger in the well-differentiated HCC (a, 200×) than that in the moderate (b, 200×) and poor differentiated HCC (c, 200×)
Fig. 6
Fig. 6
The results of RT-PCR showed that the expression levels of CSMD1 mRNA were down-regulated in HepG2, SK-hep-1 and MHCC-97H compared with that in HL-7702
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