Journal of Pathology and Translational Medicine

Original Articles

Loss of Heterozygosity on Chromosome 15q15 Near Thrombospondin-1 Gene in Breast Carcinomas.: Jeana Kim, Kyoung Mee Kim, Heejeong Lee, Kyungji Lee, Mun Gan Rhyu, Anhi Lee, Seok Jin Kang, Kyo Young Lee; Korean J Pathol. 2009;43(3):221-230.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.3.221

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Abstract PDF: BACKGROUND
Chromosome 15q15 near the thrombospondin-1 (THBS-1) gene may be associated with tumor progression and metastasis. To clarify the potential role of the15q15 region in progression of breast carcinoma, we investigated the loss of heterozygosity (LOH) and the microsatellite instability (MSI) status of chromosome 15q15. Methods : LOH and MSI were detected in 84 breast carcinoma specimens using PCR-based microsatellite analysis with three microsatellite markers.
METHODS
LOH and MSI were detected in 84 breast carcinoma specimens using PCR-based microsatellite analysis with three microsatellite markers.
RESULTS
Of 77 breast carcinomas containing the heterozygous alleles, 25 (32%) showed LOH in at least one microsatellite marker. Partial LOH and total LOH were detected in 14 (18.27%) and 11 (14.3%) cases. The total LOH were inversely correlated with node metastasis. A single LOH at D15S514 was inversely correlated with nuclear grade and a single LOH at the D15S129 allele was associated with increased expression of the THBS-1 gene. MSI-positive breast carcinomas detected in 14 (17%) cases showed no correlation with any clinicopathologic feature.
CONCLUSIONS
These results indicate that loss of the chromosome 15q15 region delays the progression of breast carcinoma because the magnitude of LOH is large and involves the THBS-1 gene and additional genetic elements. The genes located on chromosome 15q15 probably play a tissue-type-dependent role in malignant growth of the tumor.

Loss of Heterozygosity Affecting the APC and p53 Tumor Suppressor Gene Loci in Colorectal Cancers and Its Prognostic Significance.: Eun Deok Chang, Won Sang Park, Byung Kee Kim, Sun Moo Kim, Sang In Shim; Korean J Pathol. 1997;31(3):191-200.

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Abstract PDF: Development of the human colorectal cancer is associated with several distinct genetic abnormalities involving both dominant-acting oncogenes (K-ras, c-src) and tumor suppressor genes (APC, DCC, p53) which undergo inactivation or loss. In colorectal tumors, the common molecular alteration is localized in the 17p13 and 5q21 loci encoding the p53 and the APC gene, respectively. The identification of these genes may help the understanding of the pathogenesis of colorectal neoplasia. In order to determine whether the frequency of the genetic alterations varies with sex, age, tumor size, or site, including pathologic parameters, such as degree of differentiation, tumor stage, mucin component, lymphoid reaction, tumor invasion pattern, vein and nerve invasion, lymph node metastasis, and other parameters, such as disease-free survival, distant metastasis and patient outcome, the authors analyzed the loss of heterozygosity (LOH) of the APC and the p53 genes in paraffin-embedded specimens of 48 colorectal cancers by use of the polymerase chain reaction and restriction fragment length polymorphism. The results were as follows: the LOH affecting the APC was found in 15 out of 31 (48.4%) heterozygous patients, while the LOH of the p53 locus was observed in 11 out of 26 (42.3%) patients. Among 48 patients, the LOH at both the APC and the p53 loci was observed in five (10.4%) patient. No statistically significant associations were found between the LOH of the APC gene and the proposed parameters. The relationship between the LOH of the p53 and the histologic differentiation, lymphoid reaction was significant (P<0.05), but survival was not correlated. Statistically significant associations were found between overall survival of the colorectal cancer patients and distant metastasis, Astler-Coller stage, lymphoid reaction, invasion pattern, nerve invasion, vein invasion, lymph node metastasis, and disease free survival. The above results suggest that the LOH of the p53 genes could be involved in the progression of colorectal cancers. However, neither the LOH of the APC nor that of the p53 have significant association with survival of the colorectal cancer patients.

Ethnic Differences of the p53 Genetic Alteration in Cutaneous Malignant Melanoma.: Won Sang Park, Eun Young Na, Sang Kyu Lee, Sug Hyung Lee, Su Young Kim, Seok Jin Kang, Kye Yong Song, Suk Woo Nam, Nam Jin Yoo, Jung Young Lee; Korean J Pathol. 2001;35(2):158-164.

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Abstract PDF: BACKGROUND
There are significant differences in the clincopathologic pattern including the incidence, favor site, and histopathologic type between cutaneous malignant melanomas arising from whites, asians and blacks. These differences might suggest that there is a racial difference in the molecular tumorigenesis mechanism of malignant melanoma.
METHODS
To determine the ethnic differences in tumorigenesis of malignant melanoma, we performed loss of heterozygosity (LOH) and sequencing analyses of the p53 gene in cutaneous malignant melanomas arising from 22 white American, 30 Korean and 15 black African patients.
RESULTS
The frequency of LOH of the p53 gene is only 12.5% in white American patients, but the frequency is significantly higher in Korean (42.1%) and black African (61.5%) patients. We also detected 17 mutations (nonsense: 1, missense: 16) of the p53 gene in the cutaneous malignant melanomas of Koreans and black Africans, but none in those of white Americans: among the 16 missense mutations, 10 mutations were C:G to T:A transitional mutations. Of these, we also detected one GG (CC) to AA (TT) tandem mutation at the pyrimidine sequence.
CONCLUSION
These results strongly suggest that there might be a racial difference in molecular carcinogenesis mechanisms among the cutaneous malignant melanomas occurring in white American, Korean and black African patients. But the role of the p53 genetic alteration in the genesis of melanomas in Korean and black African patients is subject to further evaluation.

Loss of Heterozygosity on Chromosome 9p21, 17p13 and 3p in Human Astrocytic Tumor.: Youn Soo Lee, Chang Suk Kang, Seung Myung Dong, Jung Yong Lee, Sang In Shim, Byung Kee Kim; Korean J Pathol. 2001;35(4):330-337.

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Abstract PDF: BACKGROUND
The purpose of this study was to determine the genetic abnormalities of chromosomes 9p21, 17p13.1, 3p25 and 3p14.2 in the development and progression of astrocytic tumors.
METHODS
We performed loss of heterozygosity (LOH) analysis in 41 astrocytic tumors, including 20 astrocytomas, 11 anaplastic astrocytomas and 10 glioblastomas, and correlated the results of LOH at different histopathologic grades. LOH was determined by multiplex polymerase chain reaction analysis of the DNA, which was extracted by microdissection.
RESULTS
LOH of 9p21 was found in 55.6% of astrocytomas, 54.6% of anaplastic astrocytomas and 100.0% of glioblastomas. LOH of 17p13.1 was found in 21.4% of astrocytomas, 28.6% of anaplastic astrocytomas, and 66.7% of glioblastomas. LOH of 3p25 was found in 37.5% of astrocytomas, 16.7% of anaplastic astrocytomas, and 14.3% of glioblastomas. LOH of 3p14.2 was found in 16.7% of astrocytomas, 40.0% of anaplastic astrocytomas, and 42.9% of glioblastomas. LOH on chromosome 9p21 and 17p13.1 was closely related with the histopathologic grades.
CONCLUSIONS
These results may suggest that LOH of 9p21, 17p13.1, 3p25 and 3p14.2 involves an early event of astrocytoma development and accumulates during progression. LOH of 3p25 may be involved in the tumorigenesis of astrocytoma. Identification of these LOH may illuminate the stepwise pathogenesis of astrocytic tumors and predict the possibility of malignant transformation.

Allelic Loss at the BRCA1 and BRCA2 Loci in Sporadic Breast Carcinoma Using Paraffin Embedded Tissue .: Ji Young Park, Myung Hoon Lee, Dong Ja Kim, Tae In Park, Young Ha Lee, Jung Wan Kim, Yoon Kyung Sohn; Korean J Pathol. 2002;36(2):100-105.

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Abstract PDF: BACKGROUND
Germline mutations in the breast cancer-associated genes BRCA1 and BRCA2 confer susceptibility and a lifetime risk of breast. Several morphological and clinical features have been attributed to hereditary tumors. However, in sporadic breast cancer, the interrelationship between the loss of heterozygosity (LOH) of these loci and clinical features remains to be fully elucidated.
METHODS
Microdissected paraffin-embedded tissue blocks of 48 cases of surgically resected breast carcinoma were investigated to identify the LOH of BRCA1 and BRCA2 using microsatellite markers.
RESULTS
Of 48 cases, 22 (45.9%) exhibited LOH at BRCA1 locus while in 29 out of 48 (60.4%) cases LOH was observed for the BRCA2 region. There was no significant correlation between LOH at BRCA1/2 and the patient's age, tumor size, histologic grade or lymph node metastasis. When comparing the frequency of LOH with the expression of several prognostic factors, such as p53, c-erb B2 protein, estrogen and progesterone receptor using immunohistochemical stain, there was only correlation with LOH at BRCA2 and the progesterone receptor.
CONCLUSIONS
Our results suggest that allelic deletion play a role to the development of sporadic breast cancers.

Inactivation Pattern of p16 Gene in Non-Hodgkin's Lymphomas.: Hyun Deuk Cho, In Sun Kim; Korean J Pathol. 2002;36(6):365-373.

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Abstract PDF: BACKGROUND
Loss of heterozygosity (LOH) and mutation of the p16 tumor suppressor gene have been detected in non-Hodgkin's lymphomas (NHLs). Recently, hypermethylation of the p16 gene has been reported. The role of p16 gene alterations in the genesis of NHLs and their high-grade transformations require explanation.
METHODS
LOH of D9S171 and IFNA microsatellite markers, DNA hypermethylation, and mutation of exon 1 and 2A were assessed in 43 cases of NHLs. The genetic abnormalities were compared with the protein expression by immunohistochemistry, and they were evaluated according to the histologic subtypes, grades and immunophenotypes.
RESULTS
DNA hypermethylation was the most common p16 gene abnormality and was found in 30 of 39 cases (76.9%). Eight cases (18.6%) showed LOH in one or both microsatellite markers, and five cases (11.6%) showed mutations in exon 1 or 2A. Loss of protein expression was seen in 17 cases (39.5%) and was associated with mutation and LOH. Loss of protein was more frequent in high-grade lymphomas than in low-grade lymphomas.
CONCLUSION
These results suggest that the functional loss of the p16 gene contributes to the development of NHLs, especially to the development of high-grade lymphomas.

Mutational and Loss of Heterozygosity Analysis of the p53 and PTEN Tumor Suppressor Genes in Breast Carcinoma.: Kwang Sun Suh, Young Ho Lee, Sun Young Na, Moon Il Park, Hun Soo Kim, Saeng Keum Lee; Korean J Pathol. 2005;39(5):313-319.

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Abstract PDF: BACKGROUND
Although the genetic determinants of most sporadic breast cancers remain unknown, the understanding of the molecular and genetic events that contribute to breast carcinogenesis has been significantly advanced. We investigated the clinicopathologic significance of allelic imbalance or mutation of both p53 and PTEN tumor suppressor genes in sporadic breast carcinomas.
METHODS
Genomic DNA from 62 breast carcinoma cases was extracted from paraffin blocks, and PCR was performed to determine loss of heterozygosity (LOH) for DNA markers around the p53 and PTEN genes and to amplify exons 5, 6, 7, and 8 of p53 and all 9 coding axons of PTEN.
RESULTS
Somatic p53 mutations were detected in 6 (9.7%) of the 62 cases. LOH for DNA markers surrounding p53 was observed in 18 (29.0%) of the 62 cases. LOH for DNA markers surrounding PTEN was detected in 29 (46.8%) of the 62 cases. Only one case (1.6%) showed somatic PTEN mutations. Tumors with LOH on 17p or p53 mutation were large in size and negative for ER, had a high Ki-67 index, and exhibited p53 immunoreactivity (p<0.05). Tumors with LOH on 10q23 were associated with c-erbB-2 positivity (p=0.018).
CONCLUSIONS
Our results indicate that LOH at 17p and/or p53 mutation is significantly associated with the aggressive pathologic parameters of breast cancer.

Adequate Microsatellite Markers for 1p/19q Loss of Heterozygosity of Oligodendroglial Tumors in Korean Patients.: Se Hoon Kim, Hoguen Kim, Tai Seung Kim; Korean J Pathol. 2005;39(1):23-33.

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Abstract PDF: BACKGROUND
It is well known that oligodendrogliomas can be divided into two groups according to the 1p/19q or 1p loss of heterozygosity (LOH) status because oligodendrogliomas with the 1p/19q LOH or the 1p LOH have a better prognosis and chemosensitivity. In this study, we investigated the adequate microsatellite markers for 1p/19q LOH of oligodendroglial tumors in Korean patients.
METHODS
We performed PCR that was based on the LOH test with the 1p (D1S508, D1S199, D1S2734, D1S186 & D1S312) and 19q (D19S219, D19S112, D19S412 & D19S596) microsatellite markers; these were the markers that were recommended by other researchers. We performed this PCR on microdissected paraffin embedded tissue blocks of 67 tumors from 56 cases.
RESULTS
The PCR based LOH analysis revealed that 3 microsatellite markers (D1S508, D1S2734 & D1S186) of 1p and 2 markers (D19S219 & D19S412) of 19q had higher heterozygosity scores than other markers. In addition, chromosomal LOH status using these selective markers showed a statistically significant difference of prognosis for oligodendroglial tumors.
CONCLUSIONS
We can suggest that the microsatellite markers with high heterozygosity scores (D1S508, D1S2734, D1S186, D19S219 and D19S412) would be adequate microsatellite markers for a PCR based LOH test of oligodendroglial tumors in Korean patients.

PTEN and p53 Mutations in Endometrial Carcinomas.: Jae Sung Choi, Kwang Sun Suh, Heung Tae Noh, Yun Ee Rhee, Sun Young Na, Hye Kyung Lee; Korean J Pathol. 2005;39(1):1-8.

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Abstract PDF: BACKGROUND
Endometrial carcinomas are pathogenetically classified into two major types; endometrioid carcinoma (EC) and serous carcinoma (SC). The most frequently altered gene in EC is the PTEN tumor suppressor gene (TSG). SC is usually associated with mutations in the p53 TSG.
METHODS
To further determine the role of PTEN and p53 mutation in endometrial carcinogenesis, the analysis of 33 endometrial carcinomas, including 28 ECs and 5 SCs, for loss of heterozygosity (LOH) on 10q23 and for mutation in all 9 coding exons of PTEN and the 5-8 exons of p53, using SSCP-PCR methods was carried out.
RESULTS
LOH was detected in at least one marker in 12 (54.5%) of 22 ECs, but in only one (20.0%) of 5 SCs. Somatic PTEN mutations were detected in 10 (35.7%) of 28 ECs. PTEN was altered in 67.9% of ECs and in 20.0% of SCs, including those with 10q23 LOH. No PTEN mutations were found among the SCs. Somatic p53 mutations were detected in 2 (7.1%) of 28 ECs and 3 (60.0%) of 5 SCs.
CONCLUSIONS
PTEN gene alterations contribute to the pathogenesis of an endometrioid subtype of endometrial carcinoma, but not to the serous type. In contrast, p53 plays an important role in the pathogenesis of SCs.

Mutation of Adenomatous Polyposis Coli Gene in Human Stomach Cancer.: Won Sang Park, Mun Gan Rhyu, Sug Hyung Lee, Yun Jun Chung, Gum Ryong Kim, Choo Soung Kim; Korean J Pathol. 1993;27(1):34-39.

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Abstract PDF: Recently the adenomaatous polyposis coli(APC) gene, a tumor suppressor gene, was identified and the cDNA was cloned from chromosome 5q21. Allelic deletion or point mutation of tumor suppressor genes(TSGs) has been considered as an important mechanism in development of human tumor. Point mutations affecting APC gene are seen in the hereditary syndrome, adenomatous polyposis and spordic colon cancer. However, the mutation of APC gene and other TSGs have not been described in gastric cancer. In order to identify the mutation of exon 11 of APC gene for gastric cancer, we amplified DNA extracted from paraffin-embedded tissues by polymerase chain reaction(PCR) and digested the PCR products with restriction enzyme Rsa I. We examined the DNA extracted from paraffin-embedded 44 gastric cancer tissues with lymph nodes. Eighteen(41%) among 44 were informative for the study exon 11 of the APC gene, and we found loss of heterozygosity(LOH) for APC in 6/18(33.3%). These data suggest that the point mutation or the base change of APC gene commonly occurs in gastric cancer. We conclude that the mutation of APC gene is strongly connected with development of human gastric cancer.

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