Loss of heterozygosity for chromosomes 16q in Wilms tumors predicts outcomes:A meta-analysis

BACKGROUND The research findings suggest that the prognosis of children with Wilms tumor(WT)is affected by various factors.Some scholars have indicated that loss of heterozygosity(LOH)on chromosome 16q is associated with a poor prognosis in patients with WT.AIM To further elucidate this relationship,we conducted a meta-analysis.METHODS This meta-analysis was registered in INPLASY(INPLASY2023100060).We systematically searched databases including Embase,PubMed,Web of Science,Cochrane,and Google Scholar up to May 31,2020,for randomized trials reporting any intrapartum fetal surveillance approach.The meta-analysis was performed within a frequentist framework,and the quality and network inconsistency of trials were assessed.Odds ratios and 95%CIs were calculated to report the relationship between event-free survival and 16q LOH in patients with WT.RESULTS Eleven cohort studies were included in this meta-analysis to estimate the relationship between event-free survival and 16q LOH in patients with WT(I^(2)=25%,P<0.001).As expected,16q LOH can serve as an effective predictor of eventfree survival in patients with WT(risk ratio=1.95,95%CI:1.52–2.49,P<0.001).CONCLUSION In pediatric patients with WT,there exists a partial correlation between 16q LOH and an unfavorable treatment prognosis.Clinical detection of 16q chromosome LOH warrants increased attention to the patient’s prognosis.

Telomere erosion is independent of microsatellite instability but related to loss of heterozygosity in gastric cancer

AIM: To correlate the length of the telomere to microsatellite instability (MSI) and loss of heterozygosity (LOH) of APC, MCC and DCC genes in gastric carcinomas. METHODS: Telomeric restriction fragment (TRF) length of gastric cancer was measured with Southern blot. LOH of APC, MCC and DCC genes, microsatellite instability (MSI) and frameshift mutation of hMSH6, TGF-betaRII and BAX genes were analyzed by PCR-based methods. RESULTS: Sixty-eight cases of sporadic gastric carcinoma were studied for MSI using five microsatellite markers. MSI in at least one locus was detected in 17 (25%) of 68 tumors analyzed. Frameshift mutations of hMSH6, TGF-betaRII and BAX were detected in 2,6 and 3 of gastric carcinomas respectively showing high MSI (】 or = 2 loci, n = 8), but none was found in those showing low MSI (only one locus, n = 9) or MSS (tumor lacking MSI or stable, n = 51). Thirty-five cases, including all high MSI and low MSI, were studied for TRF. The mean TRF length was not correlated with clinicopathological parameters. No association was observed between TRF length and MSI or frameshift mutation. On the contrary, LOH at the DCC locus was related to telomere shortening (P【0.01). This tendency was also observed in APC and MCC genes, although there was no statistical significance. CONCLUSION: The development of gastric cancer can arise through two different genetic pathways. In high MSI gastric cancers, defective mismatch repair allows mutations to accumulate and generate the high MSI phenotype. In gastric cancers showing either low MSI or MSS, multiple deletions may represent the LOH pathway. Telomere erosion is independent of high MSI phenotype but related to the LOH pathway in gastric cancer.

Loss of heterozygosity on 10q23.3 and mutation of tumor suppressor gene PTEN in gastric cancer and precancerous lesions

AIM: To investigate the loss of heterozygosity (LOH) and mutation of tumor suppressor gene PTEN in gastric cancer and precancerous lesions. METHODS: Thirty cases of normal gastric mucosa, advanced and early stage gastric cancer, intestinal metaplasia, atrophic gastritis, and atypical hyperplasia were analyzed for PTEN LOH and mutations within the entire coding region of PTEN gene by PCR-SSCP denaturing PAGE gel electrophoresis, and PTEN mutation was detected by PCR-SSCP sequencing followed by silver staining. RESULTS: LOH rate found in respectively atrophic gastritis was 10% (3/30), intestinal metaplasia 10% (3/30), atypical hyperplasia 13.3% (4/30), early stage gastric cancer 20% (6/30), and advanced stage gastric cancer 33.3% (9/30), None of the precancerous lesions and early stage gastric cancer showed PTEN mutations, but 10% (3/30) of the advanced stage gastric cancers, which were all positive for LOH, showed PTEN mutation. CONCLUSION: LOH of PTEN gene appears in precancerous lesions, and PTEN mutations are restricted to advanced gastric cancer, LOH and mutation of PTEN gene are closely related to the infiltration and metastasis of gastric cancer.

A preliminary study on the loss of heterozygosity at 17p13 in gastric and colorectal cancers

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Genetic aberration in primary hepatocellular carcinoma:correlation between p53 gene mutation and loss-of-heterozygosity on chromosome 16q21-q23 and 9p21-p23

To elucidate the molecular pathology underlying the development of hepatocellular carcinoma (HCC), we used 41 highly polymorphic microsatellite markers to examine 55 HCC and corresponding non-tumor liver tissues on chromosome 9, 16 and 17. Loss-of-heterozygosity (LOH) is observed with high frequency on chromosomal region 17p13 (36/55, 65%), 9p21-p23 (28/55, 51%), 16q21-q23 (27/55, 49%) in tumors. Meanwhile, microsatellite instability is rarely found in these microsatellite loci. Direct sequencing was performed to detect the tentative mutation of tumor suppressor genes in these regions: p53, MTS1/p16, and CDH1/E-cadherin. Within exon 5-9 of p53 gene, 14 out of 55 HCC specimens (24%) have somatic mutations, and nucleotide deletion of this gene is reported in HCC for the first time. Mutation in MTS1/pl6 is found only in one tumor case. We do not find mutations in CDH1/E-cadherin. Furthermore, a statistically significant correlation is present between p53 gene mutation and loss of chromosome region 16q21q23 and 9p21-p23, which indicates that synergism between p53 inactivation and deletion of 16q21-q23 and 9p21-p23 may play a role in the pathogenesis of HCC. Genetic aberration in hepatocellular

Frequent loss of heterozygosity in two distinct regions,8p23.1 and 8p22, in hepatocellular carcinoma

AIM： To identify the precise location of putative tumor suppressor genes （TSGs） on the short arm of chromosome 8 in patients with hepatocellular carcinoma （HCC）. METHODS： We used 16 microsatellite markers informative in Japanese patients, which were selected from 61 pub- lished markers, on 81：）, to analyze the frequency of loss of heterozygosity （LOH） in each region in 33 cases （56 lesions） of HCC. RESULTS： The frequency of LOH at 8p23.2-21 with at least one marker was 63% （20/32） in the informative cases. More specifically, the frequency of LOH at 8p23.2, 8p23.1, 8p22, and 8p21 was 6%, 52%, 47%, and 13% in HCC cases. The LOH was significantly more frequent at 8p23.1 and 8p22 than the average （52% vs 220, P = 0.0008; and 47% vs 22%, P = 0.004, respectively） or others sites, such as 8p23.2 （52% vs 60, P = 0.003; 47% vs 220, P = 0.004） and 8p21 （52% vs 13%, P = 0.001; 47% vs 13%, P = 0.005） in liver cancer on the basis of cases. Notably, LOH frequency was significantly higher at D85277, DSS503, DSS1130, DSS552, DSS254 and D8S258 than at the other sites. However, no allelic loss was detected at any marker on 8p in the lesions of nontumor liver tissues. CONCLUSION： Deletion of 8p, especially the loss of 8p23.1-22, is an important event in the initiation or promotion of HCC. Our results should be useful in identi- fying critical genes that might lie at 8p23.1-22.

Loss of heterozygosity and mRNA expression at DCC locus in gastric cancer

AIM To assess the effects of the DCC gene changes on the development and progression of gastric cancer. METHODS The loss of heterozygosity (LOH) and mRNA expression (LOE) of DCC gene was studied in 51 surgical specimens of gastric cancer with PCR based detection. RESULTS LOH was found in 35 3% (18/51) of the specimens and it was more frequently detected in stages Ⅲ and Ⅳ cancer (50 5%) than in stages Ⅰ and Ⅱ (14 3%) ( P <0 05). The occurrence of LOH was not found to be correlated to the histological type, tumor size, invasion depth and lymph node metastasis of gastric cancer. Among the 51 cases, mRNA expression of DCC gene was studied in 26 cases of which LOE was found in 30 8% (8/26). LOE was not significantly correlated to LOH and other clinicopathological parameters. CONCLUSION LOH and LOE of DCC gene are frequently encountered in gastric cancer and LOH of DCC gene is a late event and associated with progression of gastric cancer.

Clinical significance of loss of heterozygosity for M6P/IGF2R in patients with primary hepatocellular carcinoma

AIM:To investigate the relationship between loss of heterozygosity (LOH) for mannose 6-phosphate/insulin- like growth factor 2 receptor (M6P/IGF2R) and the outcomes for primary HCC patients treated with partial hepatectomy. METHODS: The LOH for M6P/IGF2R in primary HCC patients was assessed using six different gene-specific nucleotide polymorphisms. The patients studied were enrolled to undergo partial hepatectomy. RESULTS: M6P/IGF2R was found to be polymorphic in 73.3% (22/30) of the patients, and of these patients, 50.0% (11/22) had tumors showing LOH in M6P/IGF2R. Loss of heterozygosity in M6P/IGF2R was associated with significant reductions in the two year overall survival rate (24.9% vs 65.5%; P = 0.04) and the disease-free survival rate (17.8% vs 59.3%; P = 0.03). CONCLUSION: These results show M6P/IGF2R LOH predicts poor clinical outcomes in surgically resected primary HCC patients.

Frequent loss of heterozygosity at 8p22 chromosomal region in diffuse type of gastric cancer

AIM: To study the loss of heterozygosity (LOH) at 8p21-23 locus in diffuse gastric cancer.METHODS: To evaluate the involvement of this region in gastric cancer, we used eight microsatellite markers covering two Mb of mentioned region, to perform a high-resolution analysis of allele loss in 42 cases of late diffuse gastric adenocarcinoma.RESULTS: Six of these STS makers: D8S1149, D8S1645, D8S1643, D8S1508, D8S1591, and D8S1145 showed 36%, 28%, 37%, 41%, 44% and 53% LOH, respectively.CONCLUSION: A critical region of loss, close to the NAT2 locus and relatively far from FEZ1 gene currently postulated as tumor suppressor gene in this region.

Correlation analysis between loss of heterozygosity at chromosome 18q and prognosis in the stage-Ⅱ colon cancer patients

Background and Objective: Colorectal cancer is one of the most common malignant cancers in the world. Although the clinicopathologic staging is the golden criterion for the prognosis at present, the optimum prognostic criteria for colorectal cancer should be a combination of the clinicopathologic staging and the molecular markers. However, there are currently no molecular markers available for the prognosis of colorectal cancer. Several tumor-suppressor genes associated with colorectal cancer have been mapped at the 18q21-23 region. In this study we detected the frequency of loss of heterozygosity (LOH) at chromosome 18q and investigated the relationship between LOH and clinicopathologic features and its prognostic value for patients with stage Ⅱ colon cancer. Methods: A total of 106 samples of tumor tissues and corresponding normal mucosa from patients with sporadic stage-Ⅱ colon cancer were included in this study. All the samples were formalin-fixed and paraffin-embedded. DNA was extracted from tumor tissues and LOH of D18S474, D18S55, D18S58, D18S61 and D18S64 at chromosome 18q was analyzed using polymerase chain reaction (PCR), polyacrylamide gel-electrophoresis, and DNA sequencing method. Multivariate analysis for association between LOH and prognosis in colon cancer patients was performed with Cox proportional hazards regression model. Results: The median follow-up time was 68 months. For 106 patients, 5-year survival rate was 83.6%, which was associated with age and gross tumor type (P = 0.011 and 0.034, respectively). Among 102 patients who were eligible for LOH information, the overall frequency of LOH is 49.0% (50/102), and that of LOH at 5 microsatellite loci of D18S474, D18S55, D18S58, D18S61, and D18S64 was 30.2% (26/86), 23.4% (18/77), 28.6% (20/70), 35.0% (28/80), and 20.8%(15/72), respectively. The occurrence of LOH was significantly associated with tumor location and histopathologic grade (P = 0.023, 0.016 and 0.005, respectively). LOH was more frequent on the left-side, poorly-differentiated adenocarcinoma, and nonmucinous colon cancers. The occurrence of 18q-LOH was significantly associated with 5-year overall survival rate and disease free survival rate (P = 0.008 and 0.006, respectively). The occurrence of 18q-LOH at the loci of D18S474 and D18S61 was significantly associated with 5-year overall survival rate (P = 0.010 and 0.005, respectively). The multivariate analysis showed that only the occurrence of 18q-LOH was significantly associated with prognosis (P = 0.021). Conclusions: There is a high occurrence of LOH at the loci of 18q. The expression of LOH is significantly associated with tumor location and histopathologic grade. The occurrence of 18q-LOH is an independent poor prognostic factor for the patients with stage-Ⅱ colon cancer.

Loss of heterozygosity of Kras2 gene on 12p12-13 in Chinese colon carcinoma patients

AIM： To study the loss of heterozygosity （LOH） on 12p12-13 in Chinese colon carcinoma patients.METHODS： DNA was extracted from 10 specimens of cancer tissue, 10 specimens of adjacent tissue and 10 specimens of normal tissue, respectively. LOH of Kras2 gene was analyzed by polymerase chain reaction （PCR） and denaturing polyacrylamide gel electrophoresis using 11 microsatellite markers on 12p-12-13.RESULTS： LOH of Kras gene was detected at least on one marker of 12p-12-13 in 30% （3/10） of adjacent tissue specimens. The highest frequency of LOH was identified on D12S1034 in 28.57% （2]7） of adjacent tissue specimens. LOH was detected at least on one marker of 12p12-13 in 60% （6/10） of carcinoma tissue specimens, the most frequent LOH was found on D12S1034 and D12S1591 in 42.86% （3/7） of carcinoma tissue specimens. LOH was detected in 30% （3/10） of carcinoma tissue specimens, 30% （3/10） of adjacent tissue specimens, and no signal in 1% （1/0） carcinoma tissue specimen. The occurrence of LOH did not correlate with sex, age, tumor size and lymph node metastasis.CONCLUSION： Genomic instability may occur on 12p-12-13 of Kras2 gene in the development and progression of colon carcinoma. The high LOH of Kras2 gene may directly influence the transcription and translation of wild type Kras2 gene.

Loss of heterozygosity: An independent prognostic factor of colorectal cancer

AIM: Colorectal cancers result from the accumulation of several distinct genetic alterations. This study was to investigate the frequency and prognostic value of loss of heterozygosity (LOH) and microsatellite instability (MSI) at 14 genetic loci located near or within regions containing important genes implicated in colorectal tumorigenesis. METHODS: We studied colorectal cancers with corresponding normal mucosae in 207 patients (139 males and 68 females, mean age at the time of tumor resection 66.2±12.4 years, range 22-88 years). There were 37 right-sided colonic tumors, 85 left-sided colonic tumors and 85 rectal tumors. The distribution of tumor staging was stage Ⅰ in 25, stage Ⅱ in 73, stage Ⅲ in 68, and stage Ⅳ in 41. We analyzed the LOH and MSI of HPC1, hMSH2, hMLH1, APC, MET, P53, NH23-H1, DCC, BAT25, BAT26, D17S250, MYCL1 and D8S254 with fluorescent polymerase chain reaction and denatured gel electrophoresis. High-frequency LOH was determined to be greater than three, or more than 50% of the informative marker with LOH. High-frequency MSI (MSI-H) was determined as more than four markers with instability (>30%). Correlations of LOH and MSI with clinical outcomes and pathological features were analyzed and compared. RESULTS: The occurrence of MSI-H was 7.25%, located predominantly in the right colons (7/15) and had a higher frequency of poor differentiation (6/15) and mucin production (7/15). LOH in at least one genetic locus occurred in 78.7% of the tumors and was significantly associated with disease progression. Of the 166 potentially cured patients, 45 developed tumor recurrence within 36 mo of follow-up. Clinicopathological factors affecting 3-year disease-free survival (DFS) were TNM staging, grade of differentiation, preoperative CEA level, and high LOH status. Patients with high LOH tumors had a significantly lower DFS (50%) compared with patients with low LOH tumors (84%). Of the patients developing subsequent tumor recurrence, the number and percentage of LOH were 2.97 and 46.8% respectively, similar to the stage IV disease patients. TNM staging had the most significant impact on DFS, followed by high LOH status. CONCLUSION: Clinical manifestations of LOH and MSI are different in colorectal cancer patients. High-frequency LOH is associated with high metastatic potential of colorectal cancers.

STUDY OF LOSS OF HETEROZYGOSITY AT DCC AND APC/MCC GENETIC LOCI OF GASTRIC CANCER

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Loss of heterozygosity analyzed by single nucleotide polymorphism array in cancer

Neoplastic progression is generally characterized by the accumulation of multiple genetic alterations including loss of tumor suppression gene function. Loss of heterozygosity （LOH） has been used to identify genomic regions that harbor tumor suppressor genes and to characterize different tumor types, pathological stages and progression. LOH pattern has been detected by allelotyping using restriction fragment length polymorphism, and later by simple sequence length polymorphisms （SSLPs or microsatellite） for 10 years. This paper reviews the detection of LOH by recently developed single nucleotide polymorphism （SNP） arrays （all analyzed by Affymetrix array）; furthermore, its advantage and disadvantage were analyzed in several kinds of cancer.

Refined mapping of loss of heterozygosity on 1q31.1-32.1 in sporadic colorectal carcinoma

AIM: To explore precise deleted regions and screen the candidate tumor suppressor genes related to sporadic colorectal carcinoma. METHODS: Six markers on 1q31.1-32.1 were chosen. These polymorphic microsatellite markers in 83 colorectal cancer patients tumor and normal DNA were analyzed via PCR. PCR products were electrophoresed on an ABI 377 DNA sequencer. Genescan 3.1 and Genotype 2.1 software were used for Loss of heterozygosity (LOH) scanning and analysis. Comparison between LOH frequency and clinicopathological factors was performed by χ2 test. RESULTS: 1q31.1-32.1 exhibited higher LOH frequency in colorectal carcinoma. The average LOH frequency of 1q31.1-32.1 was 23.0%, with the highest frequency of 36.7% (18/49) at D1S2622, and the lowest of 16.4% (11/67) at D1S412, respectively. A minimal region of frequent deletion was located within a 2 cM genomic segment at D1S413-D1S2622 (1q31.3-32.1). There was no significant association between LOH of each marker on 1q31.1-32.1 and the clinicopathological data (patient sex, age, tumor size, growth pattern or Dukes stage), which indicated that on 1q31.1-32.1, LOH was a common phenomenon in all kinds of sporadic colorectal carcinoma. CONCLUSION: Through our refined deletion mapping,the critical and precise deleted region was located within 2 cM chromosomal segment encompassing 2 loci (D1S413, D1S2622). No significant association was found between LOH and clinicopathologic features in 1q31.1-32.1.

Loss of heterozygosity for loci on chromosome arms 1p and 10q in oligoden-droglial tumors: relationship to outcome and chemosensitivity

Oligodendroglial tumors frequently have deletions ofchromosomal loci on lp and l9q.Loas of heterozygosity(LOH)of chromosome 10 may be a negative prognostic factor.We reviewed 23 patients with oligodendroglial tumors,toevaluate the frequency of lp and 10q LOH and correlate with clinical outcome.Three loci(DlS402,DlSl 172,MCT118)on lp and 2 loci(Dl0S520 and D10S521)on 10q were analyzed for LOH using PCR techniques.

Analysis on chromosome 8 heterozygosity loss in humanprostate carcinoma and high grade prostaticintraepithelial neoplasia

Objective: To analysis the chromosome 8 heterozygosity loss in human prostate carcinoma and high grade prostatic intraepithelial neoplasia. Methods: Pure DNA was obtained from prostate neoplasms and normal tissues by tissue microdissection. The chromosome 8 heterozygosity loss was detected by PCR based micro-satellite polymorphism analysis technique using 14 pairs of microsatellite primers in 10 samples of prostate carcinoma and 10 samples of high grade prostatic intraepithelial neoplasia. Results: There were different frequencies of chromosome 8 heterozygosity loss in 10 samples of prostate carcinoma. 8p23.1-p23.2 and p21-p22 were two high frequency heterozygosity loss regions. Chromosome 8 heterozygosity loss was detected in 3 samples of high grade prostatic intraepithelial neoplasia. Conclusion: There were high frequency heterozygosity loss regions on chromosome 8 of prostate carcinoma, located at 8p23.1-p23.2 and p21-p22. The high grade prostatic intraepithelial neoplasia and prostate carcinoma share the same allelic loss on 8p. Tumor suppressor genes located at these two regions may be potentially involved in the initiation and progression of prostate carcinoma.

LOSS OF HETEROZYGOSITY OF ER GENE IN BREAST CANCER AND ITS CLINICAL SIGNIFICANCE

Objective: Clinically, the reason of resistance for breast cancer to endocrine therapy has not been well known. The current study attempted to examine loss of heterozygosity (LOH) on the estrogen receptor (ER) gene in breast cancer and its relationship to clinicopathologic findings. Methods: DNAs of tumor tissues and blood lymphocytes were collected from 40 cases of primary breast cancer patients and LOH were detected using the microsatellite repeat assay and combined with other ER immunohistochemical assays. Results: ER-positive staining was observed in 65% of breast cancer. Heterogeneity of ER expression was found. Seven of the patients (17.5%) showed LOH. In three of the seven cases, there was total loss, and there was a marked reduction in the intensity of signal in the other four cases. LOH was associated with histologic grade, occurring more frequently in ER-negative and lymph node metastasis group, but not with tumor size and patient ages. Conclusion: This result implied that LOH of the ER gene may have an important role in the progression of breast cancer. It was postulated that the lack of ER function induced by LOH may contributed to endocrine therapy resistance of breast cancer since the tumor clone would escape from the ER regulation, obtain growth predisposition and finally lost response to therapy.

LOSS OF HETEROZYGOSITY AT 17p13 IN GASTRIC CANCER AND COLORECTAL CANCER

Southern hybridization was done on DNA samples of22 gastric tumors and corresponding normal tissues, 14colorectal tumors and corresponding normal tissues by probe phs53B mapping at 17P13.1 and probe PYNZ22mapping at 17pl3.3 which were purchased from the American Type Culture Collection. RFLP heterozygosity was observed in 12 normal tissues of gastric cancers and 10 normal tissues of colorectal cancers. Among these informative tumors, 6(50%) cases of gastric cancers and 6(60%) cases of colorectal cancers showed the loss of beterozygosity at 17p13. Our results demonstrated that the inactivation of wild type p53 might be involved in the carcinogenesis of gastric cancers and colorectal cancers.Furthermore, the mode of inactivation of p53 was in accord with the 'two hits' hypothesis by Anudson. The signincance was discussed regarding the presence of LOH detected by probe PYNZ22 mapping at 17pl3.3.

LOSS OF HETEROZYGOSITY FOR MARKERS ON 22 CHROMOSOME IN SPORADIC SCHWANNOMA

Objective To analyze the loss of heterozygosity (LOH) for markers on chromosew 22 (CHR 22 ) and its significance with their clinical behaviors. Methods The frequency of CHR22 LOH in 36 schwannomas was observed by denatured polyacrylamide gels and silver staining, and the proliferative index of schwannoma wes calculated by Ki-67 and PCNA immunohistochemistry. Results 15 schwannomas (41. 6% ) shawed allele lass. The proliferative index of schwannomas with LOH were significantly higher than those without LOH (P< 0. 05). In acoustic neuromas, patients with LOH were younger at the age of diagnosis, larger size of tumor, shorter history and higher growth rate than those without LOH, but with no significance. Conclusion CHR22 IDH was the frequent event in the tumorigenesis of sporadic schwannoma. There were some links beteen CHR22 LOH and clinical behavior.