Genotyping of Adrenocortical Tumors: Very Frequent Deletions of the MEN1 Locus in 11q13 and of a 1-Centimorgan Region in 2p161

To identify chromosomal regions that may contain loci for tumor suppressor genes involved in adrenocortical tumor development, a panel of 60 tumors (39 carcinomas and 21 adenomas) were screened for loss of heterozygosity. Although the vast majority of loss of heterozygosity (LOH) were detected in the carcinomas and involved chromosomes 2, 4, 11, and 18, only few were found in the adenomas. Therefore, 2 loci that harbor the familial cancer syndromes Carney complex in 2p16 and the multiple endocrine neoplasia type 1 gene in 11q13 were further studied in 27 (13 carcinomas and 14 adenomas) of the 60 tumors. Detailed analysis of the 2p16 region mapped a minimal area of overlapping deletions to a 1-centimorgan region, which is separate from the Carney complex locus. LOH for a microsatellite marker (PYGM), very close to the MEN1 gene, was detected in all 8 informative carcinomas (100%) and in 2 of 14 adenomas. Of the 27 cases analyzed in detail, 13 cases (11 carcinomas and 2 adenomas) showed LOH on chromosome 11 and was therefore selected for MEN1 gene mutation analysis. In 6 cases a common polymorphism (Asp418Asp) was found, but no mutation was detected. In conclusion, our data indicate the existence of tumor suppressor genes at multiple chromosomal locations, whose inactivations are involved in the development of adrenocortical carcinomas. Loss of genetic material from 2p16 was strongly associated with the malignant phenotype, as it was seen in almost all carcinomas but not in any of the adenomas. LOH in 11q13 also occurred frequently in the carcinomas, but was not associated with a MEN1 mutation, suggesting the involvement of a different tumor suppressor gene on this chromosome.

Download Full-text

Analysis of loss of heterozygosity on chromosomes 10q, 11, and 16 in medulloblastomas

Journal of Neurosurgery ◽

10.3171/jns.2001.94.5.0799 ◽

2001 ◽

Vol 94 (5) ◽

pp. 799-805 ◽

Cited By ~ 16

Author(s):

Xiao-lu Yin ◽

Jesse C. Pang ◽

Yan-hui Liu ◽

Edith Y. Chong ◽

Yue Cheng ◽

...

Keyword(s):

Tumor Suppressor ◽

Loss Of Heterozygosity ◽

Tumor Suppressor Genes ◽

Molecular Genetic ◽

Genetic Material ◽

Suppressor Genes ◽

Blood Samples ◽

Content Type ◽

Targeted Deletion ◽

Fine Print

Object. The loss of genetic material from specific chromosome loci is a common feature in the oncogenesis of tumors and is often indicative of the presence of important tumor suppressor genes at these loci. Recent molecular genetic analyses have demonstrated frequent loss of chromosomes 10q, 11, and 16 in medulloblastomas. The aim of this study was to localize the targeted deletion regions on the three aforementioned chromosomes in medulloblastomas. Methods. Loss of heterozygosity (LOH) was examined on chromosomes 10q, 11, and 16 in a series of 22 primary and two recurrent medulloblastomas by using polymerase chain reaction—based microsatellite analysis. The DNA extracted from the tumors and corresponding normal blood samples were amplified independently in the presence of radioactively labeled microsatellite primers, resolved by denaturing gel electrophoresis and processed for autoradiography. The DNA obtained from control blood samples that displayed allelic heterozygosity at a given microsatellite locus were considered informative. Loss of heterozygosity was inferred when the allelic signal intensity of the tumor sample was reduced by at least 40%, relative to that of the constitutional control. The LOH analysis demonstrated that deletions of chromosomes 10q, 11p, and 16q are recurrent genetic events in the development of medulloblastomas. Three subchromosomal regions of loss have been identified and are localized to the deleted in malignant brain tumors 1 [DMBT1] gene site on chromosomes 10q25, 11p13–11p15.1, and 16q24.1–24.3. Conclusions. These results indicate that DMBT1 is closely associated with the oncogenesis of medulloblastomas and highlight regions of loss on chromosomes 11p and 16q for further fine mapping and cloning of candidate tumor suppressor genes that are important for the genesis of medulloblastoma.

Download Full-text

Analysis of Loss of Heterozygosity for Tumor-Suppressor Genes Can Accurately Classify and Predict the Clinical Behavior of Mucinous Tumors Arising From the Appendix

Annals of Surgical Oncology ◽

10.1245/s10434-006-9081-1 ◽

2006 ◽

Vol 13 (12) ◽

pp. 1610-1616 ◽

Cited By ~ 15

Author(s):

Vivek Maheshwari ◽

Allan Tsung ◽

Yan Lin ◽

Herb J. Zeh ◽

Sydney D. Finkelstein ◽

...

Keyword(s):

Tumor Suppressor ◽

Loss Of Heterozygosity ◽

Tumor Suppressor Genes ◽

Suppressor Genes ◽

Clinical Behavior

Download Full-text

Loss of Heterozygosity and Microsatellite Instability at Multiple Tumor Suppressor Genes in Gastric Carcinomas

Journal of the Korean Gastric Cancer Association ◽

10.5230/jkgca.2003.3.4.214 ◽

2003 ◽

Vol 3 (4) ◽

pp. 214 ◽

Cited By ~ 1

Author(s):

Young Gu Cho ◽

Chang Jae Kim ◽

Cho Hyun Park ◽

Young Sil Kim ◽

Su Young Kim ◽

...

Keyword(s):

Tumor Suppressor ◽

Microsatellite Instability ◽

Loss Of Heterozygosity ◽

Tumor Suppressor Genes ◽

Suppressor Genes ◽

Gastric Carcinomas ◽

Multiple Tumor

Download Full-text

A new CRISPR mediated intestinal tumor mouse model targeting four canonical tumor suppressor genes.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16064 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16064-e16064

Author(s):

Hajime Kashima ◽

Daniel Veronese-Paniagua ◽

Anthony Fischer ◽

Blair Madison ◽

Deborah Rubin

Keyword(s):

Tumor Suppressor ◽

Mouse Model ◽

Tumor Suppressor Genes ◽

Rapid Development ◽

Tumor Development ◽

Intestinal Tumor ◽

Intestinal Tumors ◽

Suppressor Genes ◽

Intestinal Tumorigenesis ◽

Guide Rnas

e16064 Background: Mouse models of intestinal tumorigenesis have been developed and many of them involve mutations in the Apc gene. However, human intestinal tumors contain multiple additional sporadic mutations in tumor suppressor genes (TSGs). Our goal is to develop a novel mouse model of intestinal tumorigenesis that can recapitulate the natural history of mutations in diverse stages of tumor development. Methods: We used multiple guide RNAs to achieve random mutations in the canonical TSGs, Apc, Pten, Smad4, and Tp53. We generated transgenic (PPAS) mice that constitutively express the appropriate guide RNAs. Moreover, we achieved inducible Cas9 expression in icCas9N mice intestine using the Villin promoter to drive both a doxycycline-dependent activator and a doxycycline-inactivated repressor. We fed the doxycycline chow to PPAS:icCas9 double transgenic mice from the age of 6 to 8 weeks, and harvested intestine at 12 weeks. Results: We examined seven PPAS;icCas9 mice, and detected intestinal tumors in all the mice. Two mice had small intestinal tumor, three mice had colonic tumor, and two mice had tumors in both small and large intestine. The average number of tumors were 0.86, 1.57, 2.43 in small intestine, colon, and both respectively. We analyzed mutations in 11 tumors in 6 mice. The mutation patterns of Apc, Pten, Smad4 and Tp53 in tumors shared three distinct patterns. One was characterized by mutations in all four TSGs (n = 9). The second showed mutation in APC and Smad4 and Pten (n = 1). The third showed mutation only in Tp53 (n = 1). Normal intestine and colon in PPAS:icCas9 mice had no mutations. Conclusions: This model provides a powerful platform for modeling intestinal tumorigenesis driven by the canonical signaling pathway which are commonly dysregulated in colon cancer. This model provides a means for rapid development of intestinal tumors in mice, enabling an investigation of the relationship between novel candidate regulators of tumorigenesis and the canonical signaling pathways regulated by these four common TSGs. [Table: see text]

Download Full-text

Frequent Occurrence of Loss of Heterozygosity among Tumor Suppressor Genes in Uterine Leiomyosarcoma

Gynecologic Oncology ◽

10.1006/gyno.1999.5629 ◽

1999 ◽

Vol 75 (3) ◽

pp. 453-459 ◽

Cited By ~ 37

Author(s):

Ya-Li Zhai ◽

Toshio Nikaido ◽

Ayaka Orii ◽

Akiko Horiuchi ◽

Toshihiko Toki ◽

...

Keyword(s):

Tumor Suppressor ◽

Loss Of Heterozygosity ◽

Tumor Suppressor Genes ◽

Frequent Occurrence ◽

Uterine Leiomyosarcoma ◽

Suppressor Genes

Download Full-text

Loss of Heterozygosity at the Ink4a/ArfLocus Facilitates Abelson Virus Transformation of Pre-B Cells

Journal of Virology ◽

10.1128/jvi.74.20.9479-9487.2000 ◽

2000 ◽

Vol 74 (20) ◽

pp. 9479-9487 ◽

Cited By ~ 4

Author(s):

Justin Mostecki ◽

Anne Halgren ◽

Arash Radfar ◽

Zohar Sachs ◽

James Ravitz ◽

...

Keyword(s):

B Cells ◽

Tumor Suppressor ◽

Loss Of Heterozygosity ◽

Cell Lines ◽

Tumor Suppressor Genes ◽

Single Copy ◽

Transformation Process ◽

Suppressor Genes ◽

Abelson Virus

ABSTRACT In many tumor systems, analysis of cells for loss of heterozygosity (LOH) has helped to clarify the role of tumor suppressor genes in oncogenesis. Two important tumor suppressor genes, p53 and the Ink4a/Arf locus, play central roles in the multistep process of Abelson murine leukemia virus (Ab-MLV) transformation. p53 and the p53 regulatory protein, p19Arf, are required for the apoptotic crisis that characterizes the progression of primary transformed pre-B cells to fully malignant cell lines. To search for other tumor suppressor genes which may be involved in the Ab-MLV transformation process, we used endogenous proviral markers and simple-sequence length polymorphism analysis to screen Abelson virus-transformed pre-B cells for evidence of LOH. Our survey reinforces the role of the p53-p19 regulatory pathway in transformation; 6 of 58 cell lines tested had lost sequences on mouse chromosome 4, including theInk4a/Arf locus. Consistent with this pattern, a high frequency of primary pre-B-cell transformants derived fromInk4a/Arf +/− mice became established cell lines. In addition, half of them retained the single copy of the locus when the transformation process was complete. These data demonstrate that a single copy of the Ink4a/Arf locus is not sufficient to fully mediate the effects of these genes on transformation.

Download Full-text