Analysis of von Hippel–Lindau Hereditary Cancer Syndrome: Implications of Oxygen Sensing

2004 ◽  
pp. 320-335 ◽  
Author(s):  
Haifeng Yang ◽  
Mircea Ivan ◽  
Jung-Hyun Min ◽  
William Y Kim ◽  
William G Kaelin
Keyword(s):  
Hereditary Cancer ◽  
Oxygen Sensing ◽  
Hereditary Cancer Syndrome ◽  
Cancer Syndrome ◽  
Von Hippel Lindau

scholarly journals RARE-24. IDENTIFYING INDIVIDUALS WITH PRIMARY CENTRAL NERVOUS SYSTEM TUMORS AT RISK FOR HEREDITARY CANCER SYNDROMES USING THE UTAH POPULATION DATABASE

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i45-i46
Author(s):  
Nicholas Whipple ◽  
Wendy Kohlmann ◽  
Samuel Cheshier ◽  
Zhe Yu ◽  
Karen Curtin ◽  
...  
Keyword(s):  
At Risk ◽  
Hereditary Cancer ◽  
Cancer Genetics ◽  
Cns Tumors ◽  
Hereditary Cancer Syndrome ◽  
Cancer Syndrome ◽  
Population Database ◽  
Cns Tumor ◽  
Von Hippel Lindau ◽  
Cancer Registry Data

Abstract Background CNS tumors are the most common solid tumors and the deadliest cancers in children. Approximately 10% of children with a CNS tumor harbor a hereditary cancer syndrome (HCS), but many will not be tested for a HCS. The Utah Population Database (UPDB) contains comprehensive cancer registry data for Utah families and can determine multigenerational cancer pedigrees across an archive of 5.8 million individuals. We hypothesize that the UPDB can identify children and families with HCSs not previously identified. Methods We queried the UPDB for individuals ages 0–39 diagnosed with a primary CNS tumor (malignant and benign) between 1966–2017 and generated cancer pedigrees of 3 generations or more for probands, extending to at least third-degree relatives. Specialized software calculated a familial standardized incidence ratio (FSIR) to determine families with excess clustering of CNS tumors. Clinical cancer genetics experts reviewed pedigrees to confirm patterns of HCS. Results We identified 4,634 CNS tumors in 4,550 individuals, of whom 2,233 (49%) reside in high-quality pedigrees containing ≥2 grandparents, at least 1 from both maternal and paternal sides. To identify families with excess clustering of CNS tumors, we selected pedigrees with an FSIR P<0.05 and ≥2 affected patients, resulting in 161 high-risk families with a mean of 170 (median 96) relatives per pedigree of 3–6 generations. Among these 161 families, there were 2,017 unique relatives (first-third degree) of CNS probands with 2,355 tumors (any site), for a per pedigree average of 14.7 tumors in 12.5 relatives. Review of the 10 highest risk pedigrees indicated that 4 meet HCS criteria, including Li-Fraumeni (n=2), von Hippel-Lindau (n=1), and rhabdoid tumor predisposition (n=1). Conclusion The UPDB can produce multigenerational cancer pedigrees that identify individuals and families at risk of harboring a HCS who warrant germline testing. These findings should encourage clinicians to perform thorough family history screening.

Thymoma associated with malignancies may herald a hereditary cancer syndrome

2010 ◽  
Vol 9 (4) ◽  
pp. 655-657 ◽  
Author(s):  
Omid Saeed Tehrani ◽  
Emily Q. Chen ◽  
David L. Schaebler ◽  
Abdul W. Mughal
Keyword(s):  
Hereditary Cancer ◽  
Hereditary Cancer Syndrome ◽  
Cancer Syndrome

Genetic Characterization of Hereditary Cancer Syndromes Based on Targeted Next-Generation Sequencing

2021 ◽  
pp. 1-9
Author(s):  
Pelin Ercoskun ◽  
Cigdem Yuce Kahraman ◽  
Guller Ozkan ◽  
Abdulgani Tatar
Keyword(s):  
Hereditary Cancer ◽  
Hereditary Cancer Syndrome ◽  
Cancer Syndrome ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Genetics And Genomics ◽  
Cancer Syndromes ◽  
Generation Sequencing

A hereditary cancer syndrome is a genetic predisposition to cancer caused by a germline mutation in cancer-related genes. Identifying the disease-causing variant is important for both the patient and relatives at risk in cancer families because this could be a guide in treatment and secondary cancer prevention. In this study, hereditary cancer panel harboring cancer-related genes was performed on MiSeq Illumina NGS system from peripheral blood samples. Sequencing files were fed into a cloud-based data analysis pipeline. Reportable variants were classified according to the American College of Medical Genetics and Genomics guidelines. Three hundred five individuals were included in the study. Different pathogenic/likely pathogenic variants were detected in 75 individuals. The majority of these variants were in the <i>MUTYH</i>, <i>BRCA2</i>, and <i>CHEK2</i> genes. Nine novel pathogenic/likely pathogenic variants were identified in <i>BRCA1</i>, <i>BRCA2</i>, <i>GALNT12</i>, <i>ATM</i>, <i>MLH1</i>, <i>MSH2</i>, <i>APC</i>, and <i>KIT</i> genes. We obtained interesting and novel variants which could be related to hereditary cancer, and this study confirmed that NGS is an indispensable method for the risk assessment in cancer families.

scholarly journals The Hereditary Spectrum of Pancreatic Cancer: The Edmonton Experience

2004 ◽  
Vol 18 (1) ◽  
pp. 17-21 ◽  
Author(s):  
Margaret Lilley ◽  
Dawna Gilchrist
Keyword(s):  
Pancreatic Cancer ◽  
At Risk ◽  
Family History ◽  
Hereditary Cancer ◽  
Cancer Genetics ◽  
Hereditary Cancer Syndrome ◽  
Molecular Testing ◽  
Cancer Syndrome ◽  
History Of ◽  
Cancer Syndromes

OBJECTIVE:Pancreatic cancer is known to aggregate in some families and has been associated with a wide variety of cancer syndromes. The authors describe their experience with pancreatic cancer and the range of associated cancer syndromes.METHODS:The charts of all patients seen for concern of a hereditary cancer syndrome in the Cancer Genetics Clinic at the University of Alberta between 1995 and 2002 were reviewed.RESULTS:Forty families reported a personal or family history of pancreatic cancer in the context of a possible hereditary cancer syndrome. Three additional families reported a history of pancreatitis. Twenty-four (56%) of those families were suspected of having a hereditary breast and ovarian cancer syndrome. A further seven (16%) were suspected of having hereditary nonpolyposis colon cancer. Only three (7%) were believed to be at risk for a site-specific pancreatic cancer syndrome. Another three (7%) were suspicious for hereditary pancreatitis. The remaining family histories were suggestive of Li-Fraumeni syndrome, von Hippel-Lindau syndrome or a nonspecific cancer predisposition.CONCLUSIONS:With such a wide variety of hereditary cancer syndromes associated with pancreatic cancer, an accurate assessment of the family history is essential to determine the most appropriate cancer screening for at-risk family members and to guide any molecular testing that may be offered.

Role of VHL Gene Mutation in Human Cancer

2004 ◽  
Vol 22 (24) ◽  
pp. 4991-5004 ◽  
Author(s):  
William Y. Kim ◽  
William G. Kaelin
Keyword(s):  
Tumor Suppressor ◽  
Target Genes ◽  
Human Cancer ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Tumor Formation ◽  
Hereditary Cancer Syndrome ◽  
Cancer Syndrome ◽  
Von Hippel Lindau

Germline inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene causes the von Hippel-Lindau hereditary cancer syndrome, and somatic mutations of this gene have been linked to the development of sporadic hemangioblastomas and clear-cell renal carcinomas. The VHL tumor suppressor protein (pVHL), through its oxygen-dependent polyubiquitylation of hypoxia-inducible factor (HIF), plays a central role in the mammalian oxygen-sensing pathway. This interaction between pVHL and HIF is governed by post-translational prolyl hydroxylation of HIF in the presence of oxygen by a conserved family of Egl-nine (EGLN) enzymes. In the absence of pVHL, HIF becomes stabilized and is free to induce the expression of its target genes, many of which are important in regulating angiogenesis, cell growth, or cell survival. Moreover, preliminary data indicate that HIF plays a critical role in pVHL-defective tumor formation, raising the possibility that drugs directed against HIF or its downstream targets (such as vascular endothelial growth factor) might one day play a role in the treatment of hemangioblastoma and renal cell carcinoma. On the other hand, clear genotype-phenotype correlations are emerging in VHL disease and can be rationalized if pVHL has functions separate from its control of HIF.

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