scholarly journals Metabolic Drivers in Hereditary Cancer Syndromes

2020 ◽  
Vol 4 (1) ◽  
pp. 77-97 ◽  
Author(s):  
Marco Sciacovelli ◽  
Christina Schmidt ◽  
Eamonn R. Maher ◽  
Christian Frezza
Keyword(s):  
Genetic Variants ◽  
Molecular Mechanisms ◽  
Familial Cancer ◽  
Germline Mutations ◽  
Tumor Formation ◽  
Mitochondrial Enzymes ◽  
Hereditary Cancer Syndromes ◽  
Metabolic Genes ◽  
Formation And Evolution ◽  
Cancer Syndromes

Cancer is a multifaceted disease in which inherited genetic variants can be important drivers of tumorigenesis. The discovery that germline mutations of metabolic genes predispose to familial forms of cancer caused a shift in our understanding of how metabolism contributes to tumorigenesis, providing evidence that metabolic alterations can be oncogenic. In this review, we focus on mitochondrial enzymes whose mutations predispose to familial cancer, and we fully appraise their involvement in cancer formation and progression. Elucidating the molecular mechanisms that orchestrate transformation in these diverse tumors may answer key biological questions about tumor formation and evolution, leading to the identification of new therapeutic targets of intervention.

Familial cancer syndromes and genetic counselling

2016 ◽  
pp. 276-290
Author(s):  
Henry T. Lynch ◽  
Carrie L. Snyder ◽  
Jane F. Lynch
Keyword(s):  
Colorectal Cancer ◽  
Molecular Genetics ◽  
Genetic Counselling ◽  
Hereditary Cancer ◽  
Genetic Model ◽  
Familial Cancer ◽  
Hereditary Cancer Syndromes ◽  
Clinical Genetic ◽  
Familial Cancer Syndromes ◽  
Cancer Syndromes

Thanks to the veritably logarithmic advances in the molecular genetics of many emerging hereditary cancer syndromes, genetic counselling has become of paramount importance. It is a key element of the emerging concepts for patient education and management, which have become the clinical bedrock for diagnosis and management of hereditary cancer. Genetic counsellors have become proficient in the understanding of the complexities of molecular genetics in relation to hereditary cancer syndromes, demonstrating their ability both to supplement and replace the customary physician’s role in this overall process. We have used colorectal cancer, in particular Lynch syndrome, as a clinical genetic model based on the authors’ experience with diagnosis, DNA testing, and counselling of thousands of families for over four decades. Undoubtedly, the surface of the proverbial iceberg has barely been grazed in regard to the developments for the genetic counseling discipline.

scholarly journals Patients Tested at a Laboratory for Hereditary Cancer Syndromes Show an Overlap for Multiple Syndromes in Their Personal and Familial Cancer Histories

Oncology ◽  
2015 ◽  
Vol 89 (5) ◽  
pp. 288-293 ◽  
Author(s):  
Jennifer Saam ◽  
Christopher Arnell ◽  
Aaron Theisen ◽  
Kelsey Moyes ◽  
Ingrid Marino ◽  
...  
Keyword(s):  
Hereditary Cancer ◽  
Familial Cancer ◽  
Hereditary Cancer Syndromes ◽  
Cancer Syndromes

scholarly journals Predisposition to Pediatric and Hematologic Cancers: A Moving Target

2014 ◽  
pp. e44-e55 ◽  
Author(s):  
David Malkin ◽  
Kim E. Nichols ◽  
Kristin Zelley ◽  
Joshua D. Schiffman
Keyword(s):  
Hereditary Cancer ◽  
Molecular Mechanisms ◽  
Pediatric Population ◽  
Bone Marrow Failure ◽  
Hematologic Malignancies ◽  
Telomere Maintenance ◽  
Hereditary Cancer Syndromes ◽  
Li Fraumeni Syndrome ◽  
Cancer Predisposition Syndrome ◽  
Cancer Syndromes

Our understanding of hereditary cancer syndromes in children, adolescents, and young adults continues to grow. In addition, we now recognize the wide variation in tumor spectrum found within each specific cancer predisposition syndrome including the risk for hematologic malignancies. An increased understanding of the genetic mutations, biologic consequences, tumor risk, and clinical management of these syndromes will improve patient outcome. In this article, we illustrate the diversity of molecular mechanisms by which these disorders develop in both children and adults with a focus on Li-Fraumeni syndrome, hereditary paraganglioma syndrome, DICER1 syndrome, and multiple endocrine neoplasia syndrome. This is followed by a detailed discussion of adult-onset tumors that can occur in the pediatric population including basal cell carcinoma, colorectal cancer, medullary thyroid cancer, and adrenal cortical carcinoma, and the underlying hereditary cancer syndromes that these tumors could indicate. Finally, the topic of leukemia predisposition syndromes is explored with a specific focus on the different categories of syndromes associated with leukemia risk (genetic instability/DNA repair syndromes, cell cycle/differentiation, bone marrow failure syndromes, telomere maintenance, immunodeficiency syndromes, and transcription factors/pure familial leukemia syndromes). Throughout this article, special attention is made to clinical recognition of these syndromes, genetic testing, and management with early tumor surveillance and screening.

The role of nursing in obtaining a three-generation familial cancer history intake tool (FCHT) and the care of patients with hereditary gastrointestinal syndromes.

2014 ◽  
Vol 32 (30_suppl) ◽  
pp. 216-216
Author(s):  
Lucia Fontes-Borts ◽  
Howard Safran ◽  
Kimberly Perez
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Sex Education ◽  
Hereditary Cancer ◽  
Familial Cancer ◽  
Hereditary Cancer Syndromes ◽  
Increased Risk ◽  
Generation Family ◽  
Cancer Syndromes ◽  
The Impact

216 Background: Of patients diagnosed with colorectal cancer, 5-10% of all cancers are associated with hereditary cancer syndromes. Since hereditary gastrointestinal cancer syndromes convey a markedly increased risk for developing cancer, identification of affected families is important. Studies have found that clinicians are unlikely to adequately or routinely collect family history information on their patients. This study assessed the implementation of a validated three-generation family history intake tool by an advanced practiced nurse practitioner (APNP) and the impact on clinical practice at a mid-size academic affiliated Medical Oncology practice. Methods: From September 2013 to January 2014, 100 patients with the diagnosis of colorectal cancer were assessed after a clinic session with a physician by an APNP. The APNP utilized a validated 3 - generation family history tool. Information regarding age, sex, education, annual income, family ethnicity, diet, exercise and previous genetic testing was also collected. Data collected was then analyzed to assess risk of hereditary syndrome. A chart review of the patients was performed to analyze microsatellite instability testing and prior genetic counseling referrals. Results: Of the 100 screened, 93 patients were evaluable. There were 52 males: 39 female participants with a median age of 60.71 years (range 28-90). The implementation of FCHT was associated with an increase in identification of individuals at risk; 16 (17.2%) patients reported a diagnosis of CRC at age less than 50. The rate of referrals for genetic evaluation tripled after the implementation of the FCHT (6.5% to 16.3%). Of the 17 referred, five had been referred prior to implementation of the FCHT. Conclusions: Institution of a separate session with an APNP to assess family history resulted in a 3-fold increase in rates of detection of patients with high risk for hereditary cancer syndromes associated with colorectal cancer.This study demonstrates that APNP’s are well positioned to promote preventative health by engaging in family history intake and genetic assessment referral.

scholarly journals Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications

2010 ◽  
Vol 28 (1) ◽  
pp. E8 ◽  
Author(s):  
Oren N. Gottfried ◽  
David H. Viskochil ◽  
William T. Couldwell
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Neurofibromatosis Type ◽  
Germline Mutations ◽  
Tumor Formation ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Peripheral Nerve Sheath Tumors

Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disease characterized by complex and multicellular neurofibroma tumors, and less frequently by malignant peripheral nerve sheath tumors (MPNSTs) and optic nerve gliomas. Significant advances have been made in elucidating the cellular, genetic, and molecular biology involved in tumor formation in NF1. Neurofibromatosis Type 1 is caused by germline mutations of the NF1 tumor suppressor gene, which generally result in decreased intracellular neurofibromin protein levels, leading to increased cascade Ras signaling to its downstream effectors. Multiple key pathways are involved with the development of tumors in NF1, including Ras/mitogen-activated protein kinase (MAPK) and Akt/mammalian target of rapamycin (mTOR). Interestingly, recent studies demonstrate that multiple other developmental syndromes (in addition to NF1) share phenotypic features resulting from germline mutations in genes responsible for components of the Ras/MAPK pathway. In general, a somatic loss of the second NF1 allele, also referred to as loss of heterozygosity, in the progenitor cell, either the Schwann cell or its precursor, combined with haploinsufficiency in multiple supporting cells is required for tumor formation. Importantly, a complex series of interactions with these other cell types in neurofibroma tumorigenesis is mediated by abnormal expression of growth factors and their receptors and modification of gene expression, a key example of which is the process of recruitment and involvement of the NF1+/– heterozygous mast cell. In general, for malignant transformation to occur, there must be accumulation of additional mutations of multiple genes including INK4A/ARF and P53, with resulting abnormalities of their respective signal cascades. Further, abnormalities of the NF1 gene and molecular cascade described above have been implicated in the tumorigenesis of NF1 and some sporadically occurring gliomas, and thus, these treatment options may have wider applicability. Finally, increased knowledge of molecular and cellular mechanisms involved with NF1 tumorigenesis has led to multiple preclinical and clinical studies of targeted therapy, including the mTOR inhibitor rapamycin, which is demonstrating promising preclinical results for treatment of MPNSTs and gliomas.

Familial cancer syndromes

2016 ◽  
pp. 276-290
Author(s):  
Carrie L. Snyder ◽  
Heather Hampel ◽  
Henry T. Lynch
Keyword(s):  
Colorectal Cancer ◽  
Genetic Counseling ◽  
Molecular Genetics ◽  
Hereditary Cancer ◽  
Genetic Model ◽  
Familial Cancer ◽  
Hereditary Cancer Syndromes ◽  
Clinical Genetic ◽  
Familial Cancer Syndromes ◽  
Cancer Syndromes

Thanks to the veritably logarithmic advances in the molecular genetics of many emerging hereditary cancer syndromes, genetic counselling has become of paramount importance. It is a key element of the emerging concepts for patient education and management, which have become the clinical bedrock for diagnosis and management of hereditary cancer. Genetic counsellors have become proficient in the understanding of the complexities of molecular genetics in relation to hereditary cancer syndromes, demonstrating their ability both to supplement and replace the customary physician’s role in this overall process. We have used colorectal cancer, in particular Lynch syndrome, as a clinical genetic model based on the authors’ experience with diagnosis, DNA testing, and counselling of thousands of families for over four decades. Undoubtedly, the surface of the proverbial iceberg has barely been grazed in regard to the developments for the genetic counseling discipline.

scholarly journals Discussing and managing hematologic germ line variants

Blood ◽  
2016 ◽  
Vol 128 (21) ◽  
pp. 2497-2503 ◽  
Author(s):  
Wendy Kohlmann ◽  
Joshua D. Schiffman
Keyword(s):  
Hereditary Cancer ◽  
Genetic Variants ◽  
Germ Line ◽  
Hematologic Malignancies ◽  
Hereditary Cancer Syndromes ◽  
Rare Disorders ◽  
Good Opportunity ◽  
Genomic Technologies ◽  
Clinical Challenge ◽  
Cancer Syndromes

Abstract With the introduction of genomic technologies, more hereditary cancer syndromes with hematologic malignancies are being described. Up to 10% of hematologic malignancies in children and adults may be the result of an underlying inherited genetic risk. Managing these patients with hereditary hematologic malignancies, including familial leukemia, remains a clinical challenge because there is little information about these relatively rare disorders. This article covers some of the issues related to the diagnosis and interpretation of variants associated with hereditary hematologic malignancies, including the importance of an accurate family history in interpreting genetic variants associated with disease. The challenges of screening other family members and offering the most appropriate early malignancy detection is also discussed. We now have a good opportunity to better define hereditary cancer syndromes with associated hematologic malignancies and contribute to clinically effective guidelines.

scholarly journals Clinical actionability of universal sequencing for germline cancer susceptibility gene mutations among patients with colorectal cancer: A prospective study.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 63-63
Author(s):  
Wu Jiang ◽  
Peirong Ding
Keyword(s):  
Colorectal Cancer ◽  
Hereditary Cancer ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Germline Mutations ◽  
Hereditary Cancer Syndromes ◽  
Tailored Treatment ◽  
History Of ◽  
Cancer Susceptibility Gene ◽  
Cancer Syndromes

63 Background: Genetic predisposition is an important cause of colorectal cancer (CRC). Previous studies have demonstrated that universal sequencing in unselected CRC patients with multi-gene panel could detect more hereditary cancer syndromes. However, it is unclear whether this strategy would change clinical management for the affected individuals. Methods: We prospectively enrolled a consecutive cohort of 486 CRC patients, comprising of unselective patients aged no more than 70 years and patients older than 70 years with hereditary risk features. All participants received germline testing using a comprehensive panel of 81 genes associated with various hereditary cancer syndromes. Results: Fifty-two pathogenic or likely pathogenic mutations were discovered in 51 (10.5%, 51/486) patients, including 20 (4.1%) Lynch syndrome, 11 (4.1%) germline mutations with known CRC risk, and 20 (4.1%) in other cancer susceptibility genes not traditionally associated with CRC. Among them, 21 (4.3%) mutation-positive patients would have been left undiagnosed if they only adhered to present guidelines. Nearly seventy percent (36/51) of the mutation-positive patients were found to carry clinicalactionable germline mutations, for whom enhanced screening and/or tailored treatment was recommended.CRC location, multiple CRC diagnoses, personal history of malignancy, or family history of malignancy was not significantly related to the presence of a mutation in non-CRC susceptibility genes. Conclusions: Universal germline sequencing for cancer susceptibility gene among CRC patients substantially identified more individuals with hereditary cancer syndrome and actionable germline mutations, and these patients might benefit from enhanced surveillance and better tailored treatment. Clinical trial information: NCT03365986.

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