Genetic/Familial High-Risk Assessment: Breast and Ovarian Clinical Practice Guidelines

2006 ◽  
Vol 4 (2) ◽  
pp. 156 ◽  
Author(s):  
_ _
Keyword(s):  
Molecular Genetics ◽  
Cancer Genetics ◽  
Cowden Syndrome ◽  
Rapid Expansion ◽  
Cancer Syndrome ◽  
Li Fraumeni Syndrome ◽  
Cancer Management ◽  
Inherited Susceptibility ◽  
Increased Risk ◽  
Risk Of Cancer

Recent advances in molecular genetics have identified several genes associated with inherited susceptibility to cancer and have provided a means to begin identifying individuals and families with an increased risk of cancer. This rapid expansion of knowledge about cancer genetics has implications for all aspects of cancer management, including prevention, screening, and treatment. These guidelines specifically address hereditary breast/ovarian cancer syndrome (HBOC), Li-Fraumeni syndrome, and Cowden syndrome. These guidelines were developed understanding that much of our knowledge of how the rapidly emerging field of molecular genetics can be applied clinically is preliminary and that flexibility is needed when applying these guidelines to individual families. For the most recent version of the guidelines, please visit NCCN.org

Neuroradiology Manifestations of Li-Fraumeni Syndrome: Epidemiology, Genetics, Imaging Findings, and Management

Neurographics ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 228-235
Author(s):  
S. Naganawa ◽  
T. Donohue ◽  
A. Capizzano ◽  
Y. Ota ◽  
J. Kim ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Soft Tissue Sarcomas ◽  
Suppressor Gene ◽  
Imaging Findings ◽  
Li Fraumeni Syndrome ◽  
Increased Risk ◽  
Li Fraumeni ◽  
Risk Of Cancer

Li-Fraumeni syndrome is a familial cancer predisposition syndrome associated with germline mutation of the tumor suppressor gene 53, which encodes the tumor suppressor p53 protein. Affected patients are predisposed to an increased risk of cancer development, including soft-tissue sarcomas, breast cancer, brain tumors, and adrenocortical carcinoma, among other malignancies. The tumor suppressor gene TP53 plays an important, complex role in regulating the cell cycle, collaborating with transcription factors and other proteins. The disruption of appropriate cell cycle regulation by mutated TP53 is considered to be the cause of tumorigenesis in Li-Fraumeni syndrome. Appropriate surveillance, predominantly by using MR imaging, is used for early malignancy screening in an effort to improve the survival rate among individuals who are affected. Patients with Li-Fraumeni syndrome are also at increased risk for neoplasm development after radiation exposure, and, therefore, avoiding unnecessary radiation in both the diagnostic and therapeutic settings is paramount. Here, we review the epidemiology, genetics, imaging findings, and the current standard surveillance protocol for Li-Fraumeni syndrome from the National Comprehensive Cancer Network as well as potential treatment options.Learning Objective: Describe the cause of second primary malignancy among patients with Li-Fraumeni syndrome.

scholarly journals Pediatric Cancer Genetics Research and an Evolving Preventive Ethics Approach for Return of Results after Death of the Subject

2015 ◽  
Vol 43 (3) ◽  
pp. 529-537
Author(s):  
Sarah Scollon ◽  
Katie Bergstrom ◽  
Laurence B. McCullough ◽  
Amy L. McGuire ◽  
Stephanie Gutierrez ◽  
...  
Keyword(s):  
Cancer Genetics ◽  
Recurrence Risk ◽  
Genomic Research ◽  
Return Of Results ◽  
Genetics Research ◽  
Personal Significance ◽  
Pediatric Diseases ◽  
Increased Risk ◽  
Preventive Ethics ◽  
Risk Of Cancer

In the pediatric clinical setting, the parent/guardian will almost always be the authorized representative and designated recipient of clinical and research results, making the issue of to whom results should be returned in the pediatric setting less complex than in adult settings. It is also clear that, in genomic research related to pediatric diseases such as cancer, results may be of considerable clinical, ethical, and personal significance for parents in a number of ways, including a genomic explanation of the origin of their child’s cancer, implications for the genetic testing and medical care of other siblings and of the parents themselves, and reproductive planning with regard to the recurrence risk for future children to have an increased risk of cancer. However, what remains unclear is which results should be disclosed, and under what circumstances, to parents of deceased children.

scholarly journals Li-Fraumeni Syndrome and p53 in 2015: Celebrating their Silver Anniversary

2016 ◽  
Vol 39 (1) ◽  
pp. 37 ◽  
Author(s):  
David Malkin
Keyword(s):  
Wilms Tumor ◽  
Cancer Genetics ◽  
Tp53 Gene ◽  
Pleuropulmonary Blastoma ◽  
Li Fraumeni Syndrome ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Li Fraumeni ◽  
Sick Children ◽  
Risk Of Cancer

In a typical morning in the Cancer Genetics Clinic at The Hospital for Sick Children in Toronto, the following array of patients and families might be seen: a family of three children, all harbouring a mutation of the succinyl dehydrogenase C gene inherited from their father who had had extensive surgery several years ago for a secreting paraganglioma; three families with Li-Fraumeni syndrome, each with at least one child harbouring a TP53 gene mutation conferring a lifetime risk of cancer approaching 100% and currently undergoing surveillance for early tumour detection; two children with Li-Fraumeni syndrome undergoing treatment for cancer – one having had three cancer diagnoses before 19 months of age and the other just completing therapy for metastatic adrenocortical carcinoma at age 3; two children with von Hippel-Lindau disease being monitored for persistent pancreatic neuroendocrine tumors and cerebellar hemangioblastomas, respectively; and one child with Beckwith-Wiedeman syndrome and Wilms tumor and another child completing therapy for a pleuropulmonary blastoma (PPB).

American Society of Clinical Oncology Policy Statement Update: Genetic Testing for Cancer Susceptibility

2003 ◽  
Vol 21 (12) ◽  
pp. 2397-2406 ◽  
Keyword(s):  
Genetic Testing ◽  
Informed Consent ◽  
Hereditary Cancer ◽  
Cancer Susceptibility ◽  
Cancer Genetics ◽  
Family Members ◽  
Educational Opportunities ◽  
Increased Risk ◽  
Post Test ◽  
Risk Of Cancer

Executive Summary: As the leading organization representing cancer specialists involved in patient care and clinical research, the American Society of Clinical Oncology (ASCO) reaffirms its commitment to integrating cancer risk assessment and management, including molecular analysis of cancer predisposition genes, into the practice of oncology and preventive medicine. The primary goal of this effort is to foster expanded access to, and continued advances in, medical care provided to patients and families affected by hereditary cancer syndromes. The 1996 ASCO Statement on Genetic Testing for Cancer Susceptibility set forth specific recommendations relating to clinical practice, research needs, educational opportunities, requirement for informed consent, indications for genetic testing, regulation of laboratories, and protection from discrimination, as well as access to and reimbursement for cancer genetics services. In updating this Statement, ASCO endorses the following principles: Indications for Genetic Testing:ASCO recommends that genetic testing be offered when 1) the individual has personal or family history features suggestive of a genetic cancer susceptibility condition, 2) the test can be adequately interpreted, and 3) the results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer. ASCO recommends that genetic testing only be done in the setting of pre- and post-test counseling, which should include discussion of possible risks and benefits of cancer early detection and prevention modalities. Special Issues in Testing Children for Cancer Susceptibility:ASCO recommends that the decision to offer testing to potentially affected children should take into account the availability of evidence-based risk-reduction strategies and the probability of developing a malignancy during childhood. Where risk-reduction strategies are available or cancer predominantly develops in childhood, ASCO believes that the scope of parental authority encompasses the right to decide for or against testing. In the absence of increased risk of a childhood malignancy, ASCO recommends delaying genetic testing until an individual is of sufficient age to make an informed decision regarding such tests. As in other areas of pediatric care, the clinical cancer genetics professional should be an advocate for the best interests of the child. Counseling About Medical Management After Testing:ASCO recommends that oncologists include in pre- and post-test counseling the discussion of possible risks and benefits of cancer early-detection and prevention modalities, some of which have presumed but unproven efficacy for individuals at increased hereditary risk of cancer. Regulation of Genetic Testing:ASCO recommends strengthening regulatory oversight of laboratories that provide clinical cancer predisposition tests. These quality assurance mechanisms should include oversight of the reagents used in genetic testing, interlaboratory comparisons of reference samples, standardization of laboratory genetic test reports, and proficiency testing. Protection From Insurance and Employment Discrimination:ASCO supports establishing a federal law to prohibit discrimination by health insurance providers and employers on the basis of an individual’s inherited susceptibility to cancer. Protections against genetic discrimination should apply to those with group coverage, those with individual health insurance policies, and the uninsured. Coverage of Services:ASCO supports efforts to ensure that all individuals at significantly increased risk of hereditary cancer have access to appropriate genetic counseling, testing, screening, surveillance, and all related medical and surgical interventions, which should be covered without penalty by public and private third-party payers. Confidentiality and Communication of Familial Risk:ASCO recommends that providers make concerted efforts to protect the confidentiality of genetic information. However, they should remind patients of the importance of communicating test results to family members, as part of pretest counseling and informed consent discussions. ASCO believes that the cancer care provider’s obligations (if any) to at-risk relatives are best fulfilled by communication of familial risk to the person undergoing testing, emphasizing the importance of sharing this information with family members so that they may also benefit. Educational Opportunities in Genetics:ASCO is committed to continuing to provide educational opportunities for physicians and other health care providers regarding the methods of cancer risk assessment, the clinical characteristics of hereditary cancer susceptibility syndromes, and the range of issues related to genetic testing, including pre- and post-test genetic counseling, and risk management, so that health professionals may responsibly integrate the care of persons at increased genetic risk of cancer into the practice of clinical and preventive oncology. Special Issues Relating to Genetic Research on Human Tissues:ASCO recommends that all researchers proposing to use or store human biologic specimens for genetic studies should consult either the responsible institutional review board (IRB) or a comparable body specifically constituted to assess human tissue research, to determine the requirements for protection specific to the study under consideration. This consultation should take place before the project is initiated. The determination of the need for informed consent or authorization in such studies should depend on whether the research involves tests for genetic markers of known clinical significance and whether research data will be linked to protected health information, as well as other considerations specific to the study proposed. Special attention should also be paid to 1) whether future research findings will be disclosed to the research participants, 2) whether future contact of participants is planned, 3) whether and how protected health information about the tissue donors will be stored, and what will happen to study specimens after the trial ends. In addition, ASCO affirms the right of people contributing tissue to a databank to rescind their permission, in accordance with federal privacy regulations.

scholarly journals Lung cancer is also a hereditary disease

2021 ◽  
Vol 30 (162) ◽  
pp. 210045
Author(s):  
Patrick R. Benusiglio ◽  
Vincent Fallet ◽  
Mateo Sanchis-Borja ◽  
Florence Coulet ◽  
Jacques Cadranel
Keyword(s):  
Lung Cancer ◽  
Cancer Susceptibility ◽  
Cancer Genetics ◽  
Susceptibility Gene ◽  
Lung Cancer Screening ◽  
Hereditary Disease ◽  
Tumour Suppressor Gene ◽  
Li Fraumeni Syndrome ◽  
Pathogenic Variants ◽  
Increased Risk

Pathogenic genetic variants (formerly called mutations) present in the germline of some individuals are associated with a clinically relevant increased risk of developing lung cancer. These germline pathogenic variants are hereditary and are transmitted in an autosomal dominant fashion. There are two major lung cancer susceptibility syndromes, and both seem to be specifically associated with the adenocarcinoma subtype. Li-Fraumeni syndrome is caused by variants in the TP53 tumour-suppressor gene. Carriers are mainly at risk of early-onset breast cancer, sarcoma, glioma, leukaemia, adrenal cortical carcinoma and lung cancer. EGFR variants, T790M in particular, cause the EGFR susceptibility syndrome. Risk seems limited to lung cancer. Emerging data suggest that variants in ATM, the breast and pancreatic cancer susceptibility gene, also increase lung adenocarcinoma risk. As for inherited lung disease, cancer risk is increased in SFTPA1 and SFTPA2 variant carriers independently of the underlying fibrosis. In this review, we provide criteria warranting the referral of a lung cancer patient to the cancer genetics clinic. Pathogenic variants are first identified in patients with cancer, and then in a subset of their relatives. Lung cancer screening should be offered to asymptomatic carriers, with thoracic magnetic resonance imaging at its core.

scholarly journals Cowden Syndrome: report of a case and brief review of literature

2013 ◽  
Vol 88 (6 suppl 1) ◽  
pp. 52-52 ◽  
Author(s):  
Ana Carolina Souza Porto ◽  
Elisabeth Roider ◽  
Thomas Ruzicka
Keyword(s):  
Cell Cycle Progression ◽  
Cowden Syndrome ◽  
Pten Gene ◽  
Benign Tumors ◽  
Cutaneous Lesions ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Increased Risk ◽  
History Of ◽  
Risk Of Cancer

We present the case of a female patient with facial cutaneous lesions, a cobblestone-like pattern of the oral mucosa, and verruciform lesions on the hand since her youth. She reported a history of breast cancer, endometrial cancer, melanoma and multiple benign tumors and cysts. PTEN gene analysis was performed and confirmed Cowden Syndrome, a rare genodermatosis with an autosomal dominant pattern of inheritance, characterized by multiple hamartomas. The phosphatase and tensin homolog (PTEN) gene negatively regulates cell proliferation and cell cycle progression. Loss of PTEN function contributes to an increased risk of cancer. We emphasize the importance of early detection and accurate management of Cowden Syndrome.

scholarly journals Early-onset renal cell carcinoma in PTEN harmatoma tumour syndrome

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Raymond H. Kim ◽  
Xiangling Wang ◽  
Andrew J. Evans ◽  
Steven C. Campbell ◽  
Jane K. Nguyen ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Early Detection ◽  
Cell Carcinoma ◽  
Kidney Cancer ◽  
Renal Cell ◽  
Cowden Syndrome ◽  
Elevated Risk ◽  
Renal Ultrasound ◽  
Increased Risk ◽  
Risk Of Cancer

Abstract Individuals with PTEN hamartoma tumour syndrome (PHTS), including Cowden syndrome (CS), are susceptible to multiple benign hamartomas and an increased risk of cancer, particularly breast, endometrial, and thyroid. As a result, individuals undergo enhanced surveillance for early detection of these cancers. However, less commonly occurring cancers, such as colorectal and kidney, have insufficient guidelines for early detection. Currently, screening for kidney cancer via renal ultrasound begins at 40 years of age, because there were only rare cases of elevated risk in prospective series under 40. There have, however, been accumulating reports of kidney cancer in individuals with CS in their 30s, illustrating a need to lower the age of surveillance. We present additional evidence of renal cell carcinoma in two individuals with CS in their early twenties, and propose a reassessment of the abdominal surveillance in patients with PHTS. We propose biannual screening for kidney cancer beginning at 20 years of age.

scholarly journals In Their Own Words: A Qualitative Study of Kenyan Breast Cancer Survivors’ Knowledge, Experiences, and Attitudes Regarding Breast Cancer Genetics

2018 ◽  
pp. 1-9 ◽  
Author(s):  
Siwon Lee ◽  
Amal Gedleh ◽  
Jessica A. Hill ◽  
Seemi Qaiser ◽  
Yvonne Umukunda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Cancer Survivors ◽  
Breast Cancer Survivors ◽  
Cancer Genetics ◽  
Cancer Data ◽  
Increased Risk ◽  
Breast Cancer Genetics ◽  
Risk Of Cancer ◽  
Testing And Counseling

Introduction Breast cancer ranks among the most common adult cancers in Kenya. Individuals with a family history of the disease are at increased risk. Mutations most commonly associated with breast cancer affect BRCA1 and BRCA2; mutations in several other genes may also confer breast cancer risk. Genetic testing and counseling can help patients understand their risk and assist clinicians in choosing therapies. We aimed to uncover what patients know, experience, and think with regard to breast cancer genetics in Kenya. Methods Participants included breast cancer survivors age > 18 years. Participants completed a demographic questionnaire before participating in focus group discussions to uncover knowledge of, experiences with, and attitudes toward the genetics of breast cancer. Data were analyzed by inductive thematic analysis. Results Four focus groups were conducted. Participants had rudimentary knowledge about genetics and cancer development, and although they understood breast cancer could be familial, many suspected environmental factors causing spontaneous disease. They reported limited experience with counseling about genetic risk, perceiving that their physicians were too busy to provide comprehensive information. Many indicated they promoted cancer screening among family to promote early diagnosis. Participants expressed a need for more comprehensive counseling and access to genetic testing, recognizing the added clarity it would bring to their families’ risk of cancer. Conclusion Improved communication from health care teams could clarify the risk of cancer for affected families. The introduction of affordable genetic testing and counseling for breast cancer in Kenya is welcomed by survivors.

scholarly journals A pedigree-based prediction model identifies carriers of deleterious de novo mutations in families with Li-Fraumeni syndrome

2020 ◽  
Author(s):  
Fan Gao ◽  
Xuedong Pan ◽  
Elissa B. Dodd-Eaton ◽  
Carlos Vera Recio ◽  
Matthew D. Montierth ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
De Novo ◽  
Cancer Genetics ◽  
De Novo Mutations ◽  
Cancer Syndrome ◽  
Li Fraumeni Syndrome ◽  
Inherited Cancer ◽  
Li Fraumeni ◽  
Validation Set ◽  
Hotspot Mutation

ABSTRACTDe novo mutations (DNMs) are increasingly recognized as rare disease causal factors. Identifying DNM carriers will allow researchers to study the likely distinct molecular mechanisms of DNMs. We developed Famdenovo to predict DNM status (DNM or familial mutation (FM)) of deleterious autosomal dominant germline mutations for any syndrome. We introduce Famdenovo.TP53 for Li-Fraumeni syndrome (LFS) and analyze 324 LFS family pedigrees from four US cohorts: a validation set of 186 pedigrees and a discovery set of 138 pedigrees. The concordance index for Famdenovo.TP53 prediction was 0.95 (95% CI: [0.92, 0.98]). Forty individuals (95% CI: [30, 50]) were predicted as DNM carriers, increasing the total number from 42 to 82. We compared clinical and biological features of FM versus DNM carriers: 1) cancer and mutation spectra along with parental ages were similarly distributed; 2) ascertainment criteria like early-onset breast cancer (age 20 to 35 years) provides a condition for an unbiased estimate of the DNM rate: 48% (23 DNMs versus 25 FMs); 3) hotspot mutation R248W was not observed in DNMs, although it was as prevalent as hotspot mutation R248Q in FMs. Furthermore, we introduce Famdenovo.BRCA for hereditary breast and ovarian cancer syndrome, and apply it to a small set of family data from the Cancer Genetics Network. In summary, we introduce a novel statistical approach to systematically evaluate deleterious DNMs in inherited cancer syndromes. Our approach may serve as a foundation for future studies evaluating how new deleterious mutations can be established in the germline, such as those in TP53.

scholarly journals Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

2021 ◽  
Vol 19 (1) ◽  
pp. 77-102
Author(s):  
Mary B. Daly ◽  
Tuya Pal ◽  
Michael P. Berry ◽  
Saundra S. Buys ◽  
Patricia Dickson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Risk Assessment ◽  
Pancreatic Cancer ◽  
High Risk ◽  
Cancer Syndrome ◽  
Li Fraumeni Syndrome ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Li Fraumeni ◽  
Familial High Risk

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

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