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Connecting molecular pathways to hereditary cancer risk syndromes.

ABSTRACT: An understanding of the genetic causes and molecular pathways of hereditary cancer syndromes has historically informed our knowledge and treatment of all types of cancers. For this review, we focus on three rare syndromes and their associated genetic mutations including BAP1, TP53, and SDHx (SDHA, SDHB, SDHC, SDHD, SDHAF2). BAP1 encodes an enzyme that catalyzes the removal of ubiquitin from protein substrates, and germline mutations of BAP1 cause a novel cancer syndrome characterized by high incidence of benign atypical melanocytic tumors, uveal melanomas, cutaneous melanomas, malignant mesotheliomas, and potentially other cancers. TP53 mutations cause Li-Fraumeni syndrome (LFS), a highly penetrant cancer syndrome associated with multiple tumors including but not limited to sarcomas, breast cancers, brain tumors, and adrenocortical carcinomas. Genomic modifiers for tumor risk and genotype-phenotype correlations in LFS are beginning to be identified. SDH is a mitochondrial enzyme complex involved in the tricarboxylic acid (TCA) cycle, and germline SDHx mutations lead to increased succinate with subsequent paragangliomas, pheochromocytomas, renal cell carcinomas (RCCs), gastrointestinal stromal tumors (GISTs), and other rarer cancers. In all of these syndromes, the molecular pathways have informed our understanding of tumor risk and successful early tumor surveillance and screening programs.

SUBMITTER: Testa JR

PROVIDER: S-EPMC5889618 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Connecting molecular pathways to hereditary cancer risk syndromes.

Testa Joseph R JR Malkin David D Schiffman Joshua D JD

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting 20130101

An understanding of the genetic causes and molecular pathways of hereditary cancer syndromes has historically informed our knowledge and treatment of all types of cancers. For this review, we focus on three rare syndromes and their associated genetic mutations including BAP1, TP53, and SDHx (SDHA, SDHB, SDHC, SDHD, SDHAF2). BAP1 encodes an enzyme that catalyzes the removal of ubiquitin from protein substrates, and germline mutations of BAP1 cause a novel cancer syndrome characterized by high inc ...[more]

PMID: 23714463

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Project description:BackgroundThe number of individuals meeting criteria for genetic counseling and testing for hereditary cancer syndromes (HCS) is far less than the number that actually receive it. To facilitate identification of patients at risk for HCS, Counsyl developed a digital identification tool (digital ID tool) to match personal and family cancer history to National Comprehensive Cancer Network (NCCN) BRCA-related Hereditary Breast and Ovarian Cancer (HBOC), Lynch syndrome, and polyposis testing criteria in one-to-one, automated fashion. The purpose of this study was to validate the ability of the digital ID tool to accurately identify histories that do and do not meet NCCN testing criteria.MethodsThird-party recorded three-generation pedigrees were retrospectively reviewed by a certified genetic counselor (CGC) to determine if independent events included in pedigree histories met NCCN guidelines, and were then sorted into groups: high risk events (meets criteria) and low risk events (does not meet criteria). Events were entered into the digital ID tool to determine the extent of its concordance with events sorted by CGC review. Statistical tests of accuracy were calculated at a 95% confidence interval (CI).ResultsOne hundred ninety-seven pedigrees were reviewed consecutively representing 765 independent events for analysis across groups. 382/382 (100%) high risk events identified by the digital ID tool and 381/383 (99.47%) low risk events identified by the digital ID tool were concordant with CGC sorting. The digital ID tool had a sensitivity of 100% (99.04-100% CI) and specificity of 99.48% (98.13-99.94% CI). The overall accuracy of the digital ID tool was estimated to be 99.74% (99.06-99.97% CI), reflecting the rate at which the digital ID tool reached the same conclusion as that of CGC review of pedigree events for the recommendation of genetic testing for individuals at risk for HCS.ConclusionsThe digital ID tool accurately matches NCCN criteria in one-to-one fashion to identify at-risk individuals for HCS and may be useful in clinical practice, specifically for BRCA-related HBOC and Lynch Syndrome.

Project description:Hereditary breast cancer syndromes are associated with an increased risk of breast cancer and constitute a unique patient population, making up approximately 5%-10% of breast cancer cases in the United States. By virtue of the germline mutations that define these syndromes, invasive breast cancers in these patients have unique mechanisms that can be rationally targeted for therapeutic opportunities distinct from standard of care treatments in nongermline mutation associated breast cancers. This review intends to describe existing data on several of the most common hereditary breast cancer syndromes, including BRCA-related breast cancer syndrome, Li-Fraumeni syndrome, Cowden syndrome, Peutz-Jeghers syndrome, and hereditary diffuse gastric cancer syndrome, specifically focusing on rational therapeutics utilized in these distinct patient subgroups and completed or ongoing clinical trials evaluating their efficacy. By exploiting the distinct biologic features associated with these syndromes, tailored treatment strategies have the potential for improved efficacy and lower toxicity. Knowledge of the emergence of these targeted cancer therapies is critical for appropriate management in these patients, extending beyond treatment to highlight the need for appropriate genetic screening to allow for early recognition of these patients and therefore appropriate treatment.Molecular testing allows for identification of germline mutations that place individuals at high risk for breast cancer and that are associated with distinct histopathology and molecular characteristics that define the invasive breast cancer cases that these patients develop. These unique characteristics may ultimately provide rational targets for systemic treatments with improvements in both morbidity and efficacy. Identification of patients with these germline mutations is important for not only appropriate screening and prophylaxis, but knowledge of therapies specifically targeting several of the most common hereditary breast cancer syndromes is essential to ensure appropriate treatment of invasive breast cancers in these patients.

Dataset Information

Connecting molecular pathways to hereditary cancer risk syndromes.

Publications

Connecting molecular pathways to hereditary cancer risk syndromes.

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