Connecting molecular pathways to hereditary cancer risk syndromes

Our plain-English summary of Connecting molecular pathways to hereditary cancer risk syndromes, by J.R. Testa, D. Malkin, J.D. Schiffman (American Society of Clinical Oncology Educational Book, 2013).

The study

• Authors: J.R. Testa, D. Malkin, J.D. Schiffman
• Journal: American Society of Clinical Oncology Educational Book
• Published: 2013:81-90
• Type of article: Review
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This article reviewed three rare inherited cancer syndromes: BAP1 cancer syndrome, Li-Fraumeni syndrome (TP53 mutations), and SDHx mutation syndromes. It mainly summarized earlier studies but also cited unpublished University of Utah MRI screening results in SDHx mutation carriers. Bott and colleagues, and separately Testa and colleagues, found tumor-acquired (somatic, not inherited) BAP1 mutations in 22% of sporadic malignant mesotheliomas. Inherited BAP1 mutations were found in two high-risk families in which mesothelioma was the main cancer. Neither family's members had been exposed to asbestos at work; only traces of asbestos were found in their homes. Inherited BAP1 mutations were also found in 2 of 26 sporadic mesotheliomas tested; both patients had previously been diagnosed with uveal melanoma. The review noted that mesothelioma is causally linked to asbestos or related fibers such as erionite. For Li-Fraumeni syndrome, it cited lifetime cancer risks of 93% for men and 68% for women. The authors concluded that BAP1 mutation carriers should be monitored regularly and avoid asbestos and sun exposure. They said genetic studies are still needed to define the full tumor range.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published studies on three hereditary cancer syndromes (BAP1, TP53/Li-Fraumeni, SDHx). It also cites some unpublished results given as a personal communication.
• Who was studied: No study population of its own. The review covers published reports on families and patients with germline BAP1, TP53 and SDHx mutations, including high-risk mesothelioma families and patients with sporadic mesothelioma.
• Exposure: Inherited (germline) mutations in BAP1, TP53 and SDHx genes. For mesothelioma, the review also discusses asbestos or related carcinogenic fibers such as erionite.
• Main results:
  • Cited studies by Testa and colleagues, and independently by Bott and colleagues: BAP1 mutations in 22% of sporadic malignant mesotheliomas. Testa and colleagues described these as somatic mutations, meaning they arose in the tumor and were not inherited.
  • Cited study: in two high-risk families with germline BAP1 mutations and mostly mesothelioma, no members had been exposed to asbestos at work, and only traces of asbestos were found in their homes.
  • Cited study: in one family, a germline BAP1 splice acceptor site mutation was found in all six family members who developed mesothelioma.
  • Cited study: in the second family, the germline BAP1 mutation was associated with various cancers, including seven mesotheliomas and two uveal melanomas.
  • Cited study: germline BAP1 mutations were found in 2 of 26 sporadic mesotheliomas tested. Both of these patients had previously been diagnosed with uveal melanoma.
  • Cited report: a germline BAP1 mutation in a family in which mesothelioma was found in four members, none with a history of asbestos exposure.
  • Cited study (Harbour and colleagues): inactivating somatic BAP1 mutations in 26/31 (84%) metastasizing uveal melanomas.
  • Cited figure for Li-Fraumeni syndrome: lifetime risk of developing cancer of 93% in men and 68% in women.
  • Cited National Institutes of Health study: 44% of adults and 81% of children with metastatic paraganglioma or pheochromocytoma had germline SDHx mutations.
  • Unpublished University of Utah prospective observational study, cited as a personal communication and submitted work. In SDHx mutation carriers, whole-body MRI had a sensitivity of 88% and specificity of 95% to detect new tumors. Biochemical testing had a sensitivity of 38% and specificity of 95%.
• The authors' conclusion: The authors concluded that BAP1 mutation carriers should be regularly monitored for early malignancy, and that preventive measures such as avoiding exposure to asbestos and sun should be implemented.
• Limitations the authors state:
  • The authors stated that genetic epidemiologic studies are still needed to determine whether BAP1 carriers have significant susceptibility to other tumor types (paraganglioma, renal cell carcinoma, lung and breast carcinomas).
  • The authors stated it is unclear whether differences in the incidence of mesothelioma among BAP1 mutation carriers reflect genetic background or differences in exposure to carcinogens.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Germline Mutation, Malignant Mesothelioma, Sarcoma, Carcinoma.

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