Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited condition caused by germline mutations of the
tumor suppressor gene encoding p53, a transcription factor triggered as a protective ...cellular mechanism against different stressors. Loss of p53 function renders affected individuals highly susceptible to a broad range of solid and hematologic cancers. It has recently become evident that children and adults with LFS benefit from intensive surveillance aimed at early tumor detection. In October 2016, the American Association for Cancer Research held a meeting of international LFS experts to evaluate the current knowledge on LFS and propose consensus surveillance recommendations. Herein, we briefly summarize clinical and genetic aspects of this aggressive cancer predisposition syndrome. In addition, the expert panel concludes that there are sufficient existing data to recommend that all patients with LFS be offered cancer surveillance as soon as the clinical or molecular LFS diagnosis is established. Specifically, the panel recommends adoption of a modified version of the "Toronto protocol" that includes a combination of physical exams, blood tests, and imaging. The panel also recommends that further research be promoted to explore the feasibility and effectiveness of these risk-adapted surveillance and cancer prevention strategies while addressing the psychosocial needs of individuals and families with LFS.
Li–Fraumeni syndrome (LFS) is a rare hereditary autosomal dominant cancer disorder. Germline mutations in TP53, the gene encoding p53, are responsible for most cases of LFS. TP53 is also the most ...commonly mutated gene in human cancers. Because inhibition of mutant p53 is considered to be a promising therapeutic strategy to treat these diseases, LFS provides a perfect genetic model to study p53 mutation-associated malignancies as well as to screen potential compounds targeting oncogenic p53. In this review we briefly summarize the biology of LFS and current understanding of the oncogenic functions of mutant p53 in cancer development. We discuss the strengths and limitations of current LFS disease models, and touch on existing compounds targeting oncogenic p53 and in vitro clinical trials to develop new ones. Finally, we discuss how recently developed methodologies can be integrated into the LFS induced pluripotent stem cell (iPSC) platform to develop precision cancer therapy.
LFS is a cancer hereditary syndrome caused by TP53 germline mutations. This syndrome serves as a useful model to study mutant p53-associated cancers. LFS patient-derived iPSCs offer several advantages compared to other LFS disease models, including unlimited supply of tissue, a human platform, and access to the heterogeneity of disease across multiple cell types. This system enables cancer modeling and facilitates in vitro drug testing.
LFS iPSCs and engineered p53 mutant PSCs can be used to discover drugs that target mutant p53 and its related pathways. LFS iPSCs can also assist in the development of in vitro assays, which are of great value in drug screening and testing in a dish. Marriage of LFS iPSC models to precise genome editing, 3D-based cell culture, and organ-on-chip systems will facilitate cancer modeling and anticancer drug discovery in a more comprehensive and nuanced way than would otherwise be possible.
Survival for childhood cancer has increased dramatically over the last 40 years with 5-year survival rates now approaching 80%. For many diagnostic groups, rapid increases in survival began in the ...1970s with the broader introduction of multimodality approaches, often including combination chemotherapy with or without radiation therapy. With this increase in rates of survivorship has come the recognition that survivors are at risk for adverse health and quality-of-life outcomes, with risk being influenced by host-, disease-, and treatment-related factors. In 1994, the US National Cancer Institute funded the Childhood Cancer Survivor Study, a multi-institutional research initiative designed to establish a large and extensively characterized cohort of more than 14,000 5-year survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. This ongoing study, which reflects the single most comprehensive body of information ever assembled on childhood and adolescent cancer survivors, provides a dynamic framework and resource to investigate current and future questions about childhood cancer survivors.
Penetrance, which plays a key role in genetic research, is defined as the proportion of individuals with the genetic variants (i.e., genotype) that cause a particular trait and who have clinical ...symptoms of the trait (i.e., phenotype). We propose a Bayesian semiparametric approach to estimate the cancer-specific age-at-onset penetrance in the presence of the competing risk of multiple cancers. We employ a Bayesian semiparametric competing risk model to model the duration until individuals in a high-risk group develop different cancers, and accommodate family data using family-wise likelihoods. We tackle the ascertainment bias arising when family data are collected through probands in a high-risk population in which disease cases are more likely to be observed. We apply the proposed method to a cohort of 186 families with Li-Fraumeni syndrome identified through probands with sarcoma treated at MD Anderson Cancer Center from 1944 to 1982. Supplementary materials for this article are available online.
Little is known about the breast cancer risk among childhood cancer survivors who did not receive chest radiotherapy. We sought to determine the magnitude of risk and associated risk factors for ...breast cancer among these women.
We evaluated cumulative breast cancer risk in 3,768 female childhood cancer survivors without a history of chest radiotherapy who were participants in the Childhood Cancer Survivor Study.
With median follow up of 25.5 years (range, 8 to 39 years), 47 women developed breast cancer at a median age of 38.0 years (range, 22 to 47 years) and median of 24.0 years (range, 10 to 34 years) from primary cancer to breast cancer. A four-fold increased breast cancer risk (standardized incidence ratio SIR = 4.0; 95% CI, 3.0 to 5.3) was observed when compared with the general population. Risk was highest among sarcoma and leukemia survivors (SIR = 5.3; 95% CI, 3.6 to 7.8 and SIR = 4.1; 95% CI, 2.4 to 6.9, respectively). By the age of 45 years, the cumulative incidence of breast cancer in sarcoma and leukemia survivors was 5.8% (95% CI, 3.7 to 8.4) and 6.3% (95% CI, 3.0 to 11.3), respectively. No other primary cancer diagnosis was associated with an elevated risk. Alkylators and anthracyclines were associated with an increased breast cancer risk in a dose-dependent manner (P values from test for trend were both < .01).
Women not exposed to chest radiotherapy who survive childhood sarcoma or leukemia have an increased risk of breast cancer at a young age. The data suggest high-dose alkylator and anthracycline chemotherapy increase the risk of breast cancer. This may suggest a possible underlying gene-environment interaction that warrants further study.
The tumor suppressor p53 gene is mutated in minimally half of all cancers. It is therefore reasonable to assume that naturally occurring polymorphic genetic variants in the p53 stress response ...pathway might determine an individual's susceptibility to cancer. A central node in the p53 pathway is the MDM2 protein, a direct negative regulator of p53. In this report, a single nucleotide polymorphism (SNP309) is found in the MDM2 promoter and is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers. A model is proposed whereby SNP309 serves as a rate-limiting event in carcinogenesis.
Individuals with Li-Fraumeni syndrome carry inherited mutations in the
p53 tumor suppressor gene and are predisposed to tumor development. To examine the mechanistic nature of these p53 missense ...mutations, we generated mice harboring a G-to-A substitution at nucleotide 515 of
p53 (
p53
+/515A
) corresponding to the p53R175H hot spot mutation in human cancers. Although
p53
+/515A
mice display a similar tumor spectrum and survival curve as
p53
+/−
mice, tumors from
p53
+/515A
mice metastasized with high frequency. Correspondingly, the embryonic fibroblasts from the
p53
515A/515A
mutant mice displayed enhanced cell proliferation, DNA synthesis, and transformation potential. The disruption of
p63 and
p73 in
p53
−/−
cells increased transformation capacity and reinitiated DNA synthesis to levels observed in
p53
515A/515A
cells. Additionally, p63 and p73 were functionally inactivated in
p53
515A
cells. These results provide in vivo validation for the gain-of-function properties of certain p53 missense mutations and suggest a mechanistic basis for these phenotypes.
Leukemia, the most common childhood cancer, has long been recognized to occasionally run in families. The first clues about the genetic mechanisms underlying familial leukemia emerged in 1990 when ...Li-Fraumeni syndrome was linked to
mutations. Since this discovery, many other genes associated with hereditary predisposition to leukemia have been identified. Although several of these disorders also predispose individuals to solid tumors, certain conditions exist in which individuals are specifically at increased risk to develop myelodysplastic syndrome (MDS) and/or acute leukemia. The increasing identification of affected individuals and families has raised questions around the efficacy, timing, and optimal methods of surveillance. As part of the AACR Childhood Cancer Predisposition Workshop, an expert panel met to review the spectrum of leukemia-predisposing conditions, with the aim to develop consensus recommendations for surveillance for pediatric patients. The panel recognized that for several conditions, routine monitoring with complete blood counts and bone marrow evaluations is essential to identify disease evolution and enable early intervention with allogeneic hematopoietic stem cell transplantation. However, for others, less intensive surveillance may be considered. Because few reports describing the efficacy of surveillance exist, the recommendations derived by this panel are based on opinion, and local experience and will need to be revised over time. The development of registries and clinical trials is urgently needed to enhance understanding of the natural history of the leukemia-predisposing conditions, such that these surveillance recommendations can be optimized to further enhance long-term outcomes.
Survivors of pediatric Hodgkin's lymphoma are at risk for radiation therapy-induced second malignant neoplasms (SMNs). We identified two variants at chromosome 6q21 associated with SMNs in survivors ...of Hodgkin's lymphoma treated with radiation therapy as children but not as adults. The variants comprise a risk locus associated with decreased basal expression of PRDM1 (encoding PR domain containing 1, with ZNF domain) and impaired induction of the PRDM1 protein after radiation exposure. These data suggest a new gene-exposure interaction that may implicate PRDM1 in the etiology of radiation therapy-induced SMNs.
Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder associated with
germline mutations and an increased lifetime risk of multiple primary cancers (MPC). Penetrance estimation of time to ...first and second primary cancer within LFS remains challenging because of limited data and the difficulty of characterizing the effects of a primary cancer on the penetrance of a second primary cancer. Using a recurrent events survival modeling approach that incorporates a family-wise likelihood to efficiently integrate the pedigree structure, we estimated the penetrance for both first and second primary cancer diagnosis from a pediatric sarcoma cohort at MD Anderson Cancer Center MDACC, Houston, TX; number of families = 189; single primary cancer (SPC) = 771; and MPC = 87. Validation of the risk prediction performance was performed using an independent MDACC clinical cohort of
tested individuals (SPC = 102 and MPC = 58). These findings showed that an individual diagnosed at a later age was more likely to be diagnosed with a second primary cancer. In addition,
mutation carriers had a HR of 1.65 (95% confidence interval, 1.1-2.5) for developing a second primary cancer versus SPC. The area under the ROC (AUC) curve for predicting individual outcomes of MPC versus SPC was 0.77. In summary, we provide the first set of penetrance estimates for first and second primary cancer for
germline mutation carriers and demonstrate its accuracy for cancer risk assessment. SIGNIFICANCE: These findings present an open-source R package LFSPRO that could be used for genetic counseling and health management of individuals with LFS as it estimates the risk of both first and second primary cancer diagnosis.
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