Hereditary cancer syndromes as model systems for chemopreventive agent development

doi:10.1053/j.seminoncol.2015.09.015

Seminars in Oncology

Volume 43, Issue 1, February 2016, Pages 134-145

https://doi.org/10.1053/j.seminoncol.2015.09.015 Get rights and content

Abstract

Research in chemoprevention has undergone a shift in emphasis for pragmatic reasons from large, phase III randomized studies to earlier phase studies focused on safety, mechanisms, and utilization of surrogate endpoints such as biomarkers instead of cancer incidence. This transition permits trials to be conducted in smaller populations and at substantially reduced costs while still yielding valuable information. This article will summarize some of the current chemoprevention challenges and the justification for the use of animal models to facilitate identification and testing of chemopreventive agents as illustrated though four inherited cancer syndromes. Preclinical models of inherited cancer syndromes serve as prototypical systems in which chemopreventive agents can be developed for ultimate application to both the sporadic and inherited cancer settings.

Section snippets

1. Introduction

The search for the ideal natural, synthetic, or biologic agents to reverse, suppress, or prevent cancer has been the aim of cancer chemoprevention research, beginning in 1976 with Dr Michael Sporn’s [1] creation of the term "chemoprevention". The approvals of tamoxifen and raloxifene by the FDA (1999 and 2007, respectively) for breast cancer chemoprevention, or more precisely risk reduction, were successes that have yet to be achieved by other agents such as aspirin and nonsteroidal

2. Hereditary breast and ovarian cancer syndrome, BRCA1 and BRCA2

Having a family history of breast and/or ovarian cancer has long been recognized as a risk factor for these malignancies [4], [5]. Of the dominant, high-penetrance susceptibility alleles identified to date, mutations in BRCA1 and BRCA2 associated with hereditary breast and ovarian cancer syndrome (HBOC) are the most prevalent affecting approximately 1/400–800 in the general population [6]. The prevalence is higher in populations such as Ashkenazi Jewish and Icelandic populations due to founder

3. Li-Fraumeni syndrome

Li-Fraumeni syndrome (LFS), a highly penetrant, autosomal-dominant, inherited cancer predisposition syndrome, was first described in 1969 by Li and Fraumeni based on a retrospective analysis of four families with childhood rhabdomyosarcoma [29]. The second most common cancer identified in these families was early age-onset breast cancer (age <30 years). In 1990, using a candidate gene approach, the underlying genetic abnormality in LFS was identified as a germline mutation of TP53 [30]. Though

4. Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is the second most common inherited colon cancer syndrome. FAP is diagnosed in individuals with more than 100 adenomatous colorectal polyps, which typically develop around a median age of 16 years [64]. Symptoms may arise in the third decade and the median age for the development of colonic cancer is 35–40 years. Progression to colorectal cancer occurs with nearly complete penetrance by age 40–50 years; however, malignancy in childhood does occur [65].

5. Lynch syndrome

Lynch syndrome (LS), previously referred to as hereditary nonpolyposis colon cancer (HNPCC) [95], is an autosomal dominantly inherited disorder of cancer susceptibility caused by germline mutations in one of the DNA mismatch repair (MMR) genes. LS was first described by Aldred Warthin in 1913 [96]. In 1966, Henry Lynch reported two large families with hereditary colorectal cancer from the midwest [97].

In the 1990s the underlying gene defects were discovered, mutation of one of the MMR genes:

6. Discussion

The concept of designing chemoprevention studies for use in genetically predisposed populations is not new. Inherited mutations have the unique potential to be used as either molecular biomarkers of cancer risk or targets for chemopreventive agents. The penetrance of these genes and the young age-of-onset of cancer in these groups reflect a shorter duration of malignant transformation than in the sporadic setting. This allows for chemoprevention trials that have smaller cohorts followed for

7. Conclusion

Syndromes with highly penetrant germline mutations have contributed information about agents and their mechanisms that may be applicable to the general population. With animal models that can inform human applications and a focus on inherited predisposition syndromes, these model systems for testing chemoprevention agents should provide insight into preventive interventions for similar cancers in the sporadic setting. With concerted efforts between animal studies and clinical human studies, the

Conflicts of interest

None.

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Patients younger than 30 years affected by TCCB from January 1999 to December 2011 were investigated. Spearman's rank test and Kruskal-Wallis test were adopted for statistical analysis.
Eighteen patients were identified (8 females, 10 males) and stratified by age at presentation: 5 in group A (12 years old and younger), 7 in group B (13-19 years), and 6 in group C (20-29 years). Females were predominant in groups A and B, whereas males were predominant in group C. Pathological grading revealed low-grade papillary urothelial carcinoma in 7, papillary urothelial neoplasm of low malignant potential in 7, and high-grade urothelial papillary carcinoma in 4 patients. At a mean follow-up of 6.5 years, recurrence was observed in 2 cases. Statistical analysis showed a positive correlation between age and grading. There was no statistical significance based on gender. Staging was significant between the age groups; older patients had more advanced tumors.
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Published by Elsevier Inc.

Hereditary cancer syndromes as model systems for chemopreventive agent development

Abstract

Section snippets

1. Introduction

2. Hereditary breast and ovarian cancer syndrome, BRCA1 and BRCA2

3. Li-Fraumeni syndrome

4. Familial adenomatous polyposis

5. Lynch syndrome

6. Discussion

7. Conclusion

Conflicts of interest

Approaches to prevention of epithelial cancer during the preneoplastic period

Cancer Res

BRCA1 deficient mouse models to study pathogenesis and therapy of triple negative breast cancer

Breast Dis

Concise handbook of familial cancer susceptibility syndromes—second edition

J Natl Cancer Inst Mongr

The calculation of breast cancer risk for women with a first-degree family history of ovarian cancer. Breast Cancer Res Treat

Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families

Proc Natl Acad Sci U S A

Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2

Genet Med

The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals

Nat Genet

The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews

N Engl J Med

A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet

A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1

Science

The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds

Nat Genet

Identification of the breast cancer susceptibility gene BRCA2

Nature

Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers

J Natl Cancer Inst

Two decades after BRCA: setting paradigms in personalized cancer care and prevention

Science

Cancer suppression by the chromosome custodians, BRCA1 and BRCA2

Science

Cancer susceptibility and the functions of BRCA1 and BRCA2

Cell

Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer

J Clin Oncol

Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Cancer Epidemiol Biomarkers Prev

Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers

J Clin Oncol

PARP inhibitor treatment in ovarian and breast cancer

Curr Probl Cancer

An update on PARP inhibitors-moving to the adjuvant setting

Nat Rev Clin Oncol

Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers

N Engl J Med

Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation

Nat Genet

High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs

Proc Natl Acad Sci U S A

The PARP inhibitors, veliparib and olaparib, are effective chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice

Cancer Prev Res (Phila)

Loss of BRCA1 leads to an increase in epidermal growth factor receptor expression in mammary epithelial cells, and epidermal growth factor receptor inhibition prevents estrogen receptor-negative cancers in BRCA1-mutant mice

Breast Cancer Res

CDDO-methyl ester delays breast cancer development in BRCA1-mutated mice

Cancer Prev Res (Phila)

Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome?

Ann Intern Med

Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms

N Engl J Med

Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations

J Clin Oncol

Li-fraumeni syndrome

Genes Cancer

Highly prevalent TP53 mutation predisposing to many cancers in the Brazilian population: a case for newborn screening?

Lancet Oncol

Detailed haplotype analysis at the TP53 locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect

Hum Mutat

Germline TP53 mutations and the changing landscape of Li-Fraumeni syndrome

Hum Mutat

Synthesis of retinoid enhancers based on 2-aminobenzothiazoles for anti-cancer therapy

Bioorg Med Chem

Heterogeneity of Li-Fraumeni syndrome links to unequal gain-of-function effects of p53 mutations