Chapter 22: Li-Fraumeni Syndrome, including Li-Fraumeni-Like Syndrome

Concise Handbook of Familial Cancer Syndromes, Second Edition
Journal of the National Cancer Institute Monographs, No. 38, 2008, pp 48-50

OMIM Number: 151623, 191170, 609265, 604373, 609266, 202300.
Inheritance pattern: Autosomal dominant.

Gene and chromosomal location: Germline mutation in TP53 (17p13.1), commonly called p53, is the molecular basis of Li-Fraumeni syndrome (LFS). p53 regulates the cell-cycle arrest that is required to permit: repair of DNA damage. In p53 mutation-negative LFS families (most of which meet Li-Fraumeni-Like [LFL] criteria), germline CHEK2 mutations have been reported (1). CHEK2 (located at 22812.1) is in the p53 pathway, and germline mutations were originally found in a few LFL families. Currently, there is disagreement as to whether CHEK2 truly causes LFS or LFL, or whether it is etiologically related only to the early-onset breast cancers which occur in this disorder (2,3). The CHEK2*1100delC mutation, the frequency of which varies across populations, appears to increase risk of breast cancer by about twofold and may predispose to earlier age at diagnosis [reviewed by Narod and Lynch (4)]. A third LFS locus has been mapped recently to chromosome 1q23, but no specific gene has yet been implicated (5).

Mutations: When clinical mutation testing targets only exons 5-8, as is often done, approximately 70% of Li-Fraumeni families meeting the stringent diagnostic criteria (see below) have p53 mutations. Mutations in exons 4-9 are found in 95% of such families. LFL kindreds have detectable imitations in 8%-22% of pro-bands, depending upon the stringency of the syndrome definition (6,7). Overall, about 75% of p53 mutations involve exons 5 through 8 (8). Missense mutations represent the majority (approximately 75%) of genetic lesions, and most generate a truncated p53 protein. Brain tumors and adrenocortical carcinomas each have been associated with a location-specific set of mutations within the p53 gene (9). Partial deficiency alleles are associated with milder family history, lower numbers of tumors, and delayed disease onset (10). A web-based repository of p53 mutation information has been created; it: contains information on nearly 300 deleterious germline mutations.

Incidence: LFS appears to be rare, with approximately 400 reported families in the cumulative literature, but: its actual population incidence is unknown. Variations in selection criteria introduce selection biases that cannot be accurately estimated. Children with adrenocortical carcinoma were found to have the highest frequency of detected p53 mutations (approximately 80%). Mutations were detected in approximately 2%-10% of childhood brain tumors, 2%-3% of patients with osteosarcomas, and in 9% of patients with rhabdomyosarcoma. Patients with multiple primary tumors had an estimated p53 mutation frequency of 7%-20%.

Diagnosis: The classical definition requires 1) one patient: with sarcoma diagnosed before age 45, 2) a first-degree relative diagnosed with cancer (of any kind) before age 45, and 3) a third affected family member (first- or second-degree relative) with either sarcoma at any age or cancer (type not specified) before age 45 years (11). Although these criteria are highly specific for LFS, they exclude some clinically atypical, mutation-positive families; consequently, relaxed criteria have been proposed.

Studies based on so-called LFL criteria detected 8%-22% of mutation-positive individuals from these clinically atypical families. The Birch LFL criteria require 1) a proband with any childhood cancer or sarcoma, brain tumor or adrenal cortical carcinoma diagnosed before age 45, 2) a first- or second-degree relative with a typical LFS malignancy (sarcoma, leukemia, or cancers of the breast, brain or adrenal cortex) regardless of age at diagnosis, and 3) a first- or second-degree relative with any cancer diagnosed before age 60 (6). The Eeles definition simply requires two first- or second-degree relatives with LFS-related malignancies at any age (7). Evans et al. (12) studied 21 families with a single proven sarcoma (any age) and a first-degree relative with early-onset breast cancer (<60 years) and found only one family (5%) with a p5.3 mutation.

A striking predilection for young age at cancer diagnosis and development of multiple primary cancers are LFS features (9,13). The probability of developing a second primary cancer in 200 LFS patients reached 57% by 30 years follow-up (14). Risk of second cancer was higher in younger patients and in those whose first primary was a sarcoma. The estimated probability of developing a third cancer was 38% at 10 years. Given the nature of the genetic defect in a gene that is central to DNA repair, there is a theoretical basis for concern regarding sensitivity to radiation carcinogenesis in p53 germline mutation-positive patients, a concern that has substantial anecdotal clinical support (14).

Laboratory features: None that are syndrome specific.

Associated malignant neoplasms: Risk of developing any invasive cancer (excluding skin cancer) was approximately 50% by age 30 (compared with 1% in the general population), and approximately 90% by age 70 (15). The tumor spectrum includes osteogenic and chondrosarcoma, rhabdomyosarcoma, breast cancer, brain cancer (especially glioblastomas), leukemia, lymphoma, and adrenocortical carcinoma (9,16). Early -onset breast cancer accounts for 25% of all LFS-related cancers, followed by soft-tissue sarcoma (20%), bone sarcoma (15%), and brain tumors (13%). The risks of sarcoma, female breast cancer, and hematopoietic malignancies in mutation carriers are more than 100 times greater than those seen in the general population (17). One specific TP53 mutation was reported to result in adrenocortical tumors in 9.9% of carriers (18). Malignancies reported (but not proven) to be associated include melanoma, Wilms and other kidney tumors, gonadal germ cell, pancreatic, gastric, and choroid plexus, colorectal (19), and prostate cancers.

The "classical" LFS malignancies (sarcoma and cancers of the breast, brain, and adrenal glands) comprise about 80% of all cancers that occur in LFS families. The incidence of these cancers varies by age, with soft-tissue sarcomas, adrenal and brain tumors predominating before age 10, bone sarcoma the most frequent in the teen years, and breast and brain tumors comprising the majority after age 20 (9). Relative to LFL families, kindreds meeting stringent LFS criteria have more brain tumors, earlier onset of breast cancer, and exclusive occurrence of adrenocortical carcinoma.

A strong interaction between gender and cancer risk has been described in LFS families, with mutation-positive women reported to be seven times more likely to develop cancer than mutation-positive men (20).

In a search for genetic modifiers of p53 penetrance in LFS families, a SNP in the promoter region of(a direct negative regulator or inactivator of p53) was found to attenuate the p53 pathway and accelerate the formation of both hereditary and sporadic tumors, as measured by significantly reduced age at cancer diagnosis (21). Multiple subsequent reports have confirmed this observation (22). Accelerated telomere attrition has been suggested to play a role in progressively earlier age-at-cancer onset in this context as well (23). Several common SNPs in the p53 gene have been suggested to increase the risk of sporadic osteogenic sarcoma, with significant odds ratios MDM2ranging from 6.7 to 7.5 (24).

Associated benign neoplasms: None known.

Cancer risk management: Breast cancer is the only LFS-related malignancy for which effective screening exists. The National Comprehensive Cancer Network Practice Guidelines (25) recommend training and education in breast self-examination by age 18, with monthly BSE thereafter. Breast imaging was advised beginning at ages 20-25 or 5-10 years before the earliest known breast cancer in the family (whichever is earlier). Based on expert consensus opinion, the American Cancer Society recommends annual breast magnetic resonance imaging screening as an adjunct to mammography in women with LFS and their first-degree relatives (26). Options for risk-reducing mastectomy should be discussed on a case-by-case basis. We would add a clinical examination of the breasts every 6 months to these published guidelines.

The risks and benefits of screening for other malignancies in this syndrome are not established; the pros and cons of embarking on cancer screening with strategies of unproven value should be frankly discussed with each family before proceeding. The costs of such an approach, both economically, medically, and emotionally (due to the consequences of false-positive test results), may be quite high. Additional surveillance activities might be tailored to the phenotype of individual families, although there is no evidence that this is beneficial. Pediatricians should be alerted to the risk of specific childhood malignancies in affected families. All annual comprehensive health examination is suggested, in which a high index of suspicion for symptoms related to syndromic malignancies (and second cancers in previously treated patients) is warranted. Patients should be advised regarding the potential genetic risk to bloodline relatives and the possibility of their undergoing genetic risk assessment and, possibly, genetic testing (25). Preimplantation genetic diagnosis has been reported in a number of LFS families (27).

Comments: The diversity of malignancies that are known or suspected to be part of LFS poses a particular challenge relative to the validity of these patients' family histories. In a study comparing the accuracy of reported cancer history among LFS and hereditary breast/ovarian cancer families, breast cancer was accurately reported in both groups, but non-breast LFS-related cancer diagnoses were accurate only 55% of the time vs 74% in breast/ovarian cancer families (28). Fewer than half of LFS historians provided information that would have led to p53 mutation testing. Confirmation of reported family history is particularly important if LFS is in the differential diagnosis. A small but encouraging experience is accruing relative to the use of a molecularly targeted therapy, Advexin (a replication-defective adenoviral vector containing the wild-type p53 gene under the control of the cytomegalovirus promoter). While still in the earliest stages of new drug development, this may evolve into another example of novel therapeutic approaches based on an understanding of the molecular basis of the cancer being treated (29).

References

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