Li-Fraumeni syndrome was first identified in 1969 in a description of four kindreds identified through children with sarcomas whose cousins or siblings also had childhood soft-tissue sarcomas and whose other relatives had excessive cancer occurrence. Subsequent epidemiologic efforts have identified the major component neoplasms, including breast cancer, soft-tissue sarcomas and osteosarcomas, brain tumors, leukemia, and adrenocortical carcinomas; several additional tumor types are likely to merit inclusion. Segregation analysis of families identified through a family member with sarcoma confirmed the autosomal dominant pattern of transmission of cancer susceptibility, with age-specific penetrance estimated to reach 90% by age 70. Nearly 30% of tumors in reported families occur before age 15 years.

The pattern of breast cancer in families with Li-Fraumeni syndrome is remarkable. In one report, among 24 families with the syndrome, 44 women had breast cancer, of whom 77% were between the ages of 22 and 45 years. Bilateral disease was documented in 25% of these women; 11% had additional primary tumors. Men may have later-onset tumors in Li-Fraumeni syndrome families because they do not get breast cancer, which is so dramatic among female family members with the syndrome.

In 1990, germ-line mutations were identified in the p53 tumor-suppressor gene in affected members of Li-Fraumeni syndrome families, identifying p53 mutations as the cause of the syndrome. Approximately 50% of such carefully defined families have alterations identified in the p53 gene. Also, p53 genes ostensibly normal by sequencing but with abnormal functional assays or expression have been observed. The prevalence of germ-line p53 mutations in women with breast cancer diagnosed before age 40 has been estimated at approximately 1%. It is therefore not a very common explanation for breast cancer occurrence in the population; nonetheless, p53 mutations formed the basis for the first predisposition testing programs for breast cancer susceptibility.

Ataxia-Telangiectasia
Ataxia-telangiectasia is an autosomal recessive disorder characterized by oculocutaneous telangiectasias, cerebellar ataxia, immune deficiency, and a predisposition to leukemia and lymphoma. ATM (A-T, mutated) is the gene mutated in ataxia-telangiectasia patients. It is a member of a large family of protein kinases, and it appears to function as a checkpoint in response to DNA damage. Two approaches have been used to address the question of whether female ATM heterozygotes may have an increased risk for breast cancer.

The first type of study, which looks at family members of patients with ataxia-telangiectasia, has observed an increased number of breast cancer cases in obligate and predicted heterozygotes. However, the controls in the two largest studies had an unusually low incidence of breast cancer. A study using linkage analysis in these families to clearly determine heterozygote status showed an increase in breast cancer risk of 3.8-fold. Interestingly, no trend was noted toward an early age at diagnosis; in fact, the odds ratio was highest in women older than age 60. The second approach is to examine families with clustering of early-onset breast cancer cases and to use linkage or mutational analysis in those groups to define the role of ATM in familial breast cancer. The first study using mutational analysis of ATM in 88 families with at least two cases of breast as well as lymphoma, leukemia, or gastric cancer in the family showed an increased frequency of ATM heterozygotes (4.3%) compared with the observed carrier frequency in the population (0.2% to 1.0%).

However, a study of 100 women affected with breast cancer who had at least one additional relative affected with breast cancer did not find an increased prevalence of ATM mutations. In addition, the tumors of patients carrying ATM mutations were examined and displayed no loss of ATM, suggesting that either ATM was not acting as a tumor-suppressor gene or that it was not involved in the etiology of breast cancer. Finally, in a study of 401 women diagnosed with breast cancer earlier than age 40, the prevalence of mutations in ATM was the same as that in 202 controls, lending further credence to the hypothesis that mutations in ATM do not contribute significantly to breast cancer susceptibility.

One controversy that has emerged as a result of the question of breast cancer risk in ATM heterozygotes is the use of mammography in women younger than age 50. Concern was raised over repeated mammography, because ATM homozygotes have increased DNA damage from ionizing radiation. This biologic defect suggests that the use of mammography for cancer detection should be weighed against the possibility of cancer induction as a result of radiation exposure. However, the increased risk of breast cancer due to mammography in ATM heterozygotes is unknown and is presumably small, and the benefit of detecting a neoplasm in its early stages is large. Thus, agreement has been almost uniform that screening mammography should be initiated when clinically appro priate.