David Cohen, M.D.·Published 12 June 2008·7 min read
Key points
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.
DeMichele: Departments of Medicine and Epidemiology, The University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania B.
The pattern of breast cancer in families with Li-Fraumeni syndrome is remarkable.
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.
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%).
Written and revised by
David Cohen, M.D.
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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. {pagebreak}
Cowden Disease Multiple hamartoma syndrome, or Cowden disease, is a rare genetic syndrome with multiple clinical features. The most consistent and characteristic findings are mucocutaneous lesions, including multiple facial trichilemmomas, papillomatosis of the lips and oral mucosa, and acral keratoses. Benign proliferations in other organ systems, including thyroid goiter and adenomata, gastrointestinal polyps, uterine leiomyomata, and lipomata, are common in patients with Cowden disease. Nonmalignant abnormalities of the breast are similarly noted in these patients and include fibroadenomas, fibrocystic lesions, areolar and nipple malformations, and ductal epithelial hyperplasia.
A marked increase in breast cancer incidence compared with that in the general population was observed in an early series of cases of Cowden disease. Breast neoplasms occurred in 10 of the 21 female patients; lesions were bilateral in 4 women. Additional cases of Cowden syndrome now have been published, bringing the total number of reported patients to 83, of whom 51 are female. The total number of women with breast cancer and Cowden syndrome totals 15 (29%). Because many of the women in these families are still alive and are at risk of developing breast cancer, the number of Cowden syndrome women with breast cancer is likely to increase, raising current estimates for the lifetime risk of developing breast cancer for women with this syndrome.
The gene for Cowden disease was mapped to band 10q22-23 in 1996. In 1997, PTEN/MMAC1/TEP1 (phosphatase and tensin homologue/mutated in multiple advanced cancers 1/transforming growth factor b–regulated and epithelial cell–enriched phosphatase 1) was identified as the responsible gene.
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The wild-type PTEN protein has been shown to be a "dual-specificity" phosphatase. These proteins remove phosphate groups from other proteins, an important regulatory function that often reversibly inactivates proteins. Tyrosine phosphatases have been postulated to act as tumor suppressors by offsetting the oncogenic, growth-promoting action of tyrosine kinases-proteins that put phosphate groups onto proteins, often activating them. PTEN also has homology to tensin, a cytoskeletal protein that binds actin in focal adhesions. The biological significance of this finding has yet to be determined, but further study of this gene product should provide additional insight into the factors that result in malignant transformation.
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Peutz-Jeghers Syndrome Peutz-Jeghers syndrome, first described in the 1920s, is characterized by the occurrence of hamartomatous polyps in the small bowel and pigmented macules of the buccal mucosa, lips, fingers, and toes. It is an autosomal dominant disorder that has been reported to occur in approximately 1 in 20,000 live births. More recently, it has been associated with an excess incidence of tumors involving the breast, gastrointestinal tract, ovary, testis, and uterine cervix. Two studies have attempted to define the degree of cancer risk associated with the syndrome.
Giardiello et al. described a cohort of 31 patients followed from 1973 to 1985. Forty-eight percent of the patients developed cancer in that interval: Four developed gastrointestinal cancer and ten developed nongastrointestinal cancer, representing a relative risk 18 times that of the general population.
Subsequently, another group of investigators reported an elevated risk of breast and gynecologic cancers in women with Peutz-Jeghers syndrome. In this cohort of 34 patients, the affected women had a relative risk of cancer of approximately 20, whereas male patients had a lower cancer risk, approximately sixfold that of the general population. {pagebreak}
These findings suggest that, despite its rare occurrence, Peutz-Jeghers syndrome is associated with a markedly increased risk of breast cancer. The gene mutated in Peutz-Jeghers syndrome was recently identified on chromosome 19 and is now known to be STKII/LKB1, a putative tumor-suppressor gene that encodes a protein kinase. The association between mutations in STKII/LKB1 and Peutz-Jeghers syndrome was subsequently confirmed in 20 additional families.
Muir-Torre Syndrome Muir-Torre syndrome, a variant of hereditary nonpolyposis colon cancer (HNPCC, also called Lynch Type II syndrome) is the eponym given to the association between multiple skin tumors and multiple benign and malignant tumors of the upper and lower gastrointestinal and genitourinary tracts. Many of the manifestations of Muir-Torre syndrome are common lesions (basal cell carcinomas, keratoacanthomas, and colonic diverticula) in distributions similar to that in the general population but with earlier age of onset in affected individuals.
Females with the syndrome reportedly have an increased tendency to breast cancer, particularly after menopause, although lifetime risk has not been calculated. Multiple genes responsible for HNPCC have been described, including MLH1 and MSH2.
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Mutations in these genes are thought to lead to development of HNPCC through accumulation of DNA replication errors and associated subsequent genome instability. Confirmation that Muir-Torre syndrome is a variant of HNPCC occurred with the identification of germ-line mutations in MHS2 in individuals with the syndrome. A truncating mutation in MLH1 also has been detected in a Muir-Torre syndrome family.
Angela DeMichele and Barbara L. Weber
A. DeMichele: Departments of Medicine and Epidemiology, The University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania B. L. Weber: Departments of Medicine and Genetics, Breast Cancer Program, Population Science and Cancer Control, The University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania
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