Germline mutations of the tumor suppressor gene TP53 account for more than half of the families with classic Li-Fraumeni syndrome (LFS)
, which is an inherited condition characterized by the development of sarcomas and other early-onset tumors, including breast cancer
[2, 3]. Families presenting incomplete features of LFS are referred as having Li-Fraumeni-like syndrome (LFL). Depending on the criteria adopted to classify the cancer phenotype in a given family, up to 22% of LFL pedigrees have detectable TP53 mutations
[4–6]. Several cancer predisposition syndromes that involve breast cancer have been described to date, and include, in addition to LFS/LFL, the hereditary breast and ovarian cancer (HBOC), hereditary diffuse gastric cancer, and the Cowden and Peutz-Jeghers syndromes
. Due to the high frequency of breast and other cancers in LFS/LFL individuals, there may be an overlap of phenotypes, and often some families fulfill genetic testing criteria for more than one hereditary breast cancer syndrome
[1, 8, 9].
Several studies have investigated the frequency of BRCA1/BRCA2 and TP53 germline mutations in families with multiple early-onset breast cancers
[6, 8, 10, 11]. Approximately 5-10% of breast cancer is estimated to result from dominant mutations in known single genes
[12–14], particularly in the BRCA1 or BRCA2 genes. Germline TP53 mutations have been considered to be responsible for only a small fraction of the hereditary breast cancer cases overall
, and have mostly been described in families with the other core-cancers of LFS/LFL
[1, 8, 9]. Germline mutations of the BRCA2 gene have been described in families presenting both breast cancer and sarcomas, suggesting that BRCA2 mutations account for a proportion of LFS/LFL families negative for TP53 mutations
[16, 17]. As far as we are aware, germline BRCA1 mutations have not been detected in LFS/LFL kindreds, not even among families presenting a complex cancer history consistent both with LFL and other syndromes that constitute the HBC phenotype
[6, 8, 11, 18].
All known breast cancer susceptibility genes present germline point mutations in only approximately 20-25% of the cases fulfilling the criteria for genetic testing
. Gene rearrangements can contribute to disease through different mechanisms, resulting in either imbalance of gene dosage or gene disruption, and they are not usually detected by routine molecular diagnostic methods such as gene sequencing. In particular, large rearrangements, most often deletions, have been reported as a cause of cancer susceptibility, occurring in at least 30% of highly penetrant Mendelian cancer-predisposing genes
BRCA1 germline rearrangements have been implicated in up to 30% of HBC families in certain populations
[19–23]. The aim of the present study was to determine the frequency of germline copy number changes of TP53
BRCA1, and BRCA2 genes in breast cancer patients with clinical diagnosis of Li-Fraumeni or Li-Fraumeni-like syndrome, and without detectable germline TP53 point mutations.