Hereditary breast cancer caused by mutations in BRCA1 orBRCA2 is the most common autosomal dominant disorderassociated with a high breast cancer risk 12. Besides, thereare other rare cancer predisposing syndromes associated withan increased breast cancer risk, including Li FraumeniSyndrome, Cowden syndrome, Hereditary Diffuse GastricCancer/Familial Lobular Breast Cancer syndrome and PeutzJeghers syndrome. Li Fraumeni syndrome is a clinically and genetically het-erogeneous autosomal dominant disorder that is caused main-ly by germline mutations in the TP53 gene (chromosome17p13). The p53 protein plays a vital role in cell cycle regu-lation and apoptosis. Li Fraumeni syndrome is diagnosedbased on the following criteria 13: a proband with sarcomadiagnosed before 45 years of age, plus a first degree relativewith any cancer before 45 years of age, plus one additionalfirst or second degree relative with any cancer before the45 years of age or a sarcoma at any age. According to Birch14, Li Fraumeni-like syndrome is defined by the followingcriteria: a proband with any childhood cancer or sarcoma, abrain tumor or an adrenocortical tumor diagnosed before45 years of age, plus a first or second degree relative with aclassical Li Fraumeni syndrome tumor (i.e.
, sarcoma, premen-opausal breast cancer, brain tumor, leukemia, adrenocorticaltumor) at any age, plus a first or second degree relative withany cancer before 60 years of age. Alternatively, according toEeles 15, Li Fraumeni-like syndrome is defined by thefollowing criterion: two first or second degree relatives withLi Fraumeni syndrome-related malignancies at any age.Although no other gene has been found to be associated withLi-Fraumeni syndrome, recent data show that functional ef-fects of particular genomic variants, such as polymorphisms inthe TP53 gene or in some of its regulators such as MDM2(murine double minute 2), DNA copy number variants(CNVs), and variations in telomere length may have a strongimpact on an individual’s risk and on the tumor spectrum 16. Recent studies in large cohorts have shown that TP53 muta-tions occur in 1:5,000 individuals 16. Although TP53 mu-tations are detectable by sequencing, counseling and clinicalfollow up are problematic due to the wide variation in diseasepresentation 16.
Cowden syndrome is a rare genetic disorder related toincreased cellular proliferation of ectodermal, mesodermaland endodermal tissues 17. It is characterized by the occur-rence of multiple hamartomas in the skin, breast, thyroid,gastrointestinal tract, endometrium and brain, as well as anincreased risk for malignant tumors of the breast, thyroid,endometrium and skin 16, 17. Affected individuals exhibitcongenital abnormalities such as macrocephaly, facialtrichelimmomas, acral keratosis, and papillomatous papulesthat present in the third decade 18.
Approximately 80 % ofpatients with Cowden syndrome have an identifiable germlinemutation in the PTEN gene, a tumor suppressor gene thatnegatively regulates the pro-survival PI3K/Akt/mTOR path-way through its lipid phosphatase activity 19. Loss of PTENactivity activates this pathway and leads to increased cellulargrowth, proliferation, migration and survival. Germline PTENmutations have also been associated with syndromes that donot exhibit an increased risk of malignancy, includingBannayan-Riley-Ruvalcaba syndrome, Proteus syndromeand Proteus-like syndrome. Together, these syndromes aredefined as PTEN hamartoma syndrome (PHTS) 20.
Thediagnosis of PHTS is made only when a PTEN mutation isidentified 18. Although only Cowden syndrome is associat-ed with an increased risk of malignancy, out of precaution allindividuals with a PTEN mutation are currently recommendedto follow the cancer surveillance protocol for CowdenSyndrome 20. Surveillance for breast cancer in individualswith Cowden syndrome includes monthly self examinationbeginning at 18 years of age (females and males), annualclinical breast examinations beginning at 25 years of age,and annual mammography and breast MRI beginning at 30–35 years of age, or 5 to 10 years earlier than the youngest ageat which breast cancer has been diagnosed in the family 18.
When a PTEN mutation has been found in a proband, molec-ular genetic testing of asymptomatic relatives will reveal thosewho have the family-specific mutation and, thus, need ongo-ing surveillance.