Hereditary is defined by the following criterion: two first

Hereditary breast cancer caused by mutations in BRCA1 or
BRCA2 is the most common autosomal dominant disorder
associated with a high breast cancer risk 12. Besides, there
are other rare cancer predisposing syndromes associated with
an increased breast cancer risk, including Li Fraumeni
Syndrome, Cowden syndrome, Hereditary Diffuse Gastric
Cancer/Familial Lobular Breast Cancer syndrome and Peutz
Jeghers 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 (chromosome
17p13). The p53 protein plays a vital role in cell cycle regu-
lation and apoptosis. Li Fraumeni syndrome is diagnosed
based on the following criteria 13: a proband with sarcoma
diagnosed before 45 years of age, plus a first degree relative
with any cancer before 45 years of age, plus one additional
first or second degree relative with any cancer before the
45 years of age or a sarcoma at any age. According to Birch
14, Li Fraumeni-like syndrome is defined by the following
criteria: a proband with any childhood cancer or sarcoma, a
brain tumor or an adrenocortical tumor diagnosed before
45 years of age, plus a first or second degree relative with a
classical Li Fraumeni syndrome tumor (i.e., sarcoma, premen-
opausal breast cancer, brain tumor, leukemia, adrenocortical
tumor) at any age, plus a first or second degree relative with
any cancer before 60 years of age. Alternatively, according to
Eeles 15, Li Fraumeni-like syndrome is defined by the
following criterion: two first or second degree relatives with
Li Fraumeni syndrome-related malignancies at any age.
Although no other gene has been found to be associated with
Li-Fraumeni syndrome, recent data show that functional ef-
fects of particular genomic variants, such as polymorphisms in
the 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 strong
impact on an individual’s risk and on the tumor spectrum 16.

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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 clinical
follow up are problematic due to the wide variation in disease
presentation 16.

Cowden syndrome is a rare genetic disorder related to
increased cellular proliferation of ectodermal, mesodermal
and 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 an
increased risk for malignant tumors of the breast, thyroid,
endometrium and skin 16, 17. Affected individuals exhibit
congenital abnormalities such as macrocephaly, facial
trichelimmomas, acral keratosis, and papillomatous papules
that present in the third decade 18. Approximately 80 % of
patients with Cowden syndrome have an identifiable germline
mutation in the PTEN gene, a tumor suppressor gene that
negatively regulates the pro-survival PI3K/Akt/mTOR path-
way through its lipid phosphatase activity 19. Loss of PTEN
activity activates this pathway and leads to increased cellular
growth, proliferation, migration and survival. Germline PTEN
mutations have also been associated with syndromes that do
not exhibit an increased risk of malignancy, including
Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome
and Proteus-like syndrome. Together, these syndromes are
defined as PTEN hamartoma syndrome (PHTS) 20. The
diagnosis of PHTS is made only when a PTEN mutation is
identified 18. Although only Cowden syndrome is associat-
ed with an increased risk of malignancy, out of precaution all
individuals with a PTEN mutation are currently recommended
to follow the cancer surveillance protocol for Cowden
Syndrome 20. Surveillance for breast cancer in individuals
with Cowden syndrome includes monthly self examination
beginning at 18 years of age (females and males), annual
clinical 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 age
at 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 those
who have the family-specific mutation and, thus, need ongo-
ing surveillance.