Which genetic syndromes increase the risk of breast cancer?

Updated: Dec 16, 2019
  • Author: Jessica Katz, MD, PhD, FACP; Chief Editor: Marie Catherine Lee, MD, FACS  more...
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Answer

Answer

Li-Fraumeni syndrome, caused by TP53 mutations, is responsible for approximately 1% of cases of familial breast cancer. Bilateral breast cancer is noted in up to 25% of patients. Li-Fraumeni syndrome is also associated with multiple cancers, including the SBLLA syndrome (sarcoma, breast and brain tumors, leukemia, and laryngeal and lung cancer). Cancer susceptibility is transmitted in an autosomal dominant pattern, with a 90% lifetime risk of breast cancer (and a 56% risk by age 45), necessitating earlier screening in TP53 mutation carriers.) [17]

Cowden disease is a rare genetic syndrome caused by PTEN mutations. It is associated with intestinal hamartoma, cutaneous lesions, and thyroid cancer. The lifetime risk of breast cancer ranges from 25-50%. Benign mammary abnormalities (eg, fibroadenomas, fibrocystic breast disease, ductal epithelial hyperplasia, and nipple malformations) are also common. [17]

Other rare genetic disorders, such as Peutz-Jeghers syndrome and hereditary nonpolyposis colorectal carcinoma (HNPCC), are associated with an increased risk of breast cancer.

Hereditary syndromes may also affect the response to treatment in breast cancer. A study by Mangoni et al found an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in patients with breast cancer. The authors propose a hypothesis that mismatch repair mechanisms may be involved in the cellular response to radiotherapy and that genetic polymorphisms warrant further study as candidates for predicting acute radiosensitivity. [18]

The table below lists the most prevalent genetically determined breast cancer syndromes.

Table 3. Genetic Breast Cancer Syndromes (Open Table in a new window)

Syndrome

Gene

Inheritance

Cancers

Other Features

Breast/ovarian

BRCA1

AD

Breast, ovarian, prostate, pancreatic

 ~1-2% risk of male breast cancer

Breast/ovarian

BRCA2

AD

Breast, ovarian, prostate, pancreatic, melanoma

Fanconi anemia in homozygotes.~8% risk of male breast cancer

Li-Fraumeni syndrome

TP53

AD

Breast, brain, soft-tissue sarcomas, leukemia, adrenocortical, others

 

Cowden disease

PTEN

AD

Breast, ovary, follicular thyroid, colon

Adenomas of thyroid, fibroids, GI polyps

Peutz-Jeghers syndrome

STKII/LKB1

AD

GI, breast

Hamartomas of bowel, pigmentation of buccal mucosa

Ataxia-telangiectasia

ATM

AD

Breast

Homozygotes: leukemia, lymphoma, cerebella ataxia, immune deficiency, telangiectasias

Hereditary Diffuse Gastic Cancer Syndrome

CDH1

AD

Gastric, Breast (Lobular)

 

Site-specific

CHEK2

AD

Breast

Low penetrance

Muir-Torre syndrome

MSH2/MLH1

AD

Colorectal, breast

 

Breast/ovarian BARD1 AD Breast, ovarian, neuroblastoma Unclear if male breast cancer risk is elevated

AD = autosomal dominant; GI = gastrointestinal.


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