Breast cancer? Heredity? Yes, you're right, tumor will inherit! We recognized the risk factors leading to breast cancer in the last phase (see "90% women have misconceptions about breast cancer screening? Prevention and treatment of "breast cancer" starts from standardized screening (Part II)"), and genetic factors are successfully" shortlisted ". Studies have shown that about 10% of breast cancer is associated with genetic factors, that is, it is caused by pathogenic embryogenic mutation of breast cancer susceptibility gene, which is called hereditary breast cancer ^[1]. Therefore, the inheritance of breast cancer is actually that some genes in parental body have pathogenic variation and are transmitted to offspring, and hereditary breast cancer usually presents the situation of family aggregation. Seeing this, we may ask: what are the "susceptibility genes" associated with breast cancer?

It has been confirmed that there are more than ten "susceptible genes" related to breast cancer, including BRCA1, BRCA2, ATM, BARD1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53 and other genes ^[2]. According to the risk of breast cancer, these genes can be divided into high-risk group and medium-risk group. High-risk genes include BRCA1, BRCA2, TP53, PTEN and PALB2. The risk of breast cancer may be increased more than 5 times in the population with pathogenic mutation gene. The medium-risk genes include ATM, CHEK2, RAD51C, RAD51D, BARD1, CDH1, and STK11. The risk of breast cancer may be increased 2–4 times in the population with pathogenic mutation gene ^[3]. In the form of genetic syndrome, the following focuses on high-risk genes for breast cancer.

Part.01  Hereditary breast-ovarian cancer syndrome (HBOC)

Background

The genetic syndrome dates back as early as the 19th century, when it was recognized that women from specific families were susceptible to breast cancer. In 1866, the first case of familial hereditary breast cancer was recorded by the French doctor Pierre Paul Broca. The report showed that four generations of the patient had breast cancer, and doctors and patients quickly found ways to predict the cancer risk of family members. However, it was not until the 1990s that the molecular pathogenic mechanism of HBOC was clarified, mainly due to the pathogenic variation of BRCA1 and BRCA2 genes, which made predictive detection of breast cancer possible ^[4].

Genetic Gene

BRCA1/2 gene, as the core gene in homologous recombination repair pathway, is involved in DNA damage repair, and its encoded protein interacts with other tumor suppressor factors to inhibit tumor formation [5]. According to the research data in China, the risk of breast cancer in women with BRCA1 and BRCA2 gene mutations is 37.9% and 36.5%, respectively, which is about 10 times the risk of breast cancer in general healthy women (3.6%) ^[1].

BRCA gene

Means of prevention

1) Breast cancer risk management for healthy carriers with BRCA 1/2 gene mutation ^{[1, 6]}.

From the age of 25 years, 1 BSE/month, 1 CBE /6 to 12 months, and 1 breast ultrasound/6 months.

• 1 additional mammogram or mammogram per year from age 30.

(Note: BSE breast self-examination, CBE clinical breast examination, MRI magnetic resonance imaging)

2) Drug prevention for healthy carriers with BRCA 1/2 gene mutation ^{[1, 7]}.  

A small sample of retrospective studies have shown that the use of tamoxifen in premenopausal women with BRCA2 mutations can reduce the risk of breast cancer by 62%, but the preventive effect on people with BRCA1 mutations is still unclear. It is suggested in the domestic and foreign guidelines that patients may participate in clinical studies.

3) Preventive resection for healthy carriers with BRCA 1/2 gene mutation ^[1].

Multiple prospective studies have shown that preventive double mastectomy (BRRM) can reduce the risk of breast cancer by more than 90% in people with BRCA1/2 gene mutation. However, whether BRRM can bring survival benefits to healthy carriers is still controversial.

Part.02  Li-Fraumeni syndrome

Background

The genetic syndrome was first reported in 1969, and was jointly discovered and named by two American doctors, Frederick P. Li (Chinese American) and Joseph F. Fraumeni. The main features of this syndrome include familial aggregation, early onset age and high risk of multiple malignancies (common breast cancer, adrenocortical cancer, central nervous system tumors, osteosarcoma and soft tissue sarcoma).

In order to understand why the cancer risk in some families was higher than normal, in 1988, two doctors carried out research and analysis on 24 families suffering from multiple tumors (151 members were found to have malignant tumors, 119 patients were diagnosed with cancer before the age of 45, and 15 patients suffered from multiple primary tumors), inferring that the cancer in these families might be caused by genetic susceptibility. In 1990, under the cooperation of Stephen Friend and David Malkin, Frederick P. Li and Joseph F. Fraumeni finally found that TP53 gene was the main pathogenic gene of this syndrome ^[8].

Genetic Gene

TP53 gene is an important tumor suppressor gene, and its encoded tumor suppressor protein P53 protein is an important regulatory factor for cell growth, proliferation, and injury repair, preventing the production of cancerous cells. Studies have shown that 70%–80% of Li-Fraumeni syndrome families can detect the pathogenic embryogenic mutation of TP53 gene. Women and men with Li-Fraumeni syndrome have a lifetime cancer risk of 90% and 70%, respectively, and about half of them suffer from cancer before the age of 40 [9].

TP53 Gene

Means of prevention ^{[1, 2]}

1) BSE is observed once per month from the age of 18 years old.

2) From the age of 20 years, one additional breast ultrasound/six months, one breast X-ray/year, or breast MRI.

3) TP53 gene detection is required for breast cancer patients with the onset age ≤30 years old or for women from Li-Fraumeni family.

4) Healthy carriers with 4)TP53 gene mutation may consider performing preventive double mastectomy (BRRM).

(Note: BSE breast self-examination, CBE clinical breast examination, MRI magnetic resonance imaging)

Part.03  Cowden Syndrome

Background

The genetic syndrome was first reported in 1963 by two physicians, Lloyd and Dennis, and was named after the patient. In 1972, Weary et al. found 5 patients with the same description of Cowden's syndrome, confirming the existence of this new syndrome. In 1996, the molecular pathogenic mechanism of Cowden syndrome was clarified, and the International Union for Cowden Syndrome identified the embryonic mutation of PTEN gene as the main cause of the syndrome ^[10].

Genetic Gene

The PTEN gene is an important tumor suppressor gene that acts on the PI3K/AKT/mTOR pathway and encodes a cancer suppressor protein that regulates cell growth, cell proliferation, cell survival, DNA repair, and cell movement. Studies have shown that the lifetime risk of breast cancer in women with Cowden syndrome is estimated to be 40%–60%, significantly increasing by 12% compared with the risk of breast cancer in the general population, and most of them develop tumors between the ages of 38–50 ^[2,11].

PTEN Gene

Means of prevention^[2]

1) BSE is carried out once every month and CBE is carried out once every 6 months to 12 months from the age of 25 years old .

2) From the age of 30 years old, one additional breast ultrasound /6 months, one breast X-ray/year, or breast MRI.

3) Healthy carriers with 3)PTEN gene mutation may consider performing preventive double mastectomy (BRRM).

(Note: BSE breast self-examination, CBE clinical breast examination, MRI magnetic resonance imaging)

Genes are the blueprints for building life. When a "program" in the blueprint runs incorrectly, it will lead to a certain "failure" of the "system". Therefore, when pathogenic variable genes appear in the body, they may lead to adverse diseases, and this is the molecular pathogenic mechanism of tumors. However, tumor development also depends on other external environmental factors, so even if there is genetic risk, it does not necessarily mean that a tumor will develop. Through understanding one's own family history, seeking genetic counseling in a hospital, and receiving appropriate genetic testing, one can learn about one's health risks in advance so as to take correct preventive measures and effectively reduce the possibility of illness.

References

[1] China Expert Consensus on Clinical Diagnosis and Treatment of Family Genetic Tumor (2021 Version)—Family Genetic Breast Cancer

[2]Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic,NCCN Guidelines Version 1.2025.

[3]EMQN best practice guidelines for genetic testing in hereditary breast and ovarian cancer.

[4]Nature Reviews Cancer, 2016, 16(9):599-612.

[5] Expert Consensus on BRCA Embryonic Line Mutation Screening Based on China Population (2024 Version)

[6] China female breast cancer screening guidelines (2022 edition)

[7]Breast Cancer Risk Reduction,NCCN Guidelines Version 1.2025.

[8]British journal of cancer,1997,76(1): 1.

[9]Gene Reviews®[Internet],2024.

[10]Cancer treatment reviews,2010,36(8):577-583.

[11]WB Saunders,2007,34(5):428-434.

Statement: This article is only for sharing, if it involves copyright issues, please contact us as soon as possible, we will correct the first time, thank you!