Most cancers are sporadic, caused by external environmental factors. However, about 5-10 % of breast and 20% of ovarian cancers are caused by inherited gene mutations. To identify such mutations modern next-generation sequencing diagnostic tests are needed. The BRCA1 and BRCA2 genes are the most commonly studied, as mutations in these genes cause the greatest risk to develop hereditary breast or ovarian cancer.
The identification of inherited BRCA1 and BRCA2 gene mutations encourages people to get tested more regularly and thus detect the disease earlier, when treatment is still effective. A shortcoming of testing for the BRCA1 and BRCA2 genes is that it does not detect mutations in other cancer-risk genes, which are associated with about half of hereditary breast and ovarian cancers.
The European Society of Medical Oncology (ESMO) drew attention to this and included in its recommendations, in addition to the BRCA1 and BRCA2 genes, other risk genes such as TP53 (p53), PTEN, ATM, PALB2, CHECK2, STK11, CDH1.
BRCA1 (BReast CAncer gene 1)
BRCA1 is a gene coding for cancer suppressor involved in DNA damage repair and maintains genome stability. Mutations in this gene are associated with a high risk of breast cancer, ranging from 45% to 85%, and a significant risk of ovarian cancer, ranging from 10% to 46%.
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BRCA2 (BReast CAncer gene 2)
BRCA2 is a gene coding for cancer suppressor involved in DNA damage repair and maintains genome stability. Mutations in this gene are associated with a high risk of breast cancer, ranging from 45% to 69%, and a significant risk of ovarian cancer, ranging from 11% to 17%.
ATM (ATM Serine/Threonine Kinase) ATM genas yra svarbus DNR pažaidų taisymui ir ląstelės ciklo reguliavimui. Su mutacijomis ATM gene siejamas sindromas Ataksija-telangiektazija, kurio vienas iš klinikinių požymių yra ženkliai padidėjusi navikų susidarymo rizika. Nustatyta, kad paveldimos mutacijos ATM gene apie 1,7 karto padidina krūties vėžio riziką.
ATM (ATM Serine/Threonine Kinase)
The ATM gene participates in DNA damage repair and cell cycle regulation. Ataxia-telangiectasia syndrome is associated with mutations in the ATM gene, and one of the clinical signs of this syndrome is a significantly increased risk of tumor formation. Inherited mutations in the ATM gene increase the risk of breast cancer by about 1.7.
BARD1 (BRCA1 Associated RING Domain 1)
The BARD1 gene acts as a cancer suppressor by interacting with the BRCA1 gene. The BARD1-BRCA1 complex is essential for DNA damage repair and maintaining genome stability. Pathogenic mutations leading to changes in the protein encoded by the BARD1 gene, associated with the process of oncogenesis, lead to a greater tendency to develop cancer. Women with BARD1 mutations have a 20-40% lifetime risk of developing breast cancer.
BRIP1
BRIP1, together with BRCA1, participates in DNA damage repair. In the presence of mutations in the BRP1 gene, the risk of developing ovarian cancer is 3-19 times higher than in the absence of these mutations and reaches 10%.
CDH1 (Cadherin 1)
The CDH1 gene encodes the protein E-cadherin. The protein is located in the membranes of epithelial cells. It participates in cell-to-cell interaction and helps maintain tissue integrity. CDH1 also acts as a cancer suppressor, preventing cells from growing and dividing out of control. Mutations in this gene are associated with the development of stomach cancer, with a risk of 56-83% in women and 40-70% in men. Mutations in the CDH1 gene are also associated with lobular breast cancer, with a risk of 40-60%.
CHEK2
The gene is involved in cell cycle regulation. In the presence of DNA damage, the protein encoded by the CHEK2 gene participates in the arrest of the cell cycle to repair the DNA damage or initiates the process of apoptosis (programmed cell death). CHEK2 acts as a cancer suppressor and mutations in this gene are associated with an increased risk of breast cancer. Women with a CHEK2 mutation and a family history of breast cancer have a 40% risk of developing breast cancer, while women without a family history have a 20% risk.
NBN (Nibrin)
The protein encoded by the gene is one of the five members of the protein complex involved in the repair of DNA damage and the maintenance of chromosomal stability. Mutations in the NBN gene are associated with a disturbed DNA damage repair process, which results in the accumulation of mutations and the creation of favorable conditions for the initiation of the cancer process. Pathogenic mutations in the NBN gene are associated with an increased risk of developing cancers of the female reproductive system, especially ovarian and breast. Currently, there is still a lack of research to know the exact risk.
PALB2 (Partner And Localizer Of BRCA2)
The PALB2 gene encodes a protein that interacts with BRCA2. This interaction is significant for DNA damage repair processes. Due to pathogenic mutations in the PALB2 gene, the function of the protein is disrupted, DNA damage is not repaired and altered, cancerous cells can form. Women with PALB2 gene mutations have a risk of developing breast cancer by the age of 80 is 44-63%.
PTEN (Phosphatase And Tensin Homolog)
The PTEN gene is a cancer suppressor, and its mutations are associated with a high risk of developing cancers of various locations. The PTEN gene is involved in DNA damage repair processes and is significant for maintaining genome stability. Mutations in the PTEN gene are associated with uncontrolled cell growth and division. Women with inherited PTEN gene mutations have a 67-85% risk of developing breast cancer. Inherited mutations in the PTEN gene are associated with Cowden syndrome, which is characterized by the formation of multiple neoplasms called hamartomas and an increased tendency to develop malignant tumors.
RAD51C (RAD51 Paralog C)
This gene belongs to the RAD51 family, which is involved in the processes of homologous recombination and DNA damage repair. Mutations in this gene are associated with Fanconi anemia syndrome, as well as breast and ovarian cancer syndrome. Women with a RAD51C gene mutation have a lifetime risk of ovarian cancer 3-6 times higher than women without these mutations, reaching about 10%. Inherited RAD51D mutations slightly increase the lifetime risk of breast cancer, reaching 20%.
RAD51D (RAD51 Paralog D)
This gene belongs to the RAD51 family, which is involved in the processes of homologous recombination and DNA damage repair. Mutations in this gene are associated with breast and ovarian cancer syndrome. Women with RAD51D mutations have a 5-12-fold increased lifetime risk of ovarian cancer compared to women without these mutations, reaching 10-20%. Inherited RAD51D mutations also lead to a multifold increased risk of breast cancer, which is 20-40%.
STK11 (Serine/Threonine Kinase 11)
This gene acts as a cancer suppressor. The protein encoded by the STK11 gene is involved in the processes of cell metabolism, apoptosis (programmed cell death), and DNA damage repair. Women with mutations in the STK11 gene have a lifetime risk of developing breast cancer of 32-54%. Hereditary mutations in this gene are usually found in patients with Peutz-Jeghers syndrome, which is associated with the formation of benign hamartomatous tumors, polyps, and an increased risk of cancer, especially cancer of the digestive system, breast, ovary, lung, and testicles. People with this syndrome, without proper medical care, have a 93% lifetime risk of developing cancer.
TP53
The mutations of this gene are frequently found in malignant tumors. The gene acts as a cancer suppressor and participates in the regulation of cell apoptosis and DNA damage repair. Mutations in this gene are associated with Li-Fraumeni syndrome, characterized by an increased risk of developing malignant tumors of various localizations at an early age. For women with TP53 gene mutations, the risk of developing breast cancer before the age of 60 is as high as 85%.
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