Gene Mutations in Hereditary Breast Cancer- A Review

Abstract

The most prevalent form of cancer in females is breast cancer. Roughly 5%-10% of breast cancers are hereditary, and they are associated with Germline gene mutations, inherited from parents. Germline gene mutations increase the risk of developing cancer earlier in life compared to noninherited cases (sporadic cancer). BRCA1 and BRCA2 are well-studied tumour suppressor genes associated with hereditary breast cancer. Even though mutations in BRCA1 and BRCA2 are assumed to responsible the majority of hereditary breast cancers cases, many other breast cancer susceptibility genes have been identified in the last few decades. Identification of many germline mutations was possible due to advance sequencing technologies. Most of these genes are belongs to tumour suppressors and DNA damage repair gene families (DNA double-strand break repair and DNA mismatch repair). These genes play a vital role in genomic stability and cell cycle control suggesting that any alteration in these genes trigger uncontrolled growth and tumour formation. These genes are categorized according to the penetrance level, the proportion of carriers express the associated trait of the mutated gene. Mutations in high penetrance genes such as BRCA1, BRCA2, TP53, PTEN, and SKT11 greatly increase the risk of developing breast cancer. Moderate penetrance gene such as PALB2, ATM, CHEK2, BARD1, BRIP1 and low penetrance gene such as PARP4, CASP8, TOX3 confer moderate to low increase risk of developing breast cancer. Aim of this review is to summarize genes associated with hereditary breast cancer according to their penetrance level (high, moderate and low penetrance).

Genetic Basis of Breast and Ovarian Cancer: Approaches and Lessons Learnt from Three Decades of Inherited Predisposition Testing

“…The PALB2 gene participates in the HR process as a binding partner of BRCA2. Biallelic modifications in PALB2, also known as FANCN, led to a distinct type of Fanconi anemia, while monoallelic PALB2 variants are linked to breast cancer and ovarian cancer with a 41-60% and 3-5% absolute risk, respectively [41,42]. The prevalence of these pathogenic variants ranges from 0.4% to 3.9%.…”

“…The tumor suppressor gene TP53 is situated on chromosome 17p13, and its protein product, p53, assumes significant roles in the regulation of both the cell cycle and apoptosis. Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder due to germline TP53 pathogenic variants and characterized by high cancer predisposition for a wide range of tumors, including brain cancer, sarcomas, acute leukemia, and early-onset breast cancer [41]. The occurrence of breast tumor in TP53-carrying women is remarkably high with a cumulative incidence at 60 years of 85%; screening suggests clinical breast surveillance every 6-12 months starting from 20 years of age, annual breast MRI with contrast from 20 to 75 years, and annual mammography from 30 to 75 years [42,46].…”

A Molecular Characterization of the Allelic Expression of the BRCA1 Founder Δ9–12 Pathogenic Variant and Its Potential Clinical Relevance in Hereditary Cancer

“…Among these, hereditary breast and ovarian cancer syndrome (HBOC) is the most prevalent, constituting 10% of all breast cancer (BrCa) cases and 20% of all ovarian cancer (OvCa) cases [ 1 , 2 , 3 , 4 ]. HBOC is linked to heterozygous and germline pathogenic variants (PVs) in cancer predisposition genes, with BRCA1 and BRCA2 being the most commonly affected genes [ 5 , 6 ]. Identifying individuals with PVs in HBOC has the following significant implications: (I) facilitating timely cancer diagnosis through high-risk screening methods (e.g., magnetic resonance imaging for breast cancer); (II) enabling targeted therapies, such as poly(ADP-ribose) polymerase (PARP) inhibitors, recognized as treatment options for major HBOC-related malignancies; (III) implementing cancer risk reduction strategies, including risk-reducing surgeries (mastectomy and/or salpingo-oophorectomy) or chemoprevention with agents such as tamoxifen or raloxifene for breast cancer; and (IV) identifying asymptomatic individuals at a high risk for cancer through cascade molecular diagnostics, thereby enabling the effective prevention of cancer morbidity and mortality [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ].…”