4bases’Paper of the Month – October 2024 – Understanding genetic variations associated with familial breast cancer

Breast cancer (BC) is the most frequent type of cancer in women, with approximately 2.2 million new cases diagnosed each year, making it the fourth leading cause of cancer-related mortality. Genetics play a significant role as the primary risk factor for breast cancer, with 15-25% of cases being inherited from cancer-prone relatives. The most common gene mutations associated with familial breast cancer include BRCA1BRCA2TP53CDH1PTEN, and STK11, which together account for around 80% of these cases. These mutations are considered high penetrance, meaning that individuals who carry these genetic alterations are highly likely to develop the disease.

Both environmental and genetic factors contribute to the development of BC in patients. Classification of the disease considers multiple aspects such as histological grade, metastasis, and receptor status. The main biomarkers of BC – oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), have enabled the identification of five major subtypes: luminal, HER2-enriched, triple-negative, basal-like, and normal-like. Familial breast cancer (FBC) refers to cases that occur more frequently in families than would be expected by chance, due to an inherited genetic predisposition. The suggested review article this month discusses twenty genes linked to FBC identified in literature, with a highlight on the most common.

BRCA1 and BRCA2 are genes that code for proteins involved in the homologous recombination (HR) repair of DNA replication errors and in the regulation of cell growth. A single mutation in either of these genes is sufficient to change the phenotype due to their autosomal dominant inheritance. HR mechanism failures lead to an increased likelihood of DNA replication errors, favouring tumorigenesis. BRCA mutations are responsible for 16-25% of FBC cases. BRCA1-linked tumours typically lack oestrogen receptor (ER) expression, making them resistant to hormonal therapies like tamoxifen. In contrast, BRCA2-linked tumours are usually ER-positive, meaning they can often be treated more effectively with hormonal therapies. The most common BRCA mutations vary geographically; for example, in Brazil, the most frequent mutation involves a duplication of a BRCA2 exon, while in India, hotspot deletions in BRCA1 are more common.

TP53 is widely recognised as a master regulator of the cell cycle and is often referred to as the “genome caretaker” due to its critical role in detecting abnormal cell replication and initiating apoptosis (programmed cell death). Mutations in the p53 protein disrupt key transcriptional processes, impacting mechanisms like DNA repair, cellular senescence, apoptosis, autophagy, mitotic catastrophe, angiogenesis, and responses to cellular stress. Despite being a tumour suppressor, TP53 frequently mutates through hotspot substitutions, converting it into an oncogene with gain-of-function mutations that drive cancer development. Around 30% of BC cases involve a p53 mutation.

CDH1 encodes E-cadherin, a protein that plays a key role in controlling cell signalling, apoptosis, and cell invasion. Under normal conditions, CDH1 functions as a tumour-suppressor gene, helping to prevent metastasis. However, loss-of-function mutations in CDH1 result in impaired cell adhesion, leading to lymph node tumour invasion. These mutations are found in 5-15% of BC cases, contributing to the spread of cancer within the body.

PTEN is a key regulator of the PI3K-Akt intracellular signalling pathway, where it functions to repress cellular proliferation and promote normal cell growth regulation. In 40-50% of BC cases, there is loss of heterozygosity (LOH) of PTEN, meaning the patient loses the only remaining functional copy of the gene. This loss leads to uncontrolled cell proliferation, contributing to tumour development and progression.

STK11 encodes a serine/threonine kinase that acts as a tumour suppressor, regulating cell growth and preventing cancer development. Mutations in STK11 significantly increase the risk of breast cancer, with a 32-54% chance of developing the disease by age 60. Peutz-Jeghers syndrome (PJS), a genetic condition marked by the formation of polyps in the gastrointestinal tract, combined with STK11 loss-of-function, further elevates the risk, with over a 50% probability of developing breast cancer by age 40.

Understanding the penetrance of a specific mutation is crucial for identifying the origins of breast cancer in a patient and for refining therapies to tailor treatment effectively. As a result, next-generation sequencing (NGS) shows great potential for improving gene identification and enabling more precise clinical interventions. Additionally, genome-wide association studies (GWAS) can assist in the early detection of cancer by identifying genetic variants associated with increased risk. We at 4bases are happy to celebrate Pink October, which aims to raise awareness about breast cancer and provide education on this disease.


Pal, M., Das, D. & Pandey, M. Understanding genetic variations associated with familial breast cancer. World J Surg Onc 22, 271 (2024). https://doi.org/10.1186/s12957-024-03553-9

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