Cancer risk is shaped by a complex interplay of genetics, environment, medical history, and lifestyle. Within the realm of cancer genetics, inherited risk factors are a critical area of study. Understanding the influence of genetic variants, particularly those associated with hereditary cancer syndromes, has led to significant advancements in cancer biology. This knowledge is essential for identifying individuals with a higher likelihood of developing cancer, improving our understanding of malignancies, and creating treatments based on the unique molecular profiles of specific cancers. The ongoing development of this knowledge influences cancer management on multiple fronts, such as prevention, screening, and treatment options.
Family medical history plays a pivotal role in determining those who may be at higher risk for cancer, often leading to genetic testing to identify hereditary risks. Such testing can reveal genetic predispositions, increasing an individual’s susceptibility to cancer. The term “variant” refers to genetic differences compared to a standard DNA reference sequence. Although the word “mutation” is sometimes still used in medical settings, variants are more accurately classified as benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants, which can affect gene function, are linked to disease.
Ongoing research continues to update cancer risks associated with specific genes. For example, Lynch syndrome genes have been studied for years, yet new information continues to refine the risk assessments associated with these genes. Understanding the terminology in hereditary cancer genetics is essential for interpreting research in this area.
Different hereditary cancer genes carry varying levels of risk, which can also differ among pathogenic or likely pathogenic variants within the same gene. Typically, rare variants are associated with higher cancer risks than common variants. Furthermore, individuals with certain genetic variants may be at risk of developing cancer at a younger age than is typically observed in the general population. Beyond genetic factors, environmental and lifestyle influences also play a role in shaping cancer risk, especially for those carrying variants in genes like BRCA1 or BRCA2. The hereditary gene and specific pathogenic variant involved will determine the types and risks of cancers, such as breast, ovarian, and pancreatic cancers linked to BRCA variants.
In cancer genetics, germline variants refer to those found in reproductive cells, meaning they are present in every cell of an individual’s body and can be inherited. In contrast, somatic variants occur during or before tumour development and are not present in reproductive cells, so they are not passed from parent to offspring.
Genetic variants in hereditary cancer testing are classified based on their association with disease. They may be identified as pathogenic, likely pathogenic, of uncertain significance, benign, or likely benign. Sometimes, genetic tests reveal “secondary” or “incidental” findings, which are not related to the primary reason for testing but may still hold clinical relevance. Secondary findings are those deliberately sought out during testing, while incidental findings are unexpected discoveries.
Hereditary cancer risks are usually inherited in an autosomal dominant manner, where an individual only needs to inherit one pathogenic variant to be at risk for developing cancer. However, some hereditary cancer syndromes follow different inheritance patterns. For example, MUTYH-associated polyposis is inherited in an autosomal recessive manner, requiring two copies of a pathogenic variant for the risk to be realised.
Health care providers and primary care physicians play a crucial role in identifying individuals and families at increased risk for cancer. These professionals can then refer patients for genetic counselling, where further risk assessments and genetic testing can be considered. Several clues may suggest hereditary cancer risk, such as early-age cancer diagnosis, multiple cancers within the same individual or family, or a pattern of cancer inheritance across generations. In some cases, hereditary cancer can also be a feature of broader syndromic conditions.
Understanding the genetic factors that contribute to cancer risk is vital for identifying those at increased risk and tailoring cancer prevention and treatment strategies accordingly. Genetic testing offers valuable insights into cancer predisposition and provides a framework for personalised care.
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