Components of the Risk Assessment Process
When a deleterious mutation has been identified in a family and a test report documents that finding, prior probabilities can be ascertained with a greater degree of reliability. In this setting, probabilities can be calculated based on the pattern of inheritance associated with the gene in which the mutation has been identified. In addition, critical to the application of Mendelian inheritance is the consideration of integrating Bayes Theorem, which incorporates other variables, such as current age, into the calculation for a more accurate posterior probability.[4,59] This is especially useful in individuals who have lived to be older than the age at which cancer is likely to develop based on the mutation identified in their family and therefore have a lower likelihood of harboring the family mutation when compared with the probability based on their relationship to the mutation carrier in the family.
Even in the case of a documented mutation on one side of the family, careful assessment and evaluation of the individual's personal and family history of cancer is essential to rule out cancer risk or suspicion of a cancer susceptibility gene mutation on the other side of the family (maternal or paternal, as applicable). Segregation of more than one mutation in a family is possible (e.g., in circumstances in which a cancer syndrome has founder mutations associated with families of particular ancestral origin).
Risk of developing cancer
Unlike mutation probability models that predict the likelihood that a given personal and/or family history of cancer could be associated with a mutation in a specific gene(s), other methods and models can be used to estimate the risk of developing cancer over time. Similar to mutation probability assessments, cancer risk calculations are also complex and necessitate a detailed health history and family history. In the presence of a documented deleterious mutation, cancer risk estimates can be derived from peer reviewed penetrance data. Penetrance data are constantly being refined and many gene mutations have variable penetrance because other variables may impact the absolute risk of cancer in any given patient. Modifiers of cancer risk in mutation carriers include the mutation's effect on the function of the gene/protein, (e.g., mutation type and position), the contributions of modifier genes, and personal and environmental factors (e.g., the impact of bilateral salpingo-oophorectomy performed for other indications in a woman who harbors a BRCA mutation). When there is evidence of an inherited susceptibility to cancer but genetic testing has not been performed, analysis of the pedigree can be used to estimate cancer risk. This type of calculation uses the probability the individual harbors a gene mutation and gene mutation-specific penetrance data to calculate cancer risk.
In the absence of evidence of a hereditary cancer syndrome, several methods can be utilized to estimate cancer risk. Relative risk data from studies of specific risk factors provide ratios of observed versus expected cancers associated with a given risk factor. However, utilizing relative risk data for individualized risk assessment can have significant limitations: relative risk calculations will differ based on the type of control group and other study-associated biases, and comparability across studies can vary widely. In addition, relative risks are lifetime ratios and do not provide age-specific calculations, nor can the relative risk be multiplied by population risk to provide an individual's risk estimate.[59,62]