Hereditary cancer has been a long-standing research field, but recent advances in technology have allowed for extensive gene expression analysis, offering results for large populations. The growing volume of data presents an advantage in the validity of conclusions, but on the other hand is accompanied by new dilemmas and questions on data interpretation. However, despite increasing availability of gene testing globally, hereditary cancer still remains a rare event. The majority of cancer cases are sporadic, without any correlation with known pathogenic gene mutations. Gradually, the ratio of hereditary to sporadic cancers is expected to increase, as more patients are tested and more mutations are registered as pathogenic. The chapter summarizes the main hereditary syndromes related with gynaecological cancer along with current implications and innovations in clinical practice.
TopIntroduction
Hereditary cancer has been a long-standing research field, but recent advances in technology have allowed for extensive gene expression analysis, offering results for large populations. The growing volume of data presents an advantage in the validity of conclusions, but on the other hand is accompanied by new dilemmas and questions on data interpretation.
However, despite increasing availability of gene testing globally, hereditary cancer still remains a rare event. The majority of cancer cases are sporadic, without any correlation with known pathogenic gene mutations. Gradually, the ratio of hereditary to sporadic cancers is expected to increase, as more patients are tested and more mutations are registered as pathogenic.
Regarding patient and family genetic counseling, it is important to clarify that the identification of a mutation in a healthy carrier, does not confer a cancer diagnosis, but only expresses a possibility. This possibility may lead to cancer at some point during lifetime, but quite often it is extremely difficult to give an accurate estimation. Several mutations may appear in one gene, each with different oncogenic potentials. This explains the wide variations in risk assessment found in literature, as it is impossible to design clinical trials where all patients will carry exactly the same mutation. Data analysis is performed on gene mutation levels and penetrance is not assessed individually. It is also significant to remember that lifestyle may also affect cancer risk in different carriers of the same mutation.
Tumor Suppressor Genes
Most cancer-related mutations refer to tumor-suppressor genes, whose function regulates maintenance of the double DNA strand integrity. These genes are either involved in the repair of the numerous breaks that daily occur in the DNA strand (BRCA1/2), or act as checkpoint regulators that hold the cell cycle until all errors in the chain replication are fixed (p53, Rb). In case of irreparable damage, they will lead the cell to apoptotic death. When one of the alleles is mutated, the gene may become inactive immediately or at a later time if the other allele also becomes mutated, as this event leads to the encoding of a non-functioning protein.
Each gene comprises of two alleles, one inherited from each parent, therefore there is 50% chance for each decendant to inherit a mutation from one parent within the autosomal dominant pattern. All correlations between mutations and gynecologic cancers regard this pattern of inheritance. It is also important during documentation of family history, to clarify to the patients that breast and gynecologic cancers have equal possibilities to be inherited from each parent, in contrast to the wide -spread impression that women can only inherit them from their mothers’ side.
Inherited and Non-Inherited Mutations
Genetic counseling information should include the difference between germline mutations that can be inherited because they are located in the germ cells that form the embryo and are the progenitors of all cells and the somatic mutations that only exist in the tumor cells and are significant to know in regards of treatment decisions and management of the disease of the particular patient. As new targeted treatments emerge, more options may become available for treating tumors with specific mutations. This can never have any interest for the healthy family members, who can only be tested for germline mutations.