Gynaecological neoplasms in common familial syndromes (Lynch and HBOC)

Recognising hereditary predisposition in a cancer patient has implications both for the patient and the patient's kindred. For the latter, cascade germline testing can reassure those not-at-risk family members while carriers can be enrolled in cancer screening and prevention programs that are medically effective and economically sustainable for health care systems. Furthermore, in many of these syndromes, ramifications of molecular phenotypes are increasing, and it is now emerging that, in addition, they convey prognostic and predictive information. Although cancer predisposition syndromes are rare, these molecular phenotypes also occur as somatic events in sporadic cancer settings. The information obtained from these molecular phenotypes, regardless of germline or somatic origin, is being incorporated into clinical management in view of their manifold significance. Thus, increasingly, bespoke management of cancer patients involves testing for both germline and somatic mutations in tumours. Lynch syndrome and BRCA-1 and BRCA-2-associated hereditary breast and ovarian cancer are hereditary cancer syndromes frequently involving the gynaecological tract but tumours associated with similar molecular alterations may also occur sporadically. Thus, the molecular phenotype of mismatch repair deficiency, microsatellite instability or hypermutator phenotype may be attributable to germline or somatic events. Similarly, homologous recombination deficiency or 'BRCAness' in ovarian cancers may be syndromic or sporadic. While hereditary syndromes are well recognised, the prognostic and predictive implications of these molecular phenotypes have only recently been elucidated and these aspects will finally ensure that molecular screening may become standard of care. Thus, nowadays pathologists are asked to designate the molecular phenotype of these cancers and then determine whether it is due to hereditary or sporadic causes.