Towards improved management of Lynch syndrome; ovarian cancer profiles, risk perception, knowledge and family perspectives

Sammanfattning: Lynch syndrome (hereditary nonpolyposis colorectal cancer) is one of the most common hereditary cancer syndromes and predisposes to several cancer types, including cancer of the colorectum, endometrium and ovaries. Cancer develops at an early age and one third of the individuals are affected by a metachronous cancer. Recognition of families with Lynch syndrome is important since this allows inclusion in surveillance programs, which decrease mortality and morbidity. The major aims of the studies in this thesis were to characterize the molecular features of hereditary ovarian cancer and investigate risk perception, knowledge levels and effects on the family following learning about Lynch syndrome. In study I array comparative genomic hybridization was performed in Lynch syndrome-associated, BRCA1 mutated and sporadic ovarian cancers. While BRCA1 mutated and sporadic ovarian cancers showed extensive chromosomal copy number alterations, tumors associated with Lynch syndrome had stable genomic profiles. The distinct genomic profile of ovarian cancer associated with Lynch syndrome suggests development through different pathways. In study II, global gene expression profiling was applied to Lynch syndrome-associated and sporadic ovarian cancers and up-regulation of the mTOR and MAPK/ERK pathways in hereditary ovarian cancer was demonstrated. Clear cell cancers are overrepresented in Lynch syndrome and this subset was characterized by up-regulation of the HER2 signaling and apoptosis signaling pathways. Expression profiles differ between hereditary and sporadic ovarian cancer, though the major difference applies to clear cell histologies. In studies III and IV questionnaires related to cancer risk perception and knowledge of Lynch syndrome were distributed to mutation carriers in the Southern Sweden region and the knowledge questionnaire was distributed also to physicians. Approximately half the mutation carriers underestimated their risk of colorectal cancer, whereas they had good knowledge of key aspects of Lynch syndrome. Physicians had the same level of knowledge as mutation carriers. This suggests a need for follow-up information both for mutation carriers and physicians. In study V mutation carriers and non-carriers from nine Lynch syndrome families were interviewed about how learning about heredity had affected their family. Changes in communication related to difficulties in talking to children, and informing new family members and distant relatives about heredity. Relations were mostly described as improved, though a few adverse effects including feelings of guilt and blame were reported. Families in which members had experienced cancer at a young age tended to inform children early and shortly after learning about heredity, which was in contrast to families with less experience of cancer. In summary, we have demonstrated that ovarian cancer linked to Lynch syndrome has distinct genetic profiles, that mutation carriers frequently underestimate their risk of colorectal cancer, possess a good level of knowledge about Lynch syndrome and that families are affected by learning about Lynch syndrome, though few experience adverse effects.