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"The Integrity"of the human genome is under continual threat from endogenous and exogenous mutagens, and as a result of errors introduced during DNA replication. As the lesions generated by these processes, if left uncorrected, may lead to deleterious mutations, cells employ several sophisticated mechanisms to both prevent and repair such genomic damage. Failure of these repair mechanisms, leading to genomic instability, is common in cancer, and has even been suggested to be a universal characteristic of malignancy. This chapter outlines these cellular processes and reviews the both the mechanisms and consequences of their dysregulation in human cancer. It also highlights the emerging evidence suggesting that genomic instability is an important determinant of tumour behaviour. Finally, it discusses the possibility that targeting genomic instability may benefit patients with genomically unstable tumours in the clinic.

Background: Mismatch repair (MMR)-deficiency analysis is increasingly recommended for all endometrial cancers, as it identifies Lynch syndrome-patients, and is emerging as a prognostic classifier to guide adjuvant treatment. The aim of this study was to define the optimal approach for MMR-deficiency testing and to clarify discrepancies between microsatellite instability (MSI) analysis and immunohistochemical (IHC) analysis of MMR protein expression. Patients and Methods: 696 endometrial cancers were analyzed for MSI (pentaplex panel) and MMR protein expression (IHC). Agreement between methodologies was calculated using Cohen’s Kappa. MLH1 promoter hypermethylation, dinucleotide microsatellite markers and somatic MMR and POLE exonuclease domain (EDM) gene variants (using next-generation/Sanger sequencing) were analyzed in discordant cases. Results: MSI was found in 180 patients. Complete loss of expression of one or more MMR proteins was observed in 196 cases. A PMS2- and MSH6-antibody panel detected all cases with loss of MMR protein expression. The results of MSI and MMR protein expression were concordant in 655/696 cases (kappa=0.854, PConclusion: MSI and IHC analysis are highly concordant in endometrial cancer. This holds true for cases with subclonal loss of MMR protein expression. Discordant MMR-proficient/MSI-high cases (

Over the last two decades, multidisciplinary team (MDT) working has become an integral part of cancer care in many healthcare systems in the Western world. MDT meetings were established as part of an effort to reduce the fragmented provision of cancer care, and to ensure that each patient receives a management plan based on expert consensus following consideration of all appropriate therapeutic options. Although limited, the available evidence indicates that MDT working is associated with improved patient outcomes, though the associated costs are significant. MDTs are likely to evolve over the coming years through the development of specific software tools to aid clinical decision-making, and through the incorporation of tumour genomics and the personalization of therapy this enables.