Hereditary Tumours

Hereditary tumours account for 3–10% of all cancers. Greater susceptibility of the subjects to these types of malignancies is thought to be the result of genetic mutations in highly penetrant genes transmitted as autosomal dominant traits. Mutations in such susceptibility genes result in familial predisposition to developing a characteristic spectrum of diseases (collectively known as Hereditary Cancer Syndromes). While these mutations do not cause the disease per se, their carriers exhibit a higher risk (usually ≥50%) of developing the disease during their lifetime. Most of the studies carried out in this field have focused on the most common hereditary tumours, breast cancer and colorectal cancer, for which the major susceptibility genes, BRCA1 and BRCA2 and MLH1 and MSH2, respectively, were identified about 20 years ago. The discovery of these genes has made it possible to translate, in a relatively short amount of time, basic research findings into clinical practices (bench to bedside) by contributing appropriate diagnostic strategies. These include genetic tests that are currently used to screen families for the identification of mutation carriers and to improve both prevention and management of hereditary cancers. At the same time, the study of cancer-specific signaling pathways and pathogenetic mechanisms has allowed the development of targeted therapies. In this special issue, P. Apostolou and F. Fostira provide an overview on the current knowledge of the genes causing predisposition to breast cancer. Besides BRCA1 and BRCA2, the most frequently mutated genes, the authors also review the contribution of additional genes to hereditary breast cancer syndromes that have recently emerged through whole-genome analyses. Mutations in these newly discovered genes account for the heterogeneity found among different syndromes and result in differential diagnoses. About one hundred syndromes characterized by Mendelian inheritance can be ascribed to the presence of very rare alleles [1], yet these rare alleles are found in only 20–40% of cancers where inheritance is suspected. Given this paradox, other mechanisms must be at play, such as the presence of specific genomic structural variants that might escape common methods of detection based on Sanger sequencing. In their research article, F. Duraturo et al. show the application of multiplex ligation-dependent probe amplification (MLPA) for determining the contribution of large genomic rearrangements of MLH1 and MSH2 genes in a population of Lynch syndrome patients where analysis for point mutations was previously negative. The MLPA allows to retrieve an even small percentage of " missing heritability " due …