A substantial proportion of MLH1 and MSH2 gene mutations in hereditary nonpolyposis colon cancer syndrome (HNPCC) families are characterized by nucleotide substitutions, either within the coding sequence (missense or silent mutations) or in introns. The question of whether these mutations affect the normal function of encoding mismatch DNA repair proteins and thus lead to the predisposition to cancer is determinant in genetic testing. Recent studies have suggested that some nucleotide substitutions can induce aberrant splicing by disrupting cis‐transcription elements such as exonic enhancers (ESEs). ESE disruption has been proposed to be the mechanism that underlies the presumed pathological missense mutations identified in HNPCC families. To investigate the prevalence of aberrant splicing resulting from nucleotide substitutions, and its relevance to predicted ESEs, we conducted a systematic RNA screening of a series of 60 patients who carried unrelated exonic or intronic mutations in MLH1 or MSH2 genes. Aberrant splicing was found in 15 cases, five of which were associated with exonic mutations. We evaluated the link between those splicing mutations and predicted putative ESEs by using the computational tools ESEfinder and RESCUE‐ESE. Our study shows that the algorithm‐based ESE prediction cannot be definitely correlated to experimental observations from RNA screening. By using minigene constructs and in vitro transcription assay, we demonstrated that nucleotide substitutions are the direct cause of the splicing defect. This is the first systematic screening for the effect of missense and silent mutations on splicing in HNPCC patients. The pathogenic splicing mutations identified in this study will contribute to the assessment of “unclassified variants” in genetic counseling. Our results also suggest that one must use caution when determining the pathogenic effect of a missense or silent mutation using ESE prediction algorithms. Analysis at the RNA level is therefore necessary. Hum Mutat 27(2), 145–154, 2006.

Understanding how cancer genes are mutated in individual tumors is an important issue with potential clinical and therapeutic impact. This is especially relevant with recently developed targeted therapies since mutated genes can be targets and/or predictors. However, to date, gene mutation profiling in individual tumors is still underexplored. Breast cancer is composed of various subtypes. We presumed that this heterogeneity reflected the involvement of different molecular mechanisms including gene mutations that affect defined signaling pathways. Unlike the majority of published mutational studies, this study was aimed to draw a mutation profile in individual tumors by screening a panel of cancer genes in the same tumor. Thus, five genes frequently mutated in breast cancers: TP53, PIK3CA, PTEN, CDH1, and AKT1 were screened in each of 120 human primary breast tumors. Mutations in at least one of these genes were found in 62.5% of the tumors, of which the majority carried a single-gene mutation. Interestingly, a substantial proportion of tumors carried mutations either in TP53 or in genes of the PI3K pathway (PIK3CA or PTEN or AKT1). These two distinct mutation patterns were significantly associated to hormone receptor expression but independent of HER2 status.

Since the first report by our group in 1999, more than 20 unrelated biallelic mutations in DNA mismatch repair genes (MMR) have been identified. In the present report, we describe two novel cases: one carrying compound heterozygous mutations in the MSH6 gene; and the other, compound heterozygous mutations in the PMS2 gene. Interestingly, the inactivation of one PMS2 allele was likely caused by gene conversion. Although gene conversion has been suggested to be a mutation mechanism underlying PMS2 inactivation, this is the first report of its involvement in a pathogenic mutation. The clinical features of biallelic mutation carriers were similar to other previously described patients, with the presence of café‐au‐lait spots (CALS), early onset of brain tumors, and colorectal neoplasia. Our data provide further evidence of the existence, although rare, of a distinct recessively inherited syndrome on the basis of MMR constitutional inactivation. The identification of this syndrome should be useful for genetic counseling, especially in families with atypical hereditary nonpolyposis colon cancer (HNPCC) associated with childhood cancers, and for the clinical surveillance of these mutation carriers. Hum Mutat 28(11), 1084–1090, 2007.

Up to 10% of cancers occur through the inherited mutation of a group of genes called cancer predisposition genes. Individuals who carry a mutant allele of these genes have an increased susceptibility to cancer. A growing number of cancer susceptibility genes are being identified, and the physiopathology of germline mutation-based cancer development is also being elucidated with accumulating clinical and molecular data. More importantly, the identification of familial mutations has become routine practice, which is a perfect example of bench-to-bed translational medicine. Recently, other clinical applications of predisposition genes have been exploited, especially as efficient biomarkers predicting prognosis or response to treatment. Thus, it appears interesting to give an overview of the advances and impacts of predisposition genes in personalized cancer care by taking representative and common cancer syndromes as examples: Lynch syndrome for the first example, which is related to cancer susceptibility, and breast and ovary cancer syndrome for the second example, which involves BRCA deficiency-related targeted therapy.