S. Department of Agriculture. “
“See Covering the Cover synopsis on page 547; see editorial Vincristine cell line on page 554. Hereditary nonpolyposis colorectal cancer as defined by the Amsterdam criteria1 and 2 includes 2 distinct entities with roughly comparable shares. Families with germline mutations in

DNA mismatch repair genes represent Lynch syndrome (MIM 120435-6), with some 3000 unique predisposing mutations known.3 Familial colorectal cancer type X (FCCX) is a collective designation for families with no evidence of DNA mismatch repair deficiency, wherein type X refers to the as yet unknown nature of predisposition.4 We recently discovered germline mutations in the gene for bone morphogenetic protein receptor type IA in 2 Amsterdam-positive families of 18 FCCX families investigated (11%).5 Among families with no bone morphogenetic protein receptor type IA mutations, family F56 fulfilling the Amsterdam criteria (Figure 1A) was chosen for closer scrutiny by genetic linkage analysis, exome sequencing, and tumor investigations. The mean age at colorectal cancer diagnosis was 52.3

years, with a 6–8 ratio of proximal to distal cancers. Genome-wide linkage analysis of the core pedigree resulted in the highest multipoint lod score (1.6) for D8S507 (Genethon) and D8S1115 (Marshfield), both of which reside in the area of linkage between D8S255 and D8S1718 on chromosome Axenfeld syndrome 8p11-8q12 ( Supplementary Materials and Methods and Supplementary Figure 1). However, because a few other chromosomal regions also showed lod scores greater than 1, we opted for exome sequencing Selleck Alectinib and chose 4 siblings with colorectal cancer from F56 to be included in the analysis (Figure 1B). A single truncating alteration of RPS20 (c.147dupA, RefSeq

NM_001023.3) ( Supplementary Figure 2A), a ribosomal protein gene, turned out to be shared by all 4 affected members investigated. It leads to frameshift and premature truncation (p.Val50SerfsX23). RPS20 is located on 8q12.1 in the region identified by genetic linkage analysis. The alteration showed a full co-segregation with microsatellite-stable colorectal cancer in F56 ( Figure 1A), yielding a lod score of 3.0 for segregation. The sequence change was absent in healthy controls (allele count 0 of 584); moreover, it has not been reported in 4300 European Americans and 2203 African Americans (Exome Variant Server; available: http://evs.gs.washington.edu/EVS/; date accessed: April 1, 2014). We subsequently screened RPS20 for mutations in blood DNA from 25 other FCCX families from Finland and in tumor DNA from 61 primary colorectal cancers and cancer cell lines ( Supplementary Materials and Methods); no RPS20 mutations were detected. Based on COSMIC (http://cancer.sanger.ac.uk) and TCGA (http://cancergenome.nih.