title: Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer.
abstract: Genomic alterations play important roles in colorectal cancer (CRC) carcinogenesis. Here, we aimed to identify and characterize recurrent copy-number alterations (CNAs) associated with clinical outcome of CRC by the use of single nucleotide polymorphism arrays, genomic quantitative PCR (qPCR) and fluorescence in situ hybridization (FISH). Colorectal neoplasia specimens and paired germline samples from 144 patients (40 adenomas and 104 carcinomas) as well as 40 CRC cell lines were investigated. This large dataset revealed frequent loss, including homozygous loss, at chr16p13.2 (from 5.9 to 7.42Mb). The loss was observed in 30% of adenomas and even more frequently in carcinomas, 56%, indicating that the loss define a subset of adenomas with a propensity for invasion. Consistent with this, the loss occurred twice as frequent in villous (40%) as in tubular adenomas (20%). The loss occurred independently of microsatellite stability and could be validated by qPCR in an independent sample cohort (n = 71). In Stage II/III, microsatellite stable (MSS) CRC it was associated with poor recurrence free survival (hazard ratio 2.4; p = 0.02; Multivariate Cox regression analysis). No transcriptional consequences of the losses were observed, and the only gene, A2BP1, located in the region showed no mutations. Correlation with other CNAs was established for chr3p22 in carcinomas and chr20p (inverse) in adenomas. FISH documented the chr16p13.2 region to be involved in complex structural rearrangements that included translocation to chr3p22 in some cases. The findings indicate that structural rearrangements involving chr16p13.2 are very frequent in colorectal neoplasia, often lead to homozygous deletion, and are associated with poor clinical outcome.
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Aarhus N, Denmark. cla@ki.au.dk
authors.forename: Claus Lindbjerg
authors.initials: CL
authors.lastname: Andersen
authors.forename: Philippe
authors.initials: P
authors.lastname: Lamy
authors.forename: Kasper
authors.initials: K
authors.lastname: Thorsen
authors.forename: Eigil
authors.initials: E
authors.lastname: Kjeldsen
authors.forename: Friedrik
authors.initials: F
authors.lastname: Wikman
authors.forename: Palle
authors.initials: P
authors.lastname: Villesen
authors.forename: Bodil
authors.initials: B
authors.lastname: Øster
authors.forename: Søren
authors.initials: S
authors.lastname: Laurberg
authors.forename: Torben Falck
authors.initials: TF
authors.lastname: Ørntoft
mesh_terms: D000236:Adenoma / Q000235:genetics*; D000368:Aged; D002277:Carcinoma / Q000235:genetics; D045744:Cell Line, Tumor; D002885:Chromosomes, Human, Pair 16; D015179:Colorectal Neoplasms / Q000235:genetics*; D056915:DNA Copy Number Variations; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis