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PI13-00285 PI11-01439 ; Germline mutations in UNC5C have been suggested to increase colorectal cancer (CRC) risk, thus causing hereditary CRC. However, the evidence gathered thus far is insufficient to include the study of the UNC5C gene in the routine genetic testing of familial CRC. Here we aim at providing a more conclusive answer about the contribution of germline UNC5C mutations to genetically unexplained hereditary CRC and/or polyposis cases. To achieve this goal we sequenced the coding region and exon-intron boundaries of UNC5C in 544 familial CRC or polyposis patients (529 families), using a technique that combines pooled DNA amplification and massively parallel sequencing. A total of eight novel or rare variants, all missense, were identified in eight families. Co-segregation data in the families and association results in case-control series are not consistent with a causal effect for 7 of the 8 identified variants, including c.1882_1883delinsAA (p.A628K), previously described as a disease-causing mutation. One variant, c.2210G > A (p.S737N), remained unclassified. In conclusion, our results suggest that the contribution of germline mutations in UNC5C to hereditary colorectal cancer and to polyposis cases is negligible. ; This work was funded by the Spanish Ministry of Economy and Competitiveness and co-funded by FEDER funds -a way to build Europe- [SAF2012-38885 (LV), SAF2013-45836-R (XSP), SAF2012-33636 (GC)]; Carlos III Health Institute [PI13-00285 (CL), PI11-01439 (VM)]; Red Tematica de Investigacion Cooperativa en Cancer [RTICC RD12/0036/0031, RD12/0036/0008, RD12/0036/0067], the Government of Catalonia [2014SGR338, 2014SGR647], and the Scientific Foundation Asociacion Espanola Contra el Cancer. We thank Tirso Pons from the Spanish National Cancer Research Center (CNIO) for his assistance. We are grateful to the researchers of the MCC-Spain study for providing the data to assess the identified UNC5C rare variants in the general population. ; Sí

Germline mutations in BUB1 and BUB3 have been reported to increase the risk of developing colorectal cancer (CRC) at young age, in presence of variegated aneuploidy and reminiscent dysmorphic traits of mosaic variegated aneuploidy syndrome. We performed a mutational analysis of BUB1 and BUB3 in 456 uncharacterized mismatch repair-proficient hereditary non-polyposis CRC families and 88 polyposis cases. Four novel or rare germline variants, one splice-site and three missense, were identified in four families. Neither variegated aneuploidy nor dysmorphic traits were observed in carriers. Evident functional effects in the heterozygous form were observed for c.1965-1G>A, but not for c.2296G>A (p.E766K), in spite of the positive co-segregation in the family. BUB1 c.2473C>T (p.P825S) and BUB3 c.77C>T (p.T26I) remained as variants of uncertain significance. As of today, the rarity of functionally relevant mutations identified in familial and/or early onset series does not support the inclusion of BUB1 and BUB3 testing in routine genetic diagnostics of familial CRC. ; his work was supported by the Spanish Ministry of Economy and Competitiveness, co-funded by FEDER funds – a way to build Europe – (grants SAF2016 – 80888-R to LValle, SAF2015 – 68016-R to GC and MP, and SAF2013 – 45836-R to XSP]; Carlos III National Health Institute [PI16/00563 to CL and CIBER- ONC]; the Government of Catalonia [ Pla estratègic de recerca i innovació en salut (PERIS) and 2014SGR338]; the Scientific Foundation Asociación Española Contra el Cáncer ; and EU COST Action BM1206. PM holds a Juan de la Cierva postdoc- toral fellowship from the Spanish Ministry of Economy and Competitiveness, and RMdV, a Dutch Cancer Society (KWF) Fellowship (KUN14–666 ; Sí