N18: Deciphering The Contribution Of Recently Proposed Polyposis Predisposing Genes

M. Terradas1, 2, P. M. Muñoz1, 2, S. Belhadj1, 2, G. Aiza1, 2, 3, M. Navarro1, 2, 3, S. González1, 2, 3, E. Darder4, J. Brunet1, 3, 4, M. Pineda1, 2,3, G. Capellá1, 2, 3, L. Valle1, 2, 3

1 – Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, 08908 Hospitalet de Llobregat,Barcelona, Spain. 2 – Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, 08908 Hospitalet de Llobregat, Barcelona, Spain. 3 – Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain. 4 – Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGi, 17007 Girona, Spain.


Aim: The genetic defect responsible for colorectal polyposis remains unknown in much of the cases with adenomatous polyposis. Recently, MCM9 (recessive), FOCAD (recessive or dominant) and POLQ (dominant) have been identified as putatively new polyposis genes. Here we aim at providing a more definitive answer about the contribution of germline mutations in these genes to adenomatous polyposis.

Method: A total of 182 unrelated polyposis patients were screened for MCM9, FOCAD and POLQ mutations using PCR amplification in pooled DNAs combined with targeted parallel sequencing. Variants detected in the pooled samples were validated by genotyping and/or Sanger sequencing.

Results: While no homozygotes or compound heterozygotes where identified in MCM9 and FOCAD, a predicted deleterious missense variant (c.911A>G; p.N304S) was identified in heterozygosis in MCM9 in an individual with adenomatous polyposis, and 4 were identified in the FOCAD gene: c.401C>T (p.P134L), c.1393G>A (p.G465R), c.2861C>T (p.P954L) and c.3041A>G (p.Y1014C). A stop-gain variant (c.7537C>T; p.Q2513*) located in the DNA-polymerase domain and a predicted deleterious missense variant (c.4684G>T; p.D1562Y), were identified in POLQ.

Conclusion: Additional studies are currently being performed in order to elucidate the association of the identified variants with the predisposition to polyposis in the carrier families.