Germline cancer predisposition gene variants in patients with early-onset rectal cancer

Caroline Moraes Beltrami1, Luisa Matos do Canto1,2, Annabeth Høgh Petersen2, Mads M. Aagaard2, Maria Nirvana da Cruz Formiga1, Silvia Regina Rogatto2,3,4

1A.C.Camargo Cancer Center, São Paulo, Brazil. 2Department of Clinical Genetics, Vejle University Hospital, Vejle, Denmark. 3Institute of Regional Health Research, University of Southern Denmark, Vejle, Denmark. 4Danish Colorectal Cancer Center South, Vejle, Denmark


Objective: Rectal cancer (ReCa) incidence has increased in the last years, especially in young adults. Considering that a heritable component is associated with an early onset of cancer, we evaluated germline alterations in young patients with ReCa.

Methods: Twenty-nine patients fulfilled the Amsterdam I/II criteria (G1) and 47 patients presented ReCa at an early age (≤ 40 years old – GII). Family history and clinical-pathological features from the patients were obtained from medical records. Targeted NGS of 93 cancer-predisposing genes was performed using the SureSelectXT Custom Panel (Agilent). Nonsynonymous, protein-damaging and rare germline variants were filtered using the Golden Helix VarSeq2.1. software. All variants were classified for pathogenicity according to the American College of Medical Genetics and Genomics guidelines.

Results: The analysis revealed 153 germline variants involving 65 genes, including 26 patients of GI and 41 of GII. The most frequent altered genes were ATM (19%), followed by APC (10%), BRCA2, NOTCH1 and MTHFR (9% each). Eight genes (ATM, BRCA2, MLH1, MSH2, MSH6, MTHFR, MUTYH, and NOTCH1) with pathogenic or likely-pathogenic variants were detected in 14 patients (6: GI and 8: GII). Homologous recombination and mismatch repair pathways genes were more commonly mutated in patients from GI than in GII (19% vs 7%). Two unrelated patients presented the same germline variant in MTHFR (c.233C>G, p.Ser78Ter).

Conclusion: In agreement with previous reports (Pearlman et al. JAMA Oncol 2017; 3:464) we detected variants, so far unrelated to CRC development, which can contribute to a higher risk of developing ReCa at a younger age.


Abstract references

Financial Support: University Hospital, Institute of Regional Health Research, Vejle, DK.