1. Unité de séquençage, Centre de virologie, des maladies infectieuses et tropicales, Hôpital militaire d'Instruction Mohammed V, Faculté de Médecine et de Pharmacie, Université Mohammed V, Rabat, Maroc.
2. Laboratoire de Recherche et de Biosécurité P3, Hôpital Militaire d'Instruction Mohammed V, Faculté de Médecine et de Pharmacie, Rabat, Maroc.
3. Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, 58 rue Montalembert, Clermont-Ferrand, France.
4. INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, Clermont-Ferrand, France.
5. Laboratoire de Biodiversité, Ecologie et Génome, Faculté des Sciences, Université Mohammed V, Rabat, Maroc.
6. Service de Gynécologie Obstétrique, Hôpital Militaire d'Instruction Mohammed V, Faculté de Médecine et de Pharmacie, Rabat, Maroc.
7. Laboratoire d'Anatomopathologie, Hôpital Militaire d'Instruction Mohammed V, Faculté de Médecine et de Pharmacie, Rabat 10000, Maroc.
8. Service d'Oncologie Médicale, Hôpital Militaire d'Instruction Mohammed V, Faculté de Médecine et de Pharmacie, Rabat, Maroc.
Pathogenic variants (PVs) in BRCA genes have been mainly associated with an increasing risk of triple negative breast cancer (TNBC). The contribution of PVs in non-BRCA genes to TNBC seems likely since the processing of homologous recombination repair of double-strand DNA breaks involves several genes. Here, we investigate the susceptibility of genetic variation of the BRCA and non-BRCA genes in 30 early-onset Moroccan women with TNBC.
Methods: Targeted capture-based next generation sequencing (NGS) method was performed with a multigene panel testing (MGPT) for variant screening. Panel sequencing was performed with genes involved in hereditary predisposition to cancer and candidate genes whose involvement remains unclear using Illumina MiSeq platform. Interpretation was conducted by following the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) criteria.
Results: PVs were identified in 20% (6/30) of patients with TNBC. Of these, 16.7% (5/30) carried a BRCA PV [10% (3/30) in BRCA1, 6.7% (2/30) in BRCA2] and 6.6% (2/30) carried a non-BRCA PV. The identified PVs in BRCA genes (BRCA1 c.798_799delTT, BRCA1 c.3279delC, BRCA2 c.1310_1313del, and BRCA2 c.1658T>G) have been reported before and were classified as pathogenic. The identified founder PVs BRCA1 c.798_799del and BRCA2 c.1310_1313delAAGA represented 10% (3/30). Our MGPT allowed identification of several sequence variations in most investigated genes, among which we found novel truncating variations in PALB2 and BARD1 genes. The PALB2 c.3290dup and BARD1 c.1333G>T variants are classified as pathogenic. We also identified 42 variants of unknown/uncertain significance (VUS) in 70% (21/30) of patients with TNBC, including 50% (21/42) missense variants. The highest VUS rate was observed in ATM (13%, 4/30). Additionally, 35.7% (15/42) variants initially well-known as benign, likely benign or conflicting interpretations of pathogenicity have been reclassified as VUS according to ACMG-AMP.
Conclusions: PALB2 and BARD1 along with BRCA genetic screening could be helpful for a larger proportion of early-onset TNBC in Morocco.
Keywords: Triple negative breast cancer, Next Generation Sequencing, Multigene panel testing, ACMG-AMP guidelines, Moroccan Population