Genetics of multiple primary cancers

Within the frame of inherited cancer predisposition, single gene carriers of pathogenic variants (PVs) have been extensively represented in the literature, whereas the oligogenic coinheritance of heterozygous PVs in cancer-related genes is a poorly studied event. Currently, due to the increment of cancer survivors, the probability of presenting multiple primary cancers (MPC) is higher. This study included MPC patients younger than 45 years without known PVs in common cancer predisposition genes. We used whole exome sequencing (WES) of germline and tumoral DNA, and chromosomal microarray analysis (CMA) on germline DNA to detect variants associated with the disease. The ten patients included in the study presented a mean of 3 cancers per patient. CMA showed two microduplications and one microdeletion, while WES of the germline DNA identified 1-3 single nucleotide variants of potential interest to the disease in each patient and two additional copy number variants. Most of the identified variants were classified as variants of uncertain significance. The mapping of the germline variants into their pathways showed a possible additive effect of these as the cause of the cancer. Twelve somatic samples from 5 patients were available for sequencing. All the germline variants were also present in the somatic samples, while no second hits were identified in the same genes. The sequencing of patients with early cancers, family history and multiple tumors is already a standard of care. However, the growing evidence suggests that patients assessment should not stop at the identification of one PV in a cancer predisposition gene.