A hereditary component of breast (BC) and colorectal cancer (CRC) has been described in approximately one-third of these tumor types. BC patients have an increased risk of developing CRC as a second primary tumor and vice versa. Germline genomic variants (NextSeq550, Illumina) were investigated in 24 unrelated BC and/or CRC patients and 7 relatives from 3 index patients. Fifty-six pathogenic or likely pathogenic variants were identified in 19 of 24 patients. We detected single-nucleotide variants (SNVs) in CRC predisposition genes (MLH1 and MUTYH) and other promising candidates (CDK5RAP3, MAD1L1, NOS3, and POLM). Eighteen patients presented SNVs or copy number variants (CNVs) in DNA damage repair genes. We also identified SNVs recently associated with BC or CRC predisposition (PABPC1, TYRO3, MAP3K1, SLC15A4, and LAMA1). The PABPC1c.1255C>T variant was detected in nine unrelated patients. Each patient presented at least one SNV/CNV in a candidate gene, and most had alterations in more than one gene, reinforcing a polygenic model for BC/CRC predisposition. A significant fraction of BC/CRC patients with a family history of these tumors harbored deleterious germline variants in DNA repair genes. Our findings can lead to strategies to improve the diagnosis, genetic counseling, and treatment of patients and their relatives.

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is an autosomal dominant disease associated with a high risk of developing breast, ovarian, and other malignancies. Lynch syndrome is caused by mutations in mismatch repair genes predisposing to colorectal and endometrial cancers, among others. A rare phenotype overlapping hereditary colorectal and breast cancer syndromes is poorly characterized. Three breast and colorectal cancer unrelated patients fulfilling clinical criteria for HBOC were tested by whole exome sequencing. A family history of colorectal cancer was reported in two patients (cases 2 and 3). Several variants and copy number variations were identified, which potentially contribute to the cancer risk or prognosis. All patients presented copy number imbalances encompassing PMS2 (two deletions and one duplication), a known gene involved in the DNA mismatch repair pathway. Two patients showed gains covering the POLE2 (cases 1 and 3), which is associated with DNA replication. Germline potentially damaging variants were found in PTCH1 (patient 3), MAT1A, and WRN (patient 2). Overall, concurrent genomic alterations were described that may increase the risk of cancer appearance in HBOC patients with breast and colorectal cancers.

Testicular germ cell tumor (TGCT) is a common tumor type in young men. Family history of TGCT and its presence in twins support the involvement of inherited genetic factors. Germline exome sequencing was performed on monozygotic twins with TGCT and their parents. The twins presented compound heterozygous variants in PDE11A (rs776984134 and rs17400325) inherited from each parent. The rs776984134 variant disrupts the canonical splice acceptor site, leading to aberrant splicing and a frameshift predicted to affect protein structure. The rs17400325 missense variant, located in the catalytic domain, reduces hydrogen bonding capacity and may impair protein stability. Both variants map to a genomic region overlapping the antisense lncRNA PDE11A-AS1. In silico transcript-level analysis predicted multiple energetically favorable RNA–RNA interactions between PDE11A and PDE11A-AS1 transcripts, with rs17400325 located within predicted hybridization regions of several isoforms. These results suggest a potential impact on PDE11A–PDE11A-AS1 pairing and post-transcriptional regulation. Additional variants in MSH6 and CTU2 were also identified and may act as potential modifiers of disease susceptibility, consistent with a multigenic contribution to TGCT risk. These findings support a contributory role for the PDE11A locus in TGCT predisposition and underscore the biological relevance of overlapping sense–antisense genomic regions in hereditary cancer studies.