Gemma Caliendo

Hereditary cancer syndromes predispose to several types of cancer due to inherited pathogenic variants in susceptibility genes. We describe the case of a 57-year-old woman, diagnosed with breast cancer, and her family. The proband belongs to a family with a suspected tumor syndrome, due to other cancer cases in her family from the paternal and maternal sides. After oncogenetic counseling, she was subjected to mutational analysis with an NGS panel analyzing 27 genes. The genetic analysis showed two monoallelic mutations in low penetrance genes, c.1187G>A (p.G396D) in MUTYH and c.55dup (p.Tyr19Leufs*2) in BRIP1. One of the mutations was inherited from the maternal side and the other from the paternal side, suggesting two different cancer syndrome types in the family. MUTYH mutation was related to the onset of cancers on the paternal side, as confirmed by the occurrence of the same mutation in the proband’s cousin. BRIP1 mutation was found in the proband’s mother, indicating that it was related to the cancer cases observed on the maternal side, including breast cancer and sarcoma. Advances in NGS technologies have allowed the identification of mutations in families with hereditary cancers in genes other than those related to a specific suspected syndrome. A complete oncogenetic counseling, together with molecular tests that enable a simultaneous analysis of multiple genes, is essential for the identification of a correct tumor syndrome and for clinical decision-making in a patient and his/her family. The detection of mutations in multiple susceptibility genes allows the initiation of early risk-reducing measures for identified mutation carriers among family members and to include them in a proper surveillance program for specific syndromes. Moreover, it may enable an adapted treatment for the affected patient, permitting personalized therapeutic options.

Hereditary prostate cancer (HPCa) has the highest heritability of any cancer in men. Interestingly, it occurs in several hereditary syndromes, including breast and ovarian cancer (HBOC) and Lynch syndrome (LS). Several gene mutations related to these syndromes have been identified as biomarkers in HPCa. The goal of this study was to screen for germline mutations in susceptibility genes by using a multigene panel, and to subsequently correlate the results with clinical and laboratory parameters. This was undertaken in 180 HBOC families, which included 217 males with prostate cancer (PCa). Mutational analysis was further extended to 104 family members of mutated patients. Screening of HBOC families revealed that 30.5% harbored germline mutations in susceptibility genes, with 21.6% harboring pathogenic variants (PVs) and 8.9% having variants of uncertain significance (VUS). We found PVs at similar frequency in BRCA1 and BRCA2 genes (8.8% and 9.4%, respectively), while 0.56% of PVs were present in well-established susceptibility genes PALB2, TP53 and RAD51C. Moreover, 0.56% of monoallelic PVs were present in MUTYH, a gene whose function in tumorigenesis in the context of PCa is still unclear. Finally, we reported double heterozygosity (DH) in BRCA1/2 genes in a single family, and found double mutation (DM) present in BRCA2 in a separate family. There was no significant difference between the mean age of onset of PCa in HBOC families with or without germline mutations in susceptibility genes, while the mean survival was highest in mutated patients compared to wild type. Furthermore, PCa is the second most recurrent cancer in our cohort, resulting in 18% of cases in both mutated and non-mutated families. Our investigation shows that PVs were located mostly in the 3′ of BRCA1 and BRCA2 genes, and in BRCA2, most PVs fell in exon 11, suggesting a mutation cluster region relating to risk of HPCa. A total of 65 family members inherited the proband’s mutation; of these, 24 developed cancer, with 41 remaining unaffected.

Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer death worldwide; most of cases are sporadic, however about 5% to 10% report a hereditary predisposition. Several hereditary syndromes have been associated with familial pancreatic cancer (FPC) onset, including hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), Familial atypical multiple mole melanoma (FAMMM), Familial adenomatous polyposis (FAP), Li–Fraumeni syndrome (LFS), Peutz–Jeghers syndrome (PJS), and Hereditary pancreatitis (HP).The aim of this study was to determine the mutational status of a cohort of 56 HBOC families, 7 LS families, 3 FAP and FAMMM families, and 1 LFS family with at least one case of PDAC. Mutation analysis of BRCA1/2, ATM, CHEK2, PALB2, RAD51C, RAD51D, NBN, CDH1, TP53, MLH1, MSH2, MSH6, and PMS2 genes, showedmutation in BRCA1/2, MLH1, and APC genes. We founda high mutation rate in patients belong HBOC and LS families, with a percentage of 28.6% in both syndromes and prevalence in HBOC of BRCA2 mutations with one case of double mutation in BRCA2 gene. In FAP family, we found a pathogenic mutation in APC gene in 1/3 families. We observed an early onset of PDAC and a lower survival in PDAC patients belonging to mutated families, while no evidence of possible pancreatic cancer cluster regions was found. Moreover, we identified a novel BRCA2 germline mutation, c.5511delT (p.Phe1837LeufsX3), not reported in any database, that segregated with disease in HBOC patients. Mutational analysis was extended to family membersof mutated patients, both healthy and cancer affected, which revealed 23 unaffected family members that inherited the proband’s mutation. Although correlative by its nature, the presence of a BRCA mutation in PDAC patients may have benefits in terms of optimized treatment and longer outcome.

Prostate cancer (PCa) is globally the second most diagnosed cancer type and the most common cause of cancer-related deaths in men. Family history of PCa, hereditary breast and ovarian cancer (HBOC) and Lynch syndromes (LS), are among the most important risk factors compared to age, race, ethnicity and environmental factors for PCa development. Hereditary prostate cancer (HPCa) has the highest heritability of any major cancer in men. The proportion of PCa attributable to hereditary factors has been estimated in the range of 5–15%. To date, the genes more consistently associated to HPCa susceptibility include mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and homologous recombination genes (BRCA1/2, ATM, PALB2, CHEK2). Additional genes are also recommended to be integrated into specific research, including HOXB13, BRP1 and NSB1. Importantly, BRCA1/BRCA2 and ATM mutated patients potentially benefit from Poly (ADP-ribose) polymerase PARP inhibitors, through a mechanism of synthetic lethality, causing selective tumor cell cytotoxicity in cell lines. Moreover, the detection of germline alterations in MMR genes has therapeutic implications, as it may help to predict immunotherapy benefits. Here, we discuss the current knowledge of the genetic basis for inherited predisposition to PCa, the potential target therapy, and the role of active surveillance as a management strategy for patients with low-risk PCa. Finally, the current PCa guideline recommendations are reviewed.

Double heterozygosity (DH) in BRCA1 and BRCA2 genes and double mutation (DM) in BRCA1 or BRCA2 are extremely rare events in the general population, and few cases have been reported worldwide so far. Here, we describe five probands, all women, with breast and/or ovarian cancer and their families. Particularly, we identified two probands with DH in the BRCA1/2 genes with a frequency of 0.3% and three probands with DM in the BRCA2 gene with a frequency of 0.5%. The DH BRCA1 c.547+2T>A (IVS8+2T>A)/BRCA2 c.2830A>T (p.Lys944Ter) and BRCA1 c.3752_3755GTCT (p.Ser1253fs)/BRCA2 c.425+2T>C (IVS4+2T>C) have not been described together so far. The DM in BRCA2, c.631G>A (p.Val211Ile) and c.7008-2A>T (IVS13-2A>T), found in three unrelated probands, was previously reported in further unrelated patients. Due to its peculiarity, it is likely that both pathogenic variants descend from a common ancestor and, therefore, are founder mutations. Interestingly, analyzing the tumor types occurring in DH and DM families, we observed ovarian cancer only in DH families, probably due to the presence in DH patients of BRCA1 pathogenic variants, which predispose one more to ovarian cancer onset. Furthermore, male breast cancer and pancreatic cancer ensued in families with DM but not with DH. These data confirm that BRCA2 pathogenic variants have greater penetrance to develop breast cancer in men and are associated with an increased risk of pancreatic cancer.

APC and MUTYH genes are mutated in 70–90% and 10–30% of familial adenomatous polyposis cases (FAP) respectively. An association between mutation localization and FAP clinical phenotype is reported. The aims of this study were to determine APC and MUTYH mutational status in a small cohort of FAP patients and to evaluate the genotype-phenotype correlation in mutated patients. Here, we report the identification of a novel APC germline mutation, c.510_511insA. Overall, mutational analysis showed pathogenic mutations in 6/10 patients: 5/10 in APC and 1/10 in MUTYH. Additionally, we found three variants of unknown significance in MUTYH gene that showed no evidence of possible splicing defects by in silico analysis. Molecular analysis was also extended to family members of mutated patients. A genotype-phenotype correlation was observed for colonic signs whereas a variation of disease onset age was revealed for the same mutation. Moreover, we found an intrafamilial variability of FAP onset age. Regarding extracolonic manifestations, the development of desmoid tumors was related to surgery and not to mutation position, while a genotype-phenotype correspondence was observed for the onset of thyroid or gastric cancer. These findings can be useful in association to clinical data for early surveillance and suitable treatment of FAP patients.