Hereditary Prostate Cancer: Genes Related, Target Therapy and Prevention.

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.

Heart transplant with donor-specific antibody after immunoadsorption plus rituximab: a case report.

Different desensitization strategies are available for treating patients with preformed human leukocyte antigen (HLA) antibodies. A highly presensitized heart recipient received immunoadsorption and rituximab therapy. The patient, with end-stage heart failure, was positive only for antibodies of HLA class I (anti-A2, A10, B17), and Luminex platform (One Lambda kit) showed a panel-reactive antibody score of 64%. The patient's serum was tested repeatedly in both complement-dependent cytotoxicity and flow-cytometry crossmatches against cells from different potential organ donors. The results of these crossmatches were positive on flow cytometry when tested with HLA-A2, A10, and B17 but were still negative on cytotoxicity. The patient was treated with a desensitization regimen; this treatment immediately decreased antibody levels of 70% and the patient subsequently received a transplant with donor-specific HLA antibody (HLA-A2). After more than 2 years, graft function remains normal and the clinical status of the patient is stable.

Double mutation of APC and BRCA1 in an Italian family.

Familial adenomatous polyposis (FAP) is a rare genetic disorder caused mainly by monoallelic mutations of APC gene. The hereditary breast and ovarian cancer (HBOC) syndrome is an autosomal dominantly inherited disease, which mostly predisposes to breast and ovarian cancers as a result of germline mutations in BRCA1 or BRCA2 genes. In a family, mutations in two cancer susceptibility genes are extremely rare. We studied a family with a case of a 46 years-old woman affected with FAP and ovarian cancer. The patient was affected with profuse FAP since the age of 18 years and a serous ovarian cancer was diagnosed at the age of 45 years. She reported other FAP cases and one case of breast cancer in maternal family. Initially, she was tested for FAP predisposition with mutational analysis of APC gene that revealed the presence of a frameshift mutation, c.3927_3931delAAAGA (p.Glu1309AspfsX4). The presence of ovarian cancer in the patient and of a breast cancer case in the maternal family, suggested an extended analysis to HBOC susceptibility genes that led to the detection of a frameshift mutation, c.3756_3759delGTCT (p.Ser1253Argfs), in BRCA1 gene. The genetic analysis was extended also to family members. The occurrence of the double mutation in APC and BRCA1 genes in the patient was responsible for the onset of FAP and ovarian cancer respectively. The genetic counselling in hereditary cancer with a careful analysis of the pedigree allows identifying the gene to be analyzed. The development of multi-gene panels testing for cancer predisposition, with next generation sequencing (NGS), may reveal mutations in genes of high and moderate penetrance for cancer, although at a low frequency and allows diagnosing a possible double heterozygosity. This enables an adjusted treatment for the affected patient and is critical as it allows initiation of early risk-reducing measures for identified mutation carriers among family members.

BRCA and PALB2 mutations in a cohort of male breast cancer with one bilateral case.

INTRODUCTION: Male Breast Cancer (MBC) is a rare disease, about 1% of all breast cancers worldwide and less than 1% of cancers occurring in men. The bilateral male breast cancer (bMBC) is extremely rare. Germline mutations of BRCA1/BRCA2 genes are associated with a significantly increased risk of cancer in MBC; the role of PALB2 remains to be clarified. Our main goal was to provide contribution on characterization of BRCA1/BRCA2 and PALB2 mutations in MBC patients. METHODS: We observed 28 MBC cases; one of them was a bMBC. Screening for BRCA1, BRCA2 and PALB2 genes was performed on all 28 MBC patients. Mutational analysis was extended to family members of mutated patients. RESULTS: In our study, the MBC incidence was 5.2% and for bMBC was 3.6%. Mutation analysis showed pathogenic mutations in 11/28 (39.3%) patients; 2/28 (7.1%) displayed a mutation in BRCA1, 8/28 (28.6%) in BRCA2 and 1/28 (3.6%) in PALB2. Out of 11 mutated patients, one (9.1%) reported a double mutation in BRCA2. Personal history of other cancers was reported in 2/28 (7.1%) patients affected by bladder cancer. A first/second degree family history of breast/ovarian and other cancers occurred in 23/28 (82.1%) patients. CONCLUSION: Our findings indicate BRCA2 as the main MBC susceptibility gene and describe an increased risk of bMBC and bladder cancer in mutated patients. The identification of mutations in MBC susceptibility genes supports the usage of oncology prevention programs in affected patients and their relatives carrying the mutation.

Five Italian Families with Two Mutations in BRCA Genes.

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.

Effect of Single Sensitization Event on Human Leukocyte Antigen Alloimmunization in Kidney Transplant Candidates: A Single-Center Experience.

OBJECTIVES: Human leukocyte antigen alloimmunization is caused by exposure to HLA antigens through transfusion, pregnancy, or transplant. Our study objective was to present the rate of positivity of anti-HLA antibody considering the effects of a single sensitization event in kidney transplant candidates at our center. MATERIALS AND METHODS: Our study reviewed 606 kidney transplant candidates. Patient sera were analyzed using Luminex xMAP technology. Panel reactive antibody positivity rates and antibody strengths in patients were analyzed according to a single sensitization event. RESULTS: Our findings showed 246 patients (40.6%) with a panel reactive antibody > 0, of which 97 (39.4%) were sensitized from a single event, 119 (48.4%) were sensitized by multiple events, and 30 (12.2%) had no known sensitizing event. Considering patients sensitized by a single event with a panel reactive antibody > 0, we found that 25.8% had received transplant only, 49.5% had previous pregnancy only, and 24.7% had received transfusion only. The strength of antibodies was significantly higher in patients with previous transplant procedures than in those with transfusion for HLA-A (P < .01), HLA-B (P < .05), HLA-C (P < .05), HLA-DR (P < .001), HLA-DQ (P < .05), and HLA-DP (P < .05). Similarly, we observed significantly higher median fluorescence intensity values for HLA-A, -DR, -DQ, and -DP loci in patients with a previous transplant procedure versus pregnancy. The strength of antibodies against HLA-DR was significantly higher in patients with a previous pregnancy compared with those with transfusion (P < .01). CONCLUSIONS: This study documents the profile of HLA alloimmunization in kidney transplant candidates. In particular, transplant procedures appear to have a greater immunologic impact, followed by pregnancy and transfusion. Our data confirm and are in accordance with those of several studies in which the sensitization events were associated with higher prevalence of anti-HLA antibodies.

Anti-HLA Antibodies Testing on Solid Phase: Comparative Evaluation of Different Kit Vendors Through Luminex Technology.

OBJECTIVES: For decades, the detection of anti-HLA antibodies in candidates for solid-organ transplant has been performed with the traditional complement-dependent cytotoxicity method; this assay has been then integrated with the introduction of solid-phase assays. Over the past 20 years, the Luminex assay has become the most widely used in clinical laboratories due to both increased sensitivity and specificity versus enzyme-linked immunosorbent assay. However, even the Luminex technique has shown some critical issues, and choosing the most reliable method still remains challenging. In this study, we verified the concordance of the results obtained in detecting anti-HLA antibodies with 2 kit vendors that provide reagents for the Luminex platform. MATERIALS AND METHODS: We used 314 serum samples from patients on wait lists for solid-organ transplant. Sera were tested with LABScreen Mixed-LSM12 (One Lambda-Thermo Fisher, Canoga Park, CA, USA) and LIFECODES LifeScreen Deluxe-LMX (Gen-Probe-Immucor, Stanford, CT, USA),which we indicated as vendor A and vendor B, respectively. Anti-HLA class I and class II antibody analyses were conducted by verifying the concordance of the results with Cohen kappa coefficient statistics and confidence interval. RESULTS: The kappa coefficient statistics showed "substantial" reliability for class I (0.61; confidence interval, 0.50-0.73) and "moderate" reliability for class II (0.56; confidence interval, 0.43-0.69). There were no considerable differences in results between the 2 kits regarding overall assignment of negativity or positivity of a sample. Discordant data between positive values for a test and negative for the other were found for samples with weak antibody positivity. CONCLUSIONS: Some discordant data were probably attributable to several factors such as the composition of the kits, the antibody titer in the serum, whether sera were diluted, different washing methods, and type of plate used.

Epitope-specificities of HLA antibodies: the effect of epitope structure on Luminex technique-dependent antibody reactivity.

The search of HLA antibodies is currently more accessible by solid-phase techniques (Luminex) in the immunized patients leading to an expansion of the antibody patterns. The aim of this study was to investigate low median fluorescence intensity value in unexpected reactivity patterns. Here, we performed HLAMatchmaker analyses to evaluate the potential functional epitopes that can elicit HLA-specific alloantibody responses in a pregnancy-sensitized woman with an epitope defined by the 82LR. Surprisingly, in according to the registry of HLA epitopes, we found that 82LR epitope covered all allelic specificities of our unexpected antibody patterns, shared between Bw4-positive HLA-B antigen and HLA-A23, -A24, -A25 and -A32. This finding is consistent with the verification of HLA ABC epitope recorded in the website-based HLA Epitope Registry and addresses the importance of determining HLA antibody epitope-specificities on Luminex technique-dependent antibody reactivity.

Anti-HLA-A, -B, -DR, -DQB1 and -DQA1 antibodies reactive epitope determination with HLAMatchmaker in multipare awaiting list for heart transplant.

Human leukocyte antigen (HLA) antibodies represent a significant risk factor for transplant failure. It is very important to characterize anti-HLA antibodies as epitopes rather than antigens so that this knowledge can be applied clinically. The aim of the study was to investigate the extra reactivity patterns in sensitized multipare. Here, we have used the HLAMatchmaker program, a theoretical algorithm, to explain these unexpected antibody reactivity patterns in multipare awaiting for heart transplant. The patient was sensitized during pregnancy by alleles HLA-A(*)24:02, HLA-DRB1(*)07:01, HLA-DRB4(*)01:01, DQB1(*)02:02 and DQA1(*)02:01 mismatches with development of respective antibodies. However, the patient' sera were shown an unexpected reactivity not directed toward HLA mismatches of daughters: A(∗)23:01, A(*)24:03 and B(*)15:12 for class I and DRB4(*)01:03, DRB1(*)09:02, DRB1(*)09:01, DQB1(*)03:01, DQB1(*)03:03, DQB1(*)03:02, DQB1(*)04:02, DQB1(*)04:01 and DQB1(*)02:01 for class II. By HLAMatchmaker analysis we found that these antibodies reacted with eplet shared by antigens in single allele Luminex panels. These eplets were: 62EE, 66GKH, 70KAH, 71HS, 127K, 113YH, 144KR, 150AAH, 151AHV, 163TG and 167DG for class I and 4Q, 74RRAE, 71RRA, 98KN, 120N, and 135G, 25FT, 34HE, 41ER, 47EK2, 48LF for class II. Thus, HLAMatchmaker software together with to solid phase techniques could open new horizons for a more precise characterization of the HLA-antibodies.

Methodologies for anti-HLA antibody screening in patients awaiting kidney transplant: a comparative study.

OBJECTIVES: The relevance of anti-HLA antibodies in patients awaiting kidney transplants is well recognized. During the past 40 years, kidney transplant candidates have been tested for these antibodies, and the choice of the detection assay has become essential. Recently, the pioneer method, the complement-dependent cytotoxicity, has been integrated but has not been replaced by more-sensitive solid-phase assays, such as the enzyme-linked immunosorbent assay and the bead-based technology (ie, flow cytometry: FlowPRA, and FlowAnalyzer: Luminex). MATERIALS AND METHODS: We compared the sensitivity and antibody specificity of these 4 techniques for detecting panel-reactive antibodies in a population of 101 consecutive patients awaiting a renal transplant (which had already resulted positive in a prescreening analysis). RESULTS: Sera positive for class I and class II antibodies were 62 and 90 as assessed by the complement-dependent cytotoxicity method, 76 and 58 by using enzyme-linked immunosorbent assay, 83 and 65 with Flow-panel-reactive antibodies, and 90 and 79 by Luminex. Luminex gave more positive scores than the others for class I HLA antibodies, whereas complement-dependent cytotoxicity revealed more positives for those of class II. CONCLUSIONS: Although Luminex appears more efficient among these assays, our results indicate that use of multiple methods is still the best approach for characterizing the immunologic status of these patients.

Silent celiac disease in chronic hepatitis C: impact of interferon treatment on the disease onset and clinical outcome.

GOALS: To assess the impact of interferon treatment on celiac disease onset in hepatitis C patients and to clarify its clinical relevance and outcome. BACKGROUND: Hepatitis C is associated with autoimmunity, which can be exacerbated by interferon treatment. Cases of celiac disease activation during interferon treatment have been reported. STUDY: Retrospective evaluation of 534 hepatitis C patients with or without symptoms compatible with celiac disease onset during interferon treatment and 225 controls. Anti-transglutaminase antibodies were assayed. HLA-DQA1 and -B1 loci were typed. Upper gastrointestinal endoscopy was applied to confirm the diagnosis in antibody-positive patients. RESULTS: Anti-transglutaminase antibodies were detected before treatment in 1.3% of hepatitis C patients and in 0.4% of controls (not significant). Eighty-six percent of patients with anti-transglutaminase antibodies showed activation of celiac disease while on interferon. Symptoms ranged from mild to severe, and interferon had to be discontinued in 2 of 7 (29%) patients. Symptoms disappeared in 6 of 7 patients after interferon withdrawal. Onset of symptoms compatible with celiac disease during interferon therapy was significantly associated with the presence of anti-transglutaminase antibodies (OR 53). CONCLUSIONS: In hepatitis C patients, the activation of silent celiac disease during interferon treatment is almost universal and should be suspected, but it uncommonly requires interferon treatment discontinuation. Symptoms subside after interferon withdrawal.