Low frequency of allelic imbalance at the prostate cancer susceptibility loci HPC1 and 1p36 in Swedish men with hereditary prostate cancer

The aim of this study was to investigate allelic imbalance at the major human prostate cancer susceptibility locus HPC1 at 1q24-25 and the recently reported, putative, susceptibility locus at 1p36 in prostate tumors from Swedish families with hereditary prostate cancer. We analyzed 31 prostate tumors and two lymph node metastases from 33 Swedish men in 22 families with hereditary prostate cancer for the presence of allelic imbalance using microsatellite markers D1S158, D1S422, and D1S238 for the HPC1 locus and D1S1597, D1S407, and D1S489 for the 1p36 locus. Frequencies of allelic imbalance at the two investigated loci were quite low, 3 of 27 informative tumors at the 1p36 locus and 3 of 27 informative tumors at the HPC1 locus. Interestingly, two tumors showed allelic imbalance at both loci investigated, suggesting that they may have lost a great part of chromosome 1. Taking this possibility into consideration, the specific loss of the two investigated loci may be even lower (1 of 27 informative tumors for either locus). The very low level of allelic imbalance found at HPC1 and 1p36 makes it unlikely that these loci encode genes that are acting as classic tumor suppressor genes in the initiation or progression of hereditary prostate cancer. Of the eight tumors from HPC1-linked families, only two showed AI at the HPC1 locus, one of which had lost the wild-type allele.     

BRCA2 mutation in a family with hereditary prostate cancer

Hereditary prostate cancer is a genetically heterogeneous disease, and so far four different susceptibility loci have been identified. Reports of associated cancers are few, and it is generally considered a site-specific disease. However, some reports have shown an elevated risk for prostate cancer among BRCA2 mutation carriers. In this report, we present a family in which the father and four of his sons were diagnosed with prostate cancer at exceptionally early ages (51, 52, 56, 58, and 63 years, respectively). In addition, three daughters were diagnosed with breast cancer between the ages of 47 and 61. In this family, a truncating mutation in exon 11, 6051delA of the BRCA2 gene, leading to an early termination of the protein (codon 1962), was identified. Although BRCA2 is probably responsible only for a very small fraction of hereditary prostate cancers, this finding supports previous reports of an increased risk of prostate cancer in BRCA2 mutation carriers.     

Interest in genetic testing among affected men from hereditary prostate cancer families and their unaffected male relatives

PurposeThe objective of this study was to evaluate potential sociodemographic, medical, psychosocial, and behavioral correlates of interest in genetic testing in men from hereditary prostate cancer families.MethodsFamily members affected with prostate cancer (n = 559) and their unaffected male relatives (n = 370) completed a mailed survey. Multivariable logistic regression models were used to examine the association between potential correlates and interest in genetic testing for prostate cancer.ResultsForty-five percent of affected and 56% of unaffected men reported that they definitely would take a genetic test for prostate cancer. More affected men reported high levels of familiarity with genetic testing than unaffected men (46 vs. 25%). There were several variables that were significantly correlated with interest in either affected or unaffected men, but only age and familiarity with genetics were significant in both groups. After controlling for confounding variables, only familiarity remained a significant correlate in both groups.ConclusionsThe contrast between low levels of familiarity with genetics and high test interest among unaffected men highlights the need for increased educational efforts targeting hereditary prostate cancer families. Overall, results illuminated several novel characteristics of men from hereditary prostate cancer families that should be considered when developing future informed consent procedures or educational materials for prostate cancer genetic testing.     

Somatic mosaics in hereditary tumor predisposition syndromes

Historically, it is estimated that 5–10% of cancer patients carry a causative genetic variant for a tumor predisposition syndrome. These conditions have high clinical relevance as they are actionable regarding risk-specific surveillance, predictive genetic testing, reproductive options, and – in some cases – risk reducing surgery or targeted therapy. Every individual is born with on average 0.5–1 exonic mosaic variants prevalent in single or multiple tissues. Depending on the tissues affected, mosaic conditions can abrogate the clinical phenotype of a tumor predisposition syndrome and can even go unrecognized, because it can be impossible or difficult to detect them with routine genetic testing in blood/leucocytes. On the other hand, it is estimated that at least 4% of presumed de novo variants are the result of low-level mosaicism (variant allele frequency <10%) in a parent, while around 7% are true mosaic variants with a higher variant allele frequency, which can sometimes be confused for heterozygous variants. Clonal hematopoiesis however can simulate a mosaic tumor predisposition in genetic diagnostics and has to be taken into account, especially for TP53 variants.Depending on the technique, variant allele frequencies of 2–3% can be detected for single nucleotide variants by next generation sequencing, copy number variants with variant allele frequencies of 5–30% can be detected by array-based technologies or MLPA.Mosaic tumor predisposition syndromes are more common than previously thought and may often remain undiagnosed. The clinical suspicion and diagnostic procedure for several cases with mosaic tumor predisposition syndromes are presented.     

Roots of prostate cancer in African-American men

To fully understand the role of genetics and environment (biotic, abiotic and sociocultural) in the prostate cancer disparity experienced by African-American men, this paper examined the rates of prostate cancer among African-American men and one of their ancestral populations in west Africa. Data sources were from the World Health Organization (WHO) and reported hospital records in the literature. Based on the WHO's worldwide cancer data, west African men have much lower prostate cancer incidence and mortality compared to African-American men. For example, compared to Nigerian men, African-American men are >10 times likely to develop prostate cancer and 3.5 times likely to die from the disease. However, contrary to the global ranking by WHO, there is documented evidence in the literature indicating that prostate cancer in at least one west African country is similar to rates found in the United States and in Caribbean Islands. To better address prostate cancer disparity, future studies should study populations and subgroups from central and west Africa, the original source population for African Americans.     

Factors associated with prostate cancer screening among Indo-Guyanese men

IntroductionHealth screening is considered a vital intervention in public health practices. Despite the strong emphasis on the need for preventative health screenings, little attention is focused on many immigrant populations. Indo-Guyanese immigrants are one of the ethnically minoritized populations facing these challenges. This study aims to identify factors associated with the likelihood that Indo-Guyanese men will undergo screening for prostate cancer.MethodsThis study is guided by a mixed-method approach incorporating both quantitative and qualitative analyses. A total of 20 participants were recruited via a snowball technique. Correlation between variables was conducted using IBM SPSS Statistics Version 27, while the qualitative data underwent a rigorous process of analysis and interpretation.ResultsEducation, income, understanding of risk factors, and considering self at risk were positively correlated with screening. Knowledge of prostate cancer and knowledge of the screening process was negatively correlated with screening.ConclusionImmigrant health has a significant impact on the U.S. public health system. Timely identification of potential barriers and providing culturally competent solutions and services will ensure a safe and healthy nation.     

Serum ferritin levels and transferrin saturation in men with prostate cancer

Elevated body iron stores (serum ferritin >300 microg/L, transferrin saturation TS >50%) are associated with increased risk of liver and lung cancers. To determine whether such association also exists for prostate cancer (PC), we measured serum ferritin, serum iron, total iron-binding capacity (TIBC), and TS in serum samples from 34 men with newly diagnosed, untreated PC and 84 healthy men, ranging in age from 49-78 years. In contrast with other malignancies, men with PC had significantly lower mean concentrations of serum ferritin (156 microg/L) and TS (24.35%) than those without PC (ferritin, 245 microg/L; TS, 31.98%) (p<0.05). The 95% confidence intervals for ferritin were 109-203 microg/L and 205-286 microg/L, and those for TS were 20.29-28.4% and 28.35-35.61% for men with and without PC, respectively. Significant differences were observed between both groups in the distribution of serum ferritin (<100, 101-300, >300 microg/L) and TS (<16, 16-50, >50%) (p<0.05). A lower percentage of cases than of controls had serum ferritin (17.6% versus 29.8%) and TS (5.9% versus 14.7%) above normal. These differences persisted when the analysis was limited to African-American men (31 cases and 52 controls). Data suggest that elevated body iron stores are less common in men with PC compared to those without PC.     

Novel BRCA1/2 mutations in Serbian breast and breast-ovarian cancer patients with hereditary predisposition

Mutations in breast cancer susceptibility (BRCA) genes lead to defects in DNA repair processes resulting in elevated genome instability and predisposing to breast and ovarian cancer. The study was designed to detect mutational spectra of BRCA1/2 genes in a Serbian population. Using automated DNA sequencing, we tested individuals for BRCA mutations, based on positive family history of either breast or ovarian cancer or both. Two novel mutations (c.4765_4784del in BRCA1 exon 15 and c.4367_4368dupTT in BRCA2 exon 11) were detected, in three probands from two different families. These mutations have not been reported previously in the BIC or LOVD databases. Protein products of these mutated alleles lack domains necessary for their DNA repair functions, an indicator that these are deleterious mutations. Neither mutation was found in any proband from 50 other families with hereditary predisposition, so the two mutations are likely family-specific rather than population-specific. Although BRCA1-associated tumors are typically negative for estrogen receptor (ER), progesterone receptor (PR), and ERBB2, the novel BRCA1 mutation identified in this study was detected in a proband with ER- and PR-positive breast cancer. Steroid receptor-positive BRCA-related breast cancer in this proband supports the idea of characteristic pathological features and older age of onset among BRCA1-mutated ER-positive breast cancers.     

Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis

Prostate cancer (PrCa) is the most common male cancer in developed countries and the second most common cause of cancer death after lung cancer. We recently reported a genome-wide linkage scan in 69 Finnish hereditary PrCa (HPC) families, which replicated the HPC9 locus on 17q21-q22 and identified a locus on 2q37. The aim of this study was to identify and to detect other loci linked to HPC. Here we used ordered subset analysis (OSA), conditioned on nonparametric linkage to these loci to detect other loci linked to HPC in subsets of families, but not the overall sample. We analyzed the families based on their evidence for linkage to chromosome 2, chromosome 17 and a maximum score using the strongest evidence of linkage from either of the two loci. Significant linkage to a 5-cM linkage interval with a peak OSA nonparametric allele-sharing LOD score of 4.876 on Xq26.3-q27 (ΔLOD=3.193, empirical P=0.009) was observed in a subset of 41 families weakly linked to 2q37, overlapping the HPCX1 locus. Two peaks that were novel to the analysis combining linkage evidence from both primary loci were identified; 18q12.1-q12.2 (OSA LOD=2.541, ΔLOD=1.651, P=0.03) and 22q11.1-q11.21 (OSA LOD=2.395, ΔLOD=2.36, P=0.006), which is close to HPC6. Using OSA allows us to find additional loci linked to HPC in subsets of families, and underlines the complex genetic heterogeneity of HPC even in highly aggregated families.     

Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients

PurposeThe aim of this study was to determine the clinical and molecular characteristics of 2,079 patients who underwent hereditary cancer multigene panel testing.MethodsPanels included comprehensive analysis of 14–22 cancer susceptibility genes (BRCA1 and BRCA2 not included), depending on the panel ordered (BreastNext, OvaNext, ColoNext, or CancerNext). Next-generation sequencing and deletion/duplication analyses were performed for all genes except EPCAM (deletion/duplication analysis only). Clinical histories of ColoNext patients harboring mutations in genes with well-established diagnostic criteria were assessed to determine whether diagnostic/testing criteria were met.ResultsPositive rates were defined as the proportion of patients with a pathogenic mutation/likely pathogenic variant(s) and were as follows: 7.4% for BreastNext, 7.2% for OvaNext, 9.2% for ColoNext, and 9.6% for CancerNext. Inconclusive results were found in 19.8% of BreastNext, 25.6% of OvaNext, 15.1% of ColoNext, and 23.5% of CancerNext tests. Based on information submitted by clinicians, 30% of ColoNext patients with mutations in genes with well-established diagnostic criteria did not meet corresponding criteria.ConclusionOur data point to an important role for targeted multigene panels in diagnosing hereditary cancer predisposition, particularly for patients with clinical histories spanning several possible diagnoses and for patients with suspicious clinical histories not meeting diagnostic criteria for a specific hereditary cancer syndrome.     

Identification and management of HNPCC syndrome (hereditary non polyposis colon cancer), hereditary predisposition to colorectal and endometrial adenocarcinomas

BACKGROUND: The HNPCC syndrome (hereditary nonpolyposis colon cancer) is an inherited condition defined by clinical and genealogical information, known as Amsterdam criteria. In about 70% of cases, HNPCC syndrome is caused by germline mutations in MMR genes, leading to microsatellite instability of tumor DNA (MSI phenotype). Patients affected by the disease are at high risk for colorectal and endometrial carcinomas, but also for small intestine, urothelial, ovary, stomach and biliary tract carcinomas. HNPCC syndrome is responsible for 5% of colorectal cancers. Identification and management of this disease are part of a multidisciplinary procedure. METHODS: Twelve experts have been mandated by the French Health Ministry to analyze and synthesize their consensus position, and the resulting document has been reviewed by an additional group of 4 independent experts. MAIN RECOMMENDATIONS: The lack of sensitivity of Amsterdam criteria in recognizing patients carrying a MMR germline mutation led to an enlargement of these criteria for the recruitment of possible HNPCC patients, and to a 2-steps strategy, asking first for a tumor characterization according to MSI phenotype, especially in case of early-onset sporadic cases. The identification of germline MMR mutations has no major consequence on the cancer treatments, but influences markedly the long-term follow-up and the management of at-risk relatives. Gene carriers will enter a follow-up program regarding their colorectal and endometrial cancer risks, but other organs being at low lifetime risk, no specific surveillance will be proposed.     

Population differences in the testosterone levels of young men are associated with prostate cancer disparities in older men

Although there is evidence that greater exposure to testosterone is associated with an increased risk of prostate cancer, a recent analysis of 18 prospective studies found no relationship between levels of endogenous sex hormones and prostate cancer development. However, the reviewed studies were subject to methodological constraints that would obscure any potential relationship between prostate cancer and androgenic hormones. If prostate cancer risk is mediated by lifetime exposure to testosterone, then case‐control studies that concentrate on endogenous sex hormones near the ages that prostate cancer is diagnosed would provide limited information on cumulative testosterone exposure across the lifespan. Alternately, early adulthood has been suggested as the most salient period to evaluate the influence of steroid physiology on prostate carcinogenesis. As such, an exhaustive literature search was completed to obtain testosterone values reported for study samples of younger men, along with prostate cancer incidences for the larger populations from which the study populations were sampled. A novel analytical method was developed to standardize, organize, and examine 12 studies reporting testosterone levels for 28 population samples. Study populations were generally apportioned according to ethnicity and geographic residence: Americans of African, Asian, Caucasian, and Hispanic ancestry from several different regions within the United States as well as men from China, Germany, Japan, Kuwait, New Zealand, South Korea, and Sweden. Population differences in the testosterone levels of young men were significantly associated with population disparities in the prostate cancer incidence of older men (Spearman's rho = 0.634, p = 0.002). Am. J. Hum. Biol. 2010. © 2010 Wiley‐Liss, Inc.     

"Between men": patient perceptions and priorities in a rehabilitation program for men with prostate cancer

The objective of the study is to compare consumer aspects of an informative, a physical, and a combined informative and physical rehabilitation program included in the "Between men" project for newly diagnosed prostate cancer patients. A consecutive series of patients was randomized. Programs were especially developed for prostate cancer patients. The format was 7 weekly sessions. The results show that the perceived benefits of relaxation was greater in the combination group than in the physical training group only. In comparison with the physical group more patients in the informative groups (information and information+physical training) rated the knowledge received as very important. The majority of patients (90%) was of the opinion that the "Between men" programs, should be continued. Independent of the actual program given, patients opted for the combination program or information alone but not the physical training alone program.     

Characterization of POT1 tumor predisposition syndrome: Tumor prevalence in a clinically diverse hereditary cancer cohort

PurposeGermline variants in POT1 have been implicated in predisposition to melanoma, sarcoma, and glioma in limited studies. Here, we determine the prevalence of cancer types in individuals with POT1 pathogenic variants (PVs) undergoing multigene panel testing (MGPT) for a broad variety of cancer indications.MethodsWe performed a retrospective review of data provided on clinical documents from individuals with POT1 PVs identified via MGPT over a 5-year period. Tumor prevalence in POT1 PV heterozygotes was compared with MGPT-negative wild-type (WT) controls using χ² test.ResultsPOT1 PVs were identified in 227 individuals. POT1 PV and WT (n = 13,315) cohorts had a similar proportion of reported tumors (69.6% and 69.2%, respectively); however, POT1 PV heterozygotes were more likely to be diagnosed with multiple tumors (18.9% vs 8.7%; P < .001). Compared with POT1 WT, we identified a significant increase in melanoma (odds ratio 7.03; 95% CI 4.7-10.5; P < .001) and sarcoma (odds ratio 6.6; 95% CI 3.1-13.9; P < .001).ConclusionThis analysis of the largest POT1 PV cohort to date validates the inclusion of POT1 in hereditary cancer MGPT and has the potential to impact clinical management recommendations, particularly for patients and families at risk for melanoma and sarcoma.