Male breast cancer risk associated with pathogenic variants in genes other than BRCA1/2: an Italian case-control study.

BACKGROUND: Germline pathogenic variants (PVs) in BRCA1/2 genes are associated with breast cancer (BC) risk in both women and men. Multigene panel testing is being increasingly used for BC risk assessment, allowing the identification of PVs in genes other than BRCA1/2. While data on actionable PVs in other cancer susceptibility genes are now available in female BC, reliable data are still lacking in male BC (MBC). This study aimed to provide the patterns, prevalence and risk estimates associated with PVs in non-BRCA1/2 genes for MBC in order to improve BC prevention for male patients. METHODS: We performed a large case-control study in the Italian population, including 767 BRCA1/2-negative MBCs and 1349 male controls, all screened using a custom 50 cancer gene panel. RESULTS: PVs in genes other than BRCA1/2 were significantly more frequent in MBCs compared with controls (4.8% vs 1.8%, respectively) and associated with a threefold increased MBC risk (OR: 3.48, 95% CI: 1.88-6.44; p < 0.0001). PV carriers were more likely to have personal (p = 0.03) and family (p = 0.02) history of cancers, not limited to BC. PALB2 PVs were associated with a sevenfold increased MBC risk (OR: 7.28, 95% CI: 1.17-45.52; p = 0.034), and ATM PVs with a fivefold increased MBC risk (OR: 4.79, 95% CI: 1.12-20.56; p = 0.035). CONCLUSIONS: This study highlights the role of PALB2 and ATM PVs in MBC susceptibility and provides risk estimates at population level. These data may help in the implementation of multigene panel testing in MBC patients and inform gender-specific BC risk management and decision making for patients and their families.

Prognostic Impact of Post-Diagnosis Smoking Cessation among Bladder Cancer Patients: A Systematic Literature Review and Meta-Analysis.

We reviewed the studies examining whether quitting smoking at or around diagnosis favourably affects the prognosis of bladder cancer (BC) patients, who are often active smokers at diagnosis. We found only nine eligible articles published until 31 January 2022, which encompassed around 5500 BC in total, the majority of which were nonmuscle invasive BC (only one paper included muscle-invasive BC). We used random effects meta-analysis to obtain a summary hazard ratio (SHR) and 95% confidence intervals (CI). The median proportion of smokers who quit at or around diagnosis was 29.8% (range 8.4-43.1%). For the overall, BC-specific, and progression-free survival, the studies were limited in number (n = 3) and provided conflicting results. At the same time, quitters did not appear to have a lower risk of recurrence than continued smokers (SHR 0.99, 95% CI 0.61-1.61). In conclusion, while the evidence is currently not sufficient to draw firm conclusions (especially for patients with muscle-invasive BC), physicians should not refrain from educating smoking BC patients about the benefits of smoking cessation and provide the necessary support.

The DAMA25 Study: Feasibility of a Lifestyle Intervention Programme for Cancer Risk Reduction in Young Italian Women with Breast Cancer Family History.

BACKGROUND: Diet and physical activity (PA) can modulate sporadic and possibly familial breast cancer (BC) risk. The DAMA25 study is a single-arm 12-month intervention aimed to modify dietary and PA habits in healthy young Italian women with a positive BC family history, categorized as having intermediate or high genetic risk according to NICE (National Institute for Health and Cancer Excellence) guidelines. METHODS: Participants, aged 25-49 years, were asked to adopt a diet mainly based on plant-based foods and to increase moderate daily activities combined with 1 h/week of more intense activity. Cooking lessons, collective walks, educational sessions, brochures, booklets and online materials were implemented. Dietary, PA habits and anthropometry were collected at baseline and at the end of the intervention. Changes on dietary, lifestyle habits and anthropometry were evaluated by GLM adjusted for weight reduction counselling aimed to participant with a BMI ≥ 25, age and baseline values of each variable. RESULTS: Out of 237 eligible women 107 (45.2%) agreed to participate and among them 98 (91.6%) completed the intervention. The adherence rate of the intervention was 77.8%. We observed a reduction in red and processed meat (p < 0.0001) and cakes consumption (p < 0.0001). Consumption of whole grain bread (p < 0.001), leafy vegetables (p = 0.01) and olive oil (p = 0.04) increased. We observed an increase in moderate (p < 0.0001) and more intense (p < 0.0001) recreational activities, an average 1.4 kg weight loss (p = 0.005), a reduction of waist circumference (p < 0.001) and fat mass (p = 0.015). CONCLUSIONS: The DAMA25 study shows that it is feasible an intervention to improve in the short-term dietary and PA habits and anthropometry in women with high BC familial risk.

Transcriptome of Male Breast Cancer Matched with Germline Profiling Reveals Novel Molecular Subtypes with Possible Clinical Relevance.

Male breast cancer (MBC) is a rare and understudied disease compared with female BC. About 15% of MBCs are associated with germline mutation in BC susceptibility genes, mainly BRCA1/2 and PALB2. Hereditary MBCs are likely to represent a subgroup of tumors with a peculiar phenotype. Here, we performed a whole transcriptome analysis of MBCs characterized for germline mutations in the most relevant BC susceptibility genes in order to identify molecular subtypes with clinical relevance. A series of 63 MBCs, including 16 BRCA2, 6 BRCA1, 2 PALB2, 1 RAD50, and 1 RAD51D germline-mutated cases, was analyzed by RNA-sequencing. Differential expression and hierarchical clustering analyses were performed. Module signatures associated with central biological processes involved in breast cancer pathogenesis were also examined. Different transcriptome profiles for genes mainly involved in the cell cycle, DNA damage, and DNA repair pathways emerged between MBCs with and without germline mutations. Unsupervised clustering analysis revealed two distinct subgroups, one of which was characterized by a higher expression of immune response genes, high scores of gene-expression signatures suggestive of aggressive behavior, and worse overall survival. Our results suggest that transcriptome matched with germline profiling may be a valuable approach for the identification and characterization of MBC subtypes with possible relevance in the clinical setting.

Pre-diagnostic DNA methylation patterns differ according to mammographic breast density amongst women who subsequently develop breast cancer: a case-only study in the EPIC-Florence cohort.

PURPOSE: Mammographic breast density (MBD) is a marker of increased breast cancer (BC) risk, yet much remains to be clarified about the underlying mechanisms. We investigated whether DNA methylation patterns differ between high- vs. low-MBD women who developed BC during an 8.9-year median follow-up in the Florence section of the European Prospective Investigation into Cancer and Nutrition. METHODS: We analysed 96 pairs of women with BC arising on high- vs. low-MBD breasts (BI-RADS category III-IV vs. I). DNA methylation was determined on pre-diagnostic blood samples using the Illumina Infinium MethylationEPIC BeadChip assay. The statistical analysis was conducted by performing an epigenome-wide association study (EWAS), by searching differentially methylated regions (DMRs) in gene promoters (followed by functional enrichment and gene annotation analysis); and through a "candidate pathways" approach focusing on pre-defined inflammation-related pathways. RESULTS: In EWAS, no single CpG site was differentially methylated between high- and low-MBD women after correction for multiple testing. A total of 140 DMRs were identified, of which 131 were hyper- and 9 hypo-methylated amongst high-MBD women. These DMRs encompassed an annotation cluster of 35 genes coding for proteins implicated in transcription regulation and DNA binding. The "apoptosis signalling" was the only inflammation-related candidate pathway differentially methylated between high- and low-MBD women. CONCLUSION: Pre-diagnostic methylation patterns differ between high- vs. low-MBD women who subsequently develop BC, particularly, in genes involved in the regulation of DNA transcription and cell apoptosis. Our study provides novel clues about the mechanisms linking MBD and BC.

TERT promoter mutations and melanoma survival: A comprehensive literature review and meta-analysis.

We conducted a systematic review and meta-analysis of the association between somatic mutations of the TERT gene promoter and melanoma survival. Data from nineteen independent studies (>2,500 melanoma overall) were pooled using random effects meta-analysis models. TERT-mutated melanoma patients had a significantly worse overall survival (OS) (summary hazard ratio 1.43, 95 % confidence intervals (CI) 1.05-1.95) compared to wild-type ones. The association became stronger when combining risk estimates for overall and melanoma-specific survival (MSS) (1.52, 95 % CI 1.14-2.02), and when restricting the analysis to studies mostly based on invasive non-acral cutaneous melanomas (1.77, 95 % CI 1.00-3.15). Limited, yet suggestive evidence of a detrimental effect of TERT promoter mutations on melanoma prognosis emerged also for other survival measures (e.g. disease-free and distant metastasis-free survival). We found suggestive evidence of a detrimental effect of TERT mutations on melanoma patients' survival.

Germline MC1R variants and frequency of somatic BRAF, NRAS, and TERT mutations in melanoma: Literature review and meta-analysis.

Germline variants of the melanocortin-1-receptor (MC1R) gene are the most common genetic trait predisposing to cutaneous melanoma (CM). Here, we performed a literature review and meta-analysis of the association between MC1R gene variants and the frequency of somatic mutations of the BRAF, NRAS, and TERT genes in CM patients. We included studies published until January 2020 in MEDLINE, EMBASE, Ovid Medline, and two grey literature databases. Random effect models were used to pool study-specific estimates into summary odds ratio (SOR) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were conducted to identify potential sources of heterogeneity and assess the robustness of pooled estimates. Twelve studies published between 2006 and 2018 (encompassing 3566 CM, mostly on nonacral sites) were included. MC1R gene variants were not significantly associated with the frequency of somatic mutations of the BRAF and NRAS genes. Only three studies focused on somatic mutations of the TERT gene promoter, all of which reported moderate-to-strong positive associations with MC1R germline variants. MC1R gene variants appear to make only moderate changes, if any, to the risk of BRAF- or NRAS-mutant CM. The association with TERT promoter mutations is suggestive, yet it warrants confirmation as it is based on a still limited number of studies.

Common Susceptibility Loci for Male Breast Cancer.

BACKGROUND: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC. METHODS: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10-06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided. RESULTS: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10-30). CONCLUSIONS: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.

Circulating tumour DNA and melanoma survival: A systematic literature review and meta-analysis.

We reviewed and meta-analysed the available evidence (until December 2019) about circulating tumour DNA (ctDNA) levels and melanoma patients survival. We included twenty-six studies (>2000 patients overall), which included mostly stage III-IV cutaneous melanoma patients and differed widely in terms of systemic therapy received and somatic mutations that were searched. Patients with detectable ctDNA before treatment had worse progression-free survival (PFS) (summary hazard ratio (SHR) 2.47, 95 % confidence intervals (CI) 1.85-3.29) and overall survival (OS) (SHR 2.98, 95 % CI 2.26-3.92), with no difference by tumour stage. ctDNA detectability during follow-up was associated with poorer PFS (SHR 4.27, 95 %CI 2.75-6.63) and OS (SHR 3.91, 95 %CI 1.97-7.78); in the latter case, the association was stronger (p = 0.01) for stage IV vs. III melanomas. Between-estimates heterogeneity was low for all pooled estimates. ctDNA is a strong prognostic biomarker for advanced-stage melanoma patients, robust across tumour (e.g. genomic profile) and patients (e.g. systemic therapy) characteristics.

MC1R variants and cutaneous melanoma risk according to histological type, body site, and Breslow thickness: a pooled analysis from the M-SKIP project.

Little is known on whether melanocortin 1 receptor (MC1R) associated cutaneous melanoma (CM) risk varies depending on histological subtype and body site, and whether tumour thickness at diagnosis (the most important prognostic factor for CM patients) differs between MC1R variant carriers and wild-type individuals. We studied the association between MC1R variants and CM risk by histological subtype, body site, and Breslow thickness, using the database of the M-SKIP project. We pooled individual data from 15 case-control studies conducted during 2005-2015 in Europe and the USA. Study-specific, multi-adjusted odds ratios were pooled into summary odds ratios (SOR) and 95% confidence intervals (CI) using random-effects models. Six thousand eight hundred ninety-one CM cases and 5555 controls were included. CM risk was increased among MC1R variant carriers vs. wild-type individuals. The increase in risk was comparable across histological subtypes (SOR for any variant vs. wild-type ranged between 1.57 and 1.70, always statistical significant) except acral lentiginous melanoma (ALM), for which no association emerged; and slightly greater on chronically (1.74, 95% CI 1.47-2.07) than intermittently (1.55, 95% CI 1.34-1.78) sun-exposed skin. CM risk was greater for those carrying 'R' vs. 'r' variants; correlated with the number of variants; and was more evident among individuals not showing the red hair colour phenotype. Breslow thickness was not associated with MC1R status. MC1R variants were associated with an increased risk of CM of any histological subtype (except ALM) and occurring on both chronically and intermittently sun-exposed skin.

Evaluation of CYP17A1 and CYP1B1 polymorphisms in male breast cancer risk.

Breast cancer in men is a rare and still poorly characterized disease. Inherited mutations in BRCA1, BRCA2 and PALB2 genes, as well as common polymorphisms, play a role in male breast cancer genetic predisposition. Male breast cancer is considered a hormone-dependent tumor specifically related to hyperestrogenism. Polymorphisms in genes involved in estrogen biosynthesis and metabolism pathways, such as CYP17A1 and CYP1B1, have been associated with breast cancer risk. Here, we aimed to investigate the role of CYP17A1 and CYP1B1 polymorphisms in male breast cancer risk. A series of 597 male breast cancer cases and 1022 male controls, recruited within the Italian Multicenter Study on male breast cancer, was genotyped for CYP17A1 rs743572, CYP1B1 rs1056836 and rs1800440 polymorphisms by allelic discrimination real-time PCR with TaqMan probes. Associations with male breast cancer risk were estimated using logistic regression. No statistically significant associations between male breast cancer risk and the three analyzed polymorphisms emerged. Similar results were obtained also when BRCA1/2 mutational status was considered. No significant differences in the distribution of the genotypes according to estrogen receptor status emerged. In conclusion, our study, based on a large series of male breast cancer cases, is likely to exclude a relevant role of CYP17A1 and CYP1B1 polymorphisms in male breast cancer predisposition. Overall, these results add new data to the increasing evidence that polymorphisms in these genes may not be associated with breast cancer risk.

Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy.

Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well-characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non-BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer-associated genes. The main clinical-pathologic characteristics of MBC in pathogenic variant carriers and non-carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 non-BRCA1/2 MBC patients were examined in our study. Twenty-seven of the non-BRCA1/2 MBC patients were carriers of germline pathogenic variants in other genes, including two APC p.Ile1307Lys variant carriers and one MUTYH biallelic variant carrier. PALB2 was the most frequently altered gene (1.2%) and PALB2 pathogenic variants were significantly associated with high risk of MBC. Non-BRCA1/2 pathogenic variant carriers were more likely to have personal (p = 0.0005) and family (p = 0.007) history of cancer. Results of our study support a central role of PALB2 in MBC susceptibility and show a low impact of CHEK2 on MBC predisposition in the Italian population. Overall, our data indicate that a multigene testing approach may benefit from appropriately selected patients with implications for clinical management and counseling of MBC patients and their family members.

Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy.

Inherited mutations in BRCA1, and, mainly, BRCA2 genes are associated with increased risk of male breast cancer (MBC). Mutations in PALB2 and CHEK2 genes may also increase MBC risk. Overall, these genes are functionally linked to DNA repair pathways, highlighting the central role of genome maintenance in MBC genetic predisposition. MUTYH is a DNA repair gene whose biallelic germline variants cause MUTYH-associated polyposis (MAP) syndrome. Monoallelic MUTYH variants have been reported in families with both colorectal and breast cancer and there is some evidence on increased breast cancer risk in women with monoallelic variants. In this study, we aimed to investigate whether MUTYH germline variants may contribute to MBC susceptibility. To this aim, we screened the entire coding region of MUTYH in 503 BRCA1/2 mutation negative MBC cases by multigene panel analysis. Moreover, we genotyped selected variants, including p.Tyr179Cys, p.Gly396Asp, p.Arg245His, p.Gly264Trpfs*7, and p.Gln338His, in a total of 560 MBC cases and 1,540 male controls. Biallelic MUTYH pathogenic variants (p.Tyr179Cys/p.Arg241Trp) were identified in one MBC patient with phenotypic manifestation of adenomatous polyposis. Monoallelic pathogenic variants were identified in 14 (2.5%) MBC patients, in particular, p.Tyr179Cys was detected in seven cases, p.Gly396Asp in five cases, p.Arg245His and p.Gly264Trpfs*7 in one case each. The majority of MBC cases with MUTYH pathogenic variants had family history of cancer including breast, colorectal, and gastric cancers. In the case-control study, an association between the variant p.Tyr179Cys and increased MBC risk emerged by multivariate analysis [odds ratio (OR) = 4.54; 95% confidence interval (CI): 1.17-17.58; p = 0.028]. Overall, our study suggests that MUTYH pathogenic variants may have a role in MBC and, in particular, the p.Tyr179Cys variant may be a low/moderate penetrance risk allele for MBC. Moreover, our results suggest that MBC may be part of the tumor spectrum associated with MAP syndrome, with implication in the clinical management of patients and their relatives. Large-scale collaborative studies are needed to validate these findings.

Smoking and FGFR2 rs2981582 variant independently modulate male breast cancer survival: A population-based study in Tuscany, Italy.

AIM: Male breast cancer (MBC) is a rare disease and recommendations for its clinical management are often extrapolated from those for female breast cancer, even if breast cancer (BC) has different characteristics in the two sexes. The purpose of this study was to assess the influence of several individual characteristics including clinico-pathological, lifestyle and genetic factors on overall survival (OS) of a relatively large and well characterized population-based series of 166 MBCs enrolled in Tuscany. METHODS: We genotyped MBC cases at BRCA1/2 genes and at 9 candidate BC susceptibility SNPs. Kaplan-Meier method and multivariate Cox regression, adjusted for several individual characteristics were used. To reduce a possible selection bias related to the interval between diagnosis and enrolment of MBC cases into the study, we used the date of blood donation as the date of the start of observation for survival analysis. RESULTS: Only smoking habits had a significant effect on OS at 10 years (for current smokers, HR: 3.34; 95% CI 1.45-7.68; p = 0.004), while lymph node status fell short of reaching statistical significance (for pN positive, HR: 2.07; 95% CI 0.93-4.55; p = 0.07). In the same multivariate analysis we found a significantly higher OS in cases with FGFR2 rs2981582 variant in the dominant transmission model (HR: 0.29; 95% CI: 0.13-0.62; p = 0.028). A sensitivity analysis with left truncation showed similar results. CONCLUSIONS: Our results may contribute to shed light on factors influencing MBC survival suggesting an important role for cigarette smoking and FGFR2 rs2981582 variant, and provide clues for better patient management.

Gene-specific methylation profiles in BRCA-mutation positive and BRCA-mutation negative male breast cancers.

Male breast cancer (MBC) is a rare disease. Due to its rarity, MBC research and clinical approach are mostly based upon data derived from female breast cancer (FBC). Increasing evidence indicate that on molecular level MBC may be an heterogeneous disease different from FBC. In order to investigate whether epigenetic signatures could define molecular subgroups of MBCs, we performed promoter methylation analysis of genes involved in signal transduction and hormone signalling in BRCA1/2 mutation-positive and -negative MBCs. We examined 69 MBCs, paired blood samples, and 15 normal tissues for promoter methylation of hTERT, ESR1, RASSF1, AR, MYC and WNT1 genes. MBCs showed higher gene promoter methylation levels compared to paired blood and normal breast samples. Significantly higher RASSF1 methylation levels were observed in association with BRCA1/2 mutations, HER2 expression and high tumor grade. Significantly higher AR methylation levels were observed in BRCA1/2 wild-type cases and higher WNT1 methylation levels in PR negative cases. Overall, our results indicate that alterations in gene methylation profiles are common in MBC and that methylation pattern of tumor-associated genes may allow for the identification of MBC molecular subgroups, that could have implications in clinical management of MBC patients.

A possible role of FANCM mutations in male breast cancer susceptibility: Results from a multicenter study in Italy.

INTRODUCTION: Breast cancer (BC) in men is a rare disease, whose etiology appears to be associated with genetic factors. Inherited mutations in BRCA1/2 genes account for about 10-15% of all cases. FANCM, functionally linked to BRCA1/2, has been suggested as a novel BC susceptibility gene. Our aim was to test if FANCM germline mutations could further explain male BC (MBC) susceptibility. METHODS: We screened the entire coding region of FANCM in 286 MBCs by a multi-gene panel analysis, and compared these data with available whole exome sequencing data from 415 men used as population controls. Moreover, we genotyped the two most frequent FANCM mutations (c.5101C>T and c.5791C>T) in 506 MBCs and 854 healthy male controls. RESULTS: Two FANCM truncating mutations, the c.1432C>T (p.Arg478Ter) and c.1972C>T (p.Arg658Ter), were identified in two MBC cases (0.7%). When specifically considering cases at increased genetic risk for BC, FANCM mutation frequency raises up to 1%. One mutation, the c.2201_2202delCT (p.Ser734Terfs), was found among controls (0.24%). Mutation frequency in cases was higher than in controls, however this difference was not statistically significant. FANCM c.5101C>T was not present in any of the cases and controls analyzed, whereas FANCM c.5791C>T was found in two controls (0.23%). CONCLUSION: Rare FANCM truncating mutations, other than c.5101C>T and c.5791C>T, may have a role in MBC susceptibility. The inclusion of FANCM in gene panels for research purpose would allow for the identification of a higher number of mutation carriers, thus helping estimate BC risk associated with FANCM mutations.

A 5-Year Follow-Up of a Cohort of Italian Alcoholics: Hospital Admissions and Overall Survival.

BACKGROUND: Alcohol use disorders (AUDs), including alcohol dependence and alcohol abuse defined according to specific DSM-IV and ICD-10 criteria, can be potentially lethal, because they are associated with several medical and psychiatric conditions. This study aimed to describe the causes of hospitalization of a large cohort of subjects with alcohol dependence (alcoholics) enrolled in Florence (Italy) over a 5-year follow-up period and to evaluate the effect of hospitalization on overall survival. METHODS: One thousand one hundred and thirty alcoholics, newly diagnosed from 1997 to 2001, were linked to the Regional Mortality Registry for update of vital status as of December 31, 2006, and to the Hospital Discharge electronic archives of the Regional Health System of Tuscany to verify hospital admissions (HAs) during the 5-year postcohort enrollment follow-up. Kaplan-Meier survival and Cox regression analyses were performed to evaluate any association of HA with overall survival. RESULTS: A total of 3,916 new hospitalizations occurred during the 5-year follow-up. Most alcoholics (70.6%) reported at least 1 new hospitalization, with a first hospitalization rate of 61.7 per 100 person-years in the first year of follow-up. The mean number of hospitalizations per admitted subject was 4.87 (SD 7.4), and mean length of hospital stay was 8.5 days (SD 11.3). The main causes of hospitalization were mental disorders and diseases of the digestive system, as well as accidents or violence. Among those alcoholics alive after 1 year of follow-up, a significantly increased risk of dying in the following years could be predicted by early hospitalization in the 12 months preceding (hazard ratio [HR] 1.73; 95% confidence interval [CI] 1.15 to 2.60) or following (HR 3.59; 95% CI 2.31 to 5.61) enrollment in the cohort. CONCLUSIONS: Our results confirm the association of AUDs with several serious medical conditions. This fact may be responsible for a high impact on health resource utilization and high social costs. Early hospitalization significantly predicts vital status at 5 years.

Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene.

BACKGROUND: Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted gene sequencing were applied to high-risk, BRCA1/2 mutation-negative MBC cases. METHODS: Germ-line DNA of 1 male and 2 female BRCA1/2 mutation-negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results was performed for 48 high-risk, BRCA1/2 mutation-negative MBC cases from an Italian multicenter study of MBC. A case-control series of 433 BRCA1/2 mutation-negative MBC and female breast cancer (FBC) cases and 849 male and female controls was included in the study. RESULTS: WES in the family identified the partner and localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affected with BC) and the N-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband's maternal aunt. Targeted PALB2 sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation-negative MBC cases. NAT1 c.97C>T was not found in the case-control series. CONCLUSIONS: These results add strength to the evidence showing that PALB2 is involved in BC risk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation-negative families with multiple MBC and FBC cases. Cancer 2017;123:210-218. © 2016 American Cancer Society.

Up to one-third of breast cancer cases in post-menopausal Mediterranean women might be avoided by modifying lifestyle habits: the EPIC Italy study.

PURPOSE: Breast cancer (BC) is the most frequent cancer among women in developed countries. Physical activity (PA), body mass index (BMI), and alcohol intake have been identified as relevant lifestyle modifiable risk factors for post-menopausal BC. We aimed to evaluate the role of these factors in modulating post-menopausal BC risk and to estimate the proportion of BC cases attributable to low PA, high BMI, and alcohol taking into account non-modifiable factors. METHODS: In the Italian section of the EPIC study, 15,010 post-menopausal women were recruited and provided information about dietary and lifestyle habits including PA, smoking, reproductive history, and anthropometric measurements. During 14.8 years of median follow-up, 672 incident BC cases (607 invasive and 65 in situ) were identified. RESULTS: In multivariate models, inverse associations with BC risk emerged for increasing level of total (p trend 0.02), leisure time (p trend 0.04), and occupational (p trend 0.007) PA. High BMI (HR 1.21; 95% CI 1.02-1.43 and HR 1.33; 95% CI 1.06-1.65 for overweight and obesity, respectively) and alcohol consumption higher than 10 g/day (HR 1.30; 95% CI 1.09-1.54) were associated with BC risk. We estimated that 30% (95% CI 8-50%) of post-menopausal BC cases would be avoided through an increase of leisure time PA, a BMI below 25.0, and consuming no more than one drink/day. CONCLUSIONS: This large study carried out in Mediterranean women confirms the role of PA, BMI, and alcohol consumption in modulating post-menopausal BC risk and supports the potential benefits obtainable by modifying these lifestyle factors.