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Among prostate cancers containing Gleason pattern 4, cribriform morphology is associated with unfavorable clinicopathologic factors, but its genetic features and association with long-term outcomes are incompletely understood. In this study, genetic, transcriptional, and epigenetic features of invasive cribriform carcinoma (ICC) tumors were compared with non-cribriform Gleason 4 (NC4) in The Cancer Genome Atlas (TCGA) cohort. ICC (n ¼ 164) had distinctive molecular features when compared with NC4 (n ¼ 102). These include: (i) increased somatic copy number variations (SCNV), specifically deletions at 6q, 8p and 10q, which encompassed PTEN and MAP3K7 losses and gains at 3q; (ii) increased SPOP mut and ATM mut ; (iii) enrichment for mTORC1 and MYC pathways by gene expression; and (iv) increased methylation of selected genes. In addition, when compared with the metastatic prostate cancer, ICC clustered more closely to metastatic prostate cancer than NC4. Validation in clinical cohorts and genomically annotated murine models confirmed the association with SPOP mut (n ¼ 38) and PTEN loss (n ¼ 818). The association of ICC with lethal disease was evaluated in the Health Professionals Follow-up Study (HPFS) and Physicians' Health Study (PHS) prospective prostate cancer cohorts (median follow-up, 13.4 years; n ¼ 818). Patients with ICC were more likely to develop lethal cancer [HR, 1.62; 95% confidence interval (CI), 1.05-2.49], independent from Gleason score (GS).Implications: ICC has a distinct molecular phenotype that resembles metastatic prostate cancer and is associated with progression to lethal disease.

Does the presence of human papillomavirus (HPV) in semen impact seminal parameters and sperm DNA quality in white European men seeking medical help for primary couple's infertility? SUMMARY ANSWER: HPV seminal infections involving high-risk (HR) genotypes are associated with impaired sperm progressive motility and sperm DNA fragmentation (SDF) values.WHAT IS KNOWN ALREADY: HPV is commonly present in semen samples. However, whether the presence of HPV in semen is actually associated with impaired sperm parameters and SDF values have yet to be elucidated. STUDY DESIGN, SIZE, DURATION:In this cross-sectional study, complete demographic, clinical and laboratory data from 729 infertile men were analysed.PARTICIPANTS/MATERIALS, SETTING, METHODS: Health-significant comorbidities were scored with the Charlson comorbidity index (CCI). Serum hormones and SDF index (measured by the sperm chromatin structure assay [SCSA]) were measured in every patient (SDF ≥30% was defined as pathological). Semen analysis was based on 2010 World Health Organisation reference criteria. Amplification by nested PCR was used to detect HPV-DNA sequences in semen samples. Descriptive statistics and linear regression models were used to test the association between the presence of HPV and clinical and seminal characteristics in the whole cohort. MAIN RESULTS AND THE ROLE OF CHANCE:The overall rate of HPV positivity was 15.5% (113/729). Overall, 78/729 (10.7%) and 35/729 (4.8%) patients had HR HPV+ and low-risk HPV+, respectively. HPV16 was the most prevalent type (22.1%), followed by HPV43 (10.6%), HPV56 and HPV42 (both 8.8%). No differences were found in terms of clinical and hormonal characteristics between patients with or without seminal HPV. Sperm progressive motility was significantly lower (P = 0.01) while SDF values were higher (P = 0.005) in HPV+ men compared to those with no HPV. In particular, HR HPV+ men had lower sperm progressive motility (P = 0.007) and higher SDF values (P = 0.003) than those with a negative HPV test. Univariable analysis showed that HR HPV+ was associated with impaired sperm progressive motility (P = 0.002) and SDF values (P = 0.003). In the multivariable analysis, age, FSH levels and testicular volume were significantly associated with impaired sperm progressive motility (all P ≤ 0.04). Conversely BMI, CCI, smoking habits and HPV status were not.