SUMMARY DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ~20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.

PARP inhibitors have been proven clinically efficacious in platinum-responsive ovarian cancer regardless of BRCA1/2 status and in breast cancers with germline BRCA1/2 mutation. However, resistance to PARP inhibitors may preexist or evolve during treatment in many cancer types and may be overcome by combining PARP inhibitors with other therapies, such as immune checkpoint inhibitors, which confer durable responses and are rapidly becoming the standard of care for multiple tumor types. This study investigated the therapeutic potential of combining niraparib, a highly selective PARP1/2 inhibitor, with anti-PD-1 immune checkpoint inhibitors in preclinical tumor models. Our results indicate that niraparib treatment increases the activity of the type I (alpha) and type II (gamma) interferon pathways and enhances the infiltration of CD8+ cells and CD4+ cells in tumors. When coadministered in immunocompetent models, the combination of niraparib and anti-PD-1 demonstrated synergistic antitumor activities in both BRCA-proficient and BRCA-deficient tumors. Interestingly, mice with tumors cured by niraparib monotherapy completely rejected tumor growth upon rechallenge with the same tumor cell line, suggesting the potential establishment of immune memory in animals treated with niraparib monotherapy. Taken together, our findings uncovered immunomodulatory effects of niraparib that may sensitize tumors to immune checkpoint blockade therapies.

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Human papillomavirus (HPV) has been identified as etiologic agent of various cancers for both men and women. However, HPV vaccine has not been recommended for men in China by far. To provide more evidences to promote HPV vaccination among males at high-risk of infection, this study investigated genital HPV genotypes among male attendees of sexually transmitted disease (STD) clinic. Male attendees (⩾18 years old) were recruited from STD clinic of Beijing Ditan Hospital. Data on sociodemographic characteristics and self-reported sexual behaviors were collected based on questionnaire. Genital swab specimens were collected for HPV genotypes. Finally, a total of 198 eligible participants were included in the study. Nearly half of them were infected with at least one type of HPV. The prevalence of genital infection among participants with only heterosexual behaviors (50·91%, 56/110) was significantly higher than those with only homosexual behaviors (36·36%, 32/88) (P < 0·001). However, the distribution pattern of the most frequently observed HPV subtypes were found to be similar between these two subgroups. HPV31, HPV18, HPV16 and HPV58 were the most frequently identified high-risk types and HPV11, HPV6, HPV81 and HPV61 were the most frequently observed low-risk types. Our results, although need further verification by larger sample size, suggested that currently available HPV vaccines covered most prevalent HPV types observed in Chinese men. As HPV vaccine has been approved for application in females in China, molecular epidemiological studies and intervention studies among high-risk males should be promoted as well.

ObjectiveTo determine the prevalence and distribution of human enteroviruses (HEVs) among healthy children in Shenzhen, China.MethodClinical specimens were obtained from 320 healthy children under 5 years old in Shenzhen, China from 2010 to 2011. The specimens were evaluated using real-time PCR and cell cultures. The positive specimens were further tested using reverse transcription-seminested PCR (RT-snPCR). Molecular typing and phylogenetic analysis were based on the sequence determined.ResultsAmong the 320 samples, 34 were tested positive for HEVs (10.6%) and 22 different serotypes were identified using RT-snPCR. PV1 and PV2 were also detected. The predominant serotype observed was EV71 (17.6%), followed by CV-B4 (14.7%). HEV-B was detected most frequently, with an overall prevalence of 47.1%. HEV-A and HEV-C were found in 32.3% and 20.6% of the samples, respectively. No HEV-D was identified. Molecular phylogeny indicated that all EV71 strains were of C4 genotype.ConclusionAlthough a variety of HEVs was detected in healthy children, HEV-B was relatively more prevalent than other HEV species. Considering HEV-A is more prevalent than HEV-B among patients with hand-foot-mouth disease, additional long-term surveillance of HEV is warranted in both asymptomatic and symptomatic populations.