What's new?

The tendency for certain cancer types to cluster in families generally is explained by shared environmental exposures or inherited mutations. In particular, early-onset cancer, diagnosed between ages 0 and 40, is considered indicative of familial factors. Here, investigation of cancer risk among more than 376,760 relatives of probands, or individuals with early-onset cancer, shows that the likelihood of early-onset cancer affecting even just one other relative in addition to the proband is exceedingly rare. Nearly all early-onset cancers in the study population were sporadic. Estimated cumulative risks observed for specific cancers may prove useful in the context of genetic counseling.

What's new?

While physical activity is associated with a reduced risk of certain cancer types, its relationship with ovarian cancer risk remains unclear. In this population-based case–control study in Montreal, Canada, participation in recreational physical activities over the lifetime and in specific life periods was examined in relation to ovarian cancer risk. Analyses did not find that moderate-to-vigorous physical activity was associated with a reduced ovarian cancer risk. Rather, the data hinted toward a marginal increase in risk, which was more apparent particularly among women diagnosed with ovarian cancer before menopause and women with high-grade serous tumors.

What's new?

Human papillomavirus (HPV) testing is a sensitive approach for detecting cervical intraepithelial neoplasia grade 2 and higher (CIN2+). However, whether HPV testing alone, with extended intervals between visits, is more effective than HPV testing and liquid-based cytology (LBC) combined for cervical screening remains uncertain. Here, HPV testing every four years was found to be at least as effective as LBC every two years for CIN2+ identification. Moreover, women were more likely to comply with screening protocol when four-year intervals were used, compared to two-year intervals. Women with CIN1 at colposcopy and women initially HPV-positive may require screening with both methods.

What's new?

There is strong evidence for a genetic predisposition to prostate cancer (PrCa). Most of this information has come from European ancestry populations, with Latinos representing less than 1% of samples in cancer genome-wide association studies (GWAS). In this study, the majority of established PrCa risk variants (83.3%) were consistently associated with PrCa risk in Latinos. A polygenic risk score comprised of GWAS-identified risk variants could identify 10% of Latino men with a ~three-fold increase in PrCa risk. These findings suggest that common germline variants for PrCa can stratify risk in Latino men, which has implications for targeted screening and prevention.

What's new?

Today breast cancer is increasingly being cured, but adverse effects persist, with fatigue being the most frequently reported symptom. In this longitudinal prospective study of long-term, self-reported fatigue trajectories of breast cancer survivors, fatigue increased after surgery, peaked at the end of chemotherapy, and then decreased up until 18 months before slightly rising again. The risk of severe fatigue was decreased by a high quality of life before surgery. Severe mental fatigue and severe reduced motivation both worsened with low optimism before surgery. The findings may help provide early preventive and curative treatment for women at risk for severe fatigue.

What's new?

Polyphenols are secondary plant metabolites with health protective properties but whether a diet rich in polyphenols protects from thyroid cancer has not been conclusively explored. In this large prospective study, no associations were observed between dietary polyphenol intake and differentiated thyroid cancer risk. The authors recommend further studies to investigate potential associations specifically in overweight and obese individuals.

What's new?

Patients with high-grade serous ovarian cancer (HGSOC) with residual disease after neoadjuvant chemotherapy may be affected by tumors that harbor cells with intrinsic resistance to therapy. The present study confirms this suspicion, showing that about 40 percent of HGSOC patients with residual disease have mutations in homologous recombination repair (HRR) genes, thereby fueling drug resistance. More than 90 percent of patients studied exhibited alterations in at least one of six clinically relevant pathways or functional groups. In particular, HRR-deficient tumors showed a significant increase in PI3K-AKT-mTOR pathway alterations, which were further linked to poor overall survival in HGSOC.

What's new?

Genome-wide association studies identify genomic loci associated with certain cancers, but identifying the causal genes within these loci remains a major challenge. Here the authors performed a large transcriptome-wide association study (TWAS) for lung cancer and found on chromosome 15 the iron-responsive element-binding protein 2 as the most likely target for all histological subtypes. They also identified a new susceptibility locus for lung adenocarcinoma on chromosome 9 with aquaporin 3 as the candidate causal gene, demonstrating how TWAS can refine the biological interpretation of genomic association studies.

What's new?

Ovarian cancers carrying BRCA1 mutations are characterized by intratumoural heterogeneity, in which most malignant cells show a loss of the remaining BRCA1 allele, while some cells retain BRCA1 function. Here, investigation of BRCA1 mutation among ovarian cancer patients over the course of treatment reveals plasticity in somatic BRCA1 status, with impacts on primary cancer development, therapeutic response, and disease relapse. In particular, relapses following treatment holidays were characterized by the re-appearance of somatic BRCA1 inactivation. Plasticity in BRCA1 status likely explains the failure of systemic therapy to eradicate tumor clones and accounts for platinum sensitivity in recurrent BRCA1-driven ovarian cancers.

What's new?

Metastatic esophagogastric cancer can't be cured, but palliative therapy can improve patients’ quality of life and survival. However, there's no consensus regarding the optimal first-line palliative systemic therapy for metastatic esophagogastric cancer. Here, the authors evaluated real-world use of first-line systemic treatments. The retrospective study included a cohort of 2,204 metastatic patients and found 45 different treatment regimens administered. Patients that received doublet and triplet chemotherapy had similar survival, with triplet patients experiencing higher toxicity. Monotherapy produced significantly worse overall survival and only modest reduction in toxicity. These findings support doublet therapy as the optimal first-line treatment strategy.

What's new?

Rearrangement of the MLL/KMT2A gene results in a highly aggressive, therapy-resistant leukemia subtype, with high incidence in infants and survival rates below 50%. In this preclinical study, the authors found that a new, small-molecule curaxin drug called CBL0137 significantly reduced leukemia burden in xenograft models, and also enhanced the response to standard chemotherapy drugs. CBL0137 mediated this effect through activation of the p53 and IFN pathways. These findings support further preclinical evaluation of CBL0137 as a new approach for the treatment of MLL-r leukemia.

What's new?

About half of breast cancers positive for human epidermal growth factor (HER2) also express hormone receptors but the impact of hormone receptor status on the success of HER2-directed treatments is not fully explored. Here the authors retrospectively assessed tumor behavior and treatment outcomes in 738 women with HER2+ metastatic breast cancer treated with new generation anti-HER2 agents. Distinct hormone receptor expression patterns significantly affected the progression free and overall survival, justifying further studies to define optimal treatment regimens and the interplay between hormone receptor and HER2 signaling.

What's new?

Squamous cell carcinoma (SCC) of the bladder cancer frequently arises as a result of Schistosoma haematobium infection, particularly in North Africa. Outside this region, SCC of the bladder is suspected of being linked to recurrent urinary tract infection (UTI). In this nationwide study in Denmark, increased risk of SCC of the bladder was strongly associated with high UTI-specific antibiotic use, indicative of recurrent UTI. The association displayed a clear dose–response relationship. By contrast, no association was detected between non-UTI-specific antibiotics and SCC or other bladder cancer histologies. The findings suggest that UTIs are an important cause of SCC bladder cancer.

What's new?

The discovery of novel molecular targets is fundamental to the continued advance of therapeutic agents for gastric cancer (GC). In this study, the authors identify a pathway involving interaction between EphA2, a member of the erythropoietin-producing hepatocellular receptor family, and yes-associated protein (YAP) as a promising therapeutic target for GC. In GC cells, EphA2 phosphorylation of YAP protein resulted in YAP stabilization, translocation to the nucleus, and activation. Increased YAP stabilization and nuclear concentration in GC cells and mouse models was further associated with EphA2-induced chemoresistance. In patients, EphA2 overexpression and nuclear YAP accumulation was related to GC relapse.

What's new?

Even though significant improvements have been achieved in the therapy of mutated BRAF^V600 melanomas with the use of specific inhibitors, tumor relapse occurs frequently. This study shows that exposure to Vemurafenib induces HO-1 upregulation in primary BRAF^V600 melanoma cell lines, limiting the efficacy of the drug. Induction of HO-1 impairs melanoma cell expression of specific ligands recognized by NK cells, reducing tumor immunogenicity. Importantly, HO-1 silencing and pharmacological inhibition restore expression of NK cell activator ligands. The findings highlight HO-1 as a new potential candidate to improve the efficacy of targeted therapies and NK cell-mediated killing of BRAF inhibitor-treated cells.

What's new?

While multiple myeloma (MM) remains an incurable disease, therapeutic advances have greatly improved its clinical management. Among the agents most effective against MM is the proteasome inhibitor bortezomib, though many patients eventually develop drug resistance. Here, decreased expression of the tumor suppressor NEDD4-1 was found to serve a key role in modulating MM sensitivity to bortezomib. Reduced NEDD4-1 expression was associated with increased PTEN/PI3K/Akt signaling and tumor growth. Experiments showed that NEDD4-1 normally binds directly to Akt, enhancing its ubiquitination and thereby exerting anti-MM effects. The data warrant further investigation of NEDD4-1 reactivation as a novel therapeutic strategy for MM.

What's new?

Removal of colorectal adenomas is an effective strategy to reduce colorectal cancer (CRC) mortality rates. However, as only a minority of adenomas progress to cancer, such strategies may lead to overtreatment. While high-risk adenomas, defined by specific DNA copy number aberrations, have an increased risk of progression, the mechanisms underlying colorectal adenoma-to-carcinoma progression remain unclear. This molecular characterization of colorectal adenomas, CRCs, and normal adjacent colon samples demonstrates that biological processes inherent to CRC are already more active in high-risk adenomas compared to low-risk adenomas. Moreover, the findings highlight POFUT1 and Notch signaling as potential drivers of colorectal tumor development.

What's new?

While regulatory T cells (Tregs) are essential for immune homeostasis, they pose a major barrier to the generation of effective antitumor immunity. The latter effect may be attributed to functionally diverse Treg subsets, though how these different subsets impact antitumor immunity remains unknown. Here, the authors identified an expanded population of highly activated human leukocyte antigen-DR (HLADRhi) Tregs with potent immunosuppressive activity in the blood and tumor tissues of cervical squamous cell carcinoma (CSCC) patients. Importantly, increased numbers of HLADRhi Tregs within tumors correlated with unfavorable outcomes. Thus, HLADRhi Tregs represent a potential biomarker and immune intervention target in CSCC.

What's new?

Previous evidence suggests that the antiviral helicase RIG-I bears tumor-suppressive activity. The clinical significance of RIG-I in gynecological cancer remains unclear, however. This single-center, retrospective, explorative biomarker study of 141 cases with epithelial ovarian cancer (OC) reveals the negative prognostic impact of RIG-I. RIG-I is overexpressed in OC tissue, particularly in the more aggressive type-II OCs, and is an independent prognostic marker for overall survival. RIG-I high-expressing tumors carry an interferon signature, linking RIG-I activation to a cancer microenvironment fostering tumor immune-evasion including upregulation of immune checkpoints. RIG-I expression may indicate high-risk OC patients who may benefit from immunotherapeutic intervention.

What's new?

In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectable CLM. The risk of metastatic recurrence remains high, however, and molecular markers for long-term therapeutic benefit are needed. In this prospective cohort study of patients who received oxaliplatin-HAI, the authors assessed serum FLT3LG to monitor intratumoural immune activity. All patients experienced FLT3LG increase during therapy, but only those who experienced a rapid and substantial tumour-directed immune response were alive 8–12 years later. Monitoring the immune response via serum FLT3LG may improve the selection of CLM patients for a curative-intent ablation procedure.

What's new?

The heterogeneity of colorectal cancer makes it difficult to determine patients with a poor prognosis or in need of advanced therapy. Here, the authors constructed and validated a novel 5-gene (SMAD4, MUC16, COL6A3, FLG, and LRP1B) mutational prognostic signature to identify high-risk patients with Stage III colon cancer. Mutations of these five genes may lead to loss of intestinal barrier integrity, translocation of gut bacteria, and deregulation of interleukins and extracellular-related genes. Combining tumor genetic characteristics with dynamic tumor microenvironment changes may lead to more promising prognostic signatures, which could help better select cancer patients for systemic therapy after surgery.

What's new?

Genetic rearrangements involving androgen-regulated transmembrane protease serine 2 and genes from the ETS transcription factor family (T2E), most commonly ERG and ETV1, occur in half of prostate cancers but are currently not considered in risk predictions. The authors integrate clinical and transcriptomic data from multiple studies and show that the prognostic value of biomarkers critically depends on the T2E-status. They identify five biomarkers that predict negative outcome exclusively in T2E-negative prostate cancers, which has implications for outcome prediction based on the molecular subtype.

What's new?

Approximately 30% of cervical cancer patients are resistant to chemoradiation therapy but the causes of treatment resistance are unknown. Here the authors profiled gene expression of paired human cervical tumors before and during chemoradiation. Patients who were resistant to treatment and died of the disease showed a decreased local immune response and increased expression of biosynthetic and mitotic pathways. The results point to a combined role of diminished antitumor immunity and maintained expression of human papilloma virus E6/E7 oncogenes in patients failing chemoradiation treatment.