What's new?

Neuroblastoma strikes early in life, which suggests an influence from risk factors that occur before birth. Here, the authors looked at parental smoking and alcohol drinking in a large population sample in France. Cases were collected by a nationwide registry, so the sample was very complete, and included 357 cases of neuroblastoma. The analysis revealed no association between maternal alcohol drinking and the cancer, nor between neuroblastoma and paternal smoking. They did identify a slight positive association with maternal smoking, and the effect was stronger if both parents smoked.

What's new?

Different subtypes of breast cancer may have different risk factors. These authors investigated the diversity of risk factors relevant in “less-developed” countries, where patients tend to be younger than in wealthier countries. They conducted a case-control study comparing risk factors for invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) among 2,000 women in Iran. Many risk factors differed between the two, indicating that IDC and ILC are etiologically different diseases. Factors associated with ILC included type 2 diabetes and history of miscarriage, while IDC risk factors included family history of breast cancer and age at first childbirth.

What's new?

Patients with neurofibromatosis type 1 (NF1) are known to have a high risk of various cancers. What has not been well-studied, however, are the types of cancers that are most common among children with NF1, and how those cancers impact mortality. In this cohort study, the authors found that malignancies do cause increased mortality in patients under age 20. Brain tumors in childhood and malignant peripheral nerve sheath tumors (MPNSTs) in adolescence are of particular concern. On the other hand, the risk of myeloid malignancies may be lower than previously assumed.

What's new?

In utero and post-natal environmental exposures have been suggested to play a role in childhood acute lymphoblastic leukaemia (ALL) alongside genetic abnormalities. The aetiology of the disease however remains unclear. Here, the authors investigated whether environmental exposures associated with increased ALL risk influence changes in DNA methylation patterns in offspring, and potential concordance with methylation changes in ALL disease. They found statistically significant directionally concordant changes in methylation for maternal radiation exposure, alcohol or sugary caffeinated drink intake, and childhood daycare attendance. DNA methylation may play a mediating role in the causal pathway linking ALL risk exposures with disease risk.

What's new?

The International Agency for Research on Cancer first concluded that consuming alcoholic beverages causes cancer in humans three decades ago. Despite downward trends, in Australia 28% of men and 10% of women consume more than the recommended 20 g of alcohol/day. This study shows that under a theoretical intervention that saw the abrupt and total cessation of alcohol consumption, up to 4% of alcohol-related cancers (~50,000 cancers) could be avoided over a 25-year period. Up to 2% would be avoided if no Australian adults exceeded national guidelines. Successful interventions to reduce alcohol intake could lead to significant reductions in cancer incidence.

What's new?

Women with dense breast tissue are at increased risk of breast cancer. Here, changes in mammographic density were investigated across birth cohorts in women enrolled in a breast cancer screening program in the Netherlands. The findings reveal an increase in the average fraction of dense tissue in the breast across cohorts. In particular, greater breast density was observed in a higher proportion of women in later-born than earlier-born birth cohorts. The increase was most significant among women in their early 50s and may be linked to a reported shift toward older age at menopause among women in Europe.

What's new?

Cancer of unknown primary (CUP) often presents a difficult challenge. Is it a recurrence of a previous cancer or metastasis of a new malignancy? In this study, the authors used targeted next-generation sequencing (NGS) to compare the genetic signatures of CUPs with signatures of the patients’ previous cancers. This pair-wise testing revealed that many CUPs are clonally related to previous cancers. In cases where CUPs are clonally independent from a previous malignancy, the authors note that this should raise a red flag of a potential cancer-predisposing germline mutation.

What's new?

Prostate carcinogenesis is driven by the accumulation of genetic and epigenetic aberrations, which regulate cancer cell transition between a stem- and non-stem-cell state and accelerate tumor evolution, leading to metastatic disease. Among the known critical epigenetic regulators of prostate cancer progression is EZH2, whose overexpression results in histone methylation-driven tumor cell de-differentiation. The present study demonstrates that EZH2 tightly cooperates with genome caretaker BRCA1 in the regulation of the phenotype and properties of prostate cancer stem cells, and that targeting these mechanisms may be a promising strategy for cancer treatment.

What's new?

Neuroendocrine tumors often metastasize to the liver but primary hepatic neuroendocrine tumors are extremely rare. Here the authors sequenced tumors from 22 patients in China and provide a first look at the mutational landscape of primary hepatic neuroendocrine tumors. The study points to a possible etiological role of the SET domain containing 1B gene (SETD1B) as it was among the most frequently mutated genes, a role that needs to be further explored.

What's new?

With increasingly comprehensive molecular profiling of cancers, the clinical interpretation of genetic alterations is becoming more and more challenging. Here the authors review several classifications for gene variant interpretation that were recently introduced to guide clinical management. They highlight shared features and differences and point out major influencing factors and unresolved issues that still need to be addressed. Based on this analysis, they propose a unified classification concept that may become broadly implemented when remaining issues are solved.

What's new?

Immunotherapies such as PD-1 and PD-L1 inhibitors have been highly effective in non-small cell lung cancer (NSCLC). But how do they compare with standard chemotherapy? And what happens when the two modalities are combined? In this indirect comparative review, the authors found that the efficacy of treatment with anti-PD-1/L1 antibodies was not any better than with chemotherapy. However, when patients were treated with combined immuno- and chemotherapy, they generally had significantly better outcomes, regardless of the level of PD-L1 expression by the tumor cells.

What's new?

Activating mutations in PIK3CA occur in 15 to 20% of advanced colorectal cancers (CRCs) and are associated with increased CRC-specific mortality. Hence, therapeutic inhibition of PIK3CA is a potential strategy for improving outcome in some CRC patients. Here, the dietary flavonoid fisetin, an inhibitor of the PI3K/AKT and mTOR pathways, when given in combination with 5-fluorouracil (5-FU), was found to significantly enhance apoptosis in PIK3CA-mutant CRC cells. Fisetin further prevented tumor formation in mice, and together with 5-FU reduced the total number of intestinal tumors. The data suggest that fisetin can broaden opportunities for 5-FU use against PIK3CA-mutant CRC.

What's new?

In Sweden, women who do not attend cervical screening are a minority. Long-term non-attenders are at higher risk of cervical cancer, however, and they are still typically offered annual renewed invitations as the rest of the population. In this head-to-head randomized health services study, sending self-sampling kits for human papillomavirus testing to long-term non-attenders increases attendance eleven times compared to routine practice. Offering the chance to order a kit online also raises attendance. Targeting long-term non-attenders to achieve increased participation in organized screening is feasible, scalable, and straight-forward to evaluate.

What's new?

Epidemiologic evidence relating fiber intake to colorectal cancer (CRC) remains inconclusive and data are still limited on different food sources and heterogeneity by tumor subsite and molecular profile. Here, total dietary fiber intake within the range of a typical American diet was not found to be associated with CRC risk after adjusting for other dietary and lifestyle factors. Higher intake of cereal fiber and whole grains was associated with lower CRC risk in men. Associations of dietary fiber and CRC did not vary by tumor subsites and molecular markers (microsatellite instability, BRAF mutation, CpG island methylator phenotype, and KRAS mutation).

What's new?

Disruptions in the expression of microRNAs contribute to the onset and progression of osteosarcoma. Here, the authors looked at miRNA-16, which is downregulated in osteosarcoma. One strand of the miRNA is the guide strand, while the other, “passenger” strand, is preferentially degraded. miR-16 originates from two different loci, and though both loci produce the same guide strand, they produce different passenger strands, miR-16-1-3p and miR-16-2-3p. All three microRNAs, the authors found, act as tumor suppressors and reduce metastasis in osteosarcoma. Boosting their expression sensitizes the cells to chemotherapy. The authors also identified FGFR2 as a target of miR-16-1-3p and miR-16-2-3p.

What's new?

Cancer-associated fibroblasts (CAFs) facilitate solid tumor progression, in part by generating tension force for extracellular matrix (ECM) remodeling. Of particular significance for ECM remodeling are myoblastic CAFs expressing cytoskeletal factors, namely smooth muscle actin (αSMA). Here, in fibrosis and breast cancer, fibroblast activation was found to be dependent on methylation induced by the transcription factor Snail1, which is required for organization of the contractile αSMA cytoskeleton. Methyltransferase inhibitors, including AMI1 and sinefungin, prevented fibrotic ECM generation by CAFs, wound-healing myofibroblasts, and idiopathic pulmonary fibrosis fibroblasts, warranting further investigation of this strategy as a means of treating cancer progression and fibrosis.

What's new?

A longstanding paradigm is that the increased severity and incidence of diffuse large B-cell lymphoma (DLBCL) in HIV-infected individuals compared to the general population is largely due to their highly impaired immune surveillance. However other mechanisms may also be involved. Here, the authors examine the expression of key players in known cancer signaling pathways to determine if there are non-immune related differences between DLBCL arising in HIV-infected and uninfected individuals. They show that HIV-related DLBCL tumors are more proliferative and have enhanced expression of DNA repair genes, particularly Fanconi Anemia DNA repair genes, and are more genomically stable than HIV-negative DLBCL.

What's new?

The heat shock protein HSP70 is overexpressed in B cells from chronic lymphocytic leukemia (CLL) patients but how it contributes to leukemogenesis is unknown. Here, the authors identify its interaction with the heat shock factor HSF1 as a possible mechanism. HSF1 is activated by the phosphoinositide-3-kinase–protein kinase B (PI3K/AKT) signal transduction pathway, and inhibition of PI3K reduced the expression of both HSP70 and HSF1. Similarly, HSP70 or HSF1 inhibition induced cell death, supporting the notion that both represent possible targets in CLL treatment.

What's new?

Colorectal cancer can lead to peritoneal carcinomatosis, a terminal condition with only palliative treatments such as intraperitoneal chemotherapy currently available. To date, no consensus on treatment parameters exists. Here, hypotonic stress improves platinum derivatives-induced cell death in human and murine colon cancer cell lines. A short exposition of cancer cells to oxaliplatin in hypotonic conditions was sufficient to induce immunogenic cell death. In a peritoneal carcinomatosis model, hypotonic conditions induced mice survival in a CD8⁺ T cell-dependent manner. The findings suggest that oxaliplatin in hypotonic conditions, in the absence of hyperthermia, should be considered by surgeons practicing intraperitoneal chemotherapy.

What's new?

Oxaliplatin, like other platinum drugs, kills cancer cells through induction of DNA damage, but immunomodulatory properties have also been described. Here the authors examined the immunopeptidome in oxaliplatin-resistant colon cancer cell lines. They identified novel MHC class II-restricted peptides derived from overexpressed tumor antigens and show that these are immunogenic in metastatic colorectal cancer patients treated with oxaliplatin. These findings may lead to new immunotherapeutic approaches to oxaliplatin-resistant colon cancer.

What's new?

Worm infections usually cause unwanted gastrointestinal diseases, but their effects on colorectal cancer development remain unclear. Here the authors demonstrate a notable anti-tumor effect of molecules derived from Taenia crassiceps (TcES), a tapeworm found in wolves. The secreted molecules downregulated proinflammatory and protumorigenic signaling, such as that mediated by STAT3, AKT and NF-kappaB, underscoring the role of inflammation in colorectal tumorigenesis and pointing to potential therapeutic implications of helminth-derived molecules.

What's new?

While several online tools capable of delivering a prognostic prediction for breast cancer already exist, no such genome-wide biomarker validation tool is available to evaluate and compare predictive biomarker candidates. Here, the authors combine multiple datasets to establish a sufficiently large breast cancer cohort with transcriptomic, anticancer treatment, and clinical response data. Then, they establish a framework capable of studying new candidate genes by mining this database and demonstrate the robustness of the pipeline by cross-validating an established set of resistance-associated genes. The novel online platform provides an easily accessed resource for researchers to validate and rank future biomarker candidates.

What's new?

For oropharyngeal squamous cell carcinoma (OPSCC), HPV status and mutational profile may affect prognosis. In this study, the authors found that certain mutations, including NOTCH1 mutations in HPV-positive OPSCC and SOX2 amplification in HPV-negative OPSCC, are associated with poor prognosis. These results indicate that sub-stratification of OPSCCs based on mutational signatures may help to predict outcomes and aid treatment planning. Data from various subsites (oropharynx, larynx and oral cavity) also suggest that HPV-negative OPSCC is a genetically heterogeneous disease.

What's new?

May germline variants in genes encoding DNA repair and detoxification enzymes predict response to preoperative capecitabine-based chemoradiotherapy in rectal cancer? In response, the authors analyzed 66 germline variants of 10 candidate genes. Among them, ERCC1 rs10412761 and ERCC2 rs1799787 are associated with tumor response in patients treated with preoperative capecitabine-based chemoradiotherapy. For the first time, they described a predictive effect of XPA rs3176683 that may identify patients who benefit from adding oxaliplatin to capecitabine-based chemoradiotherapy.