What's new?

While total homocysteine (tHcy) levels are an important biomarker of B-vitamin status and may be predictive for colorectal cancer (CRC) risk, they are influenced by a variety of factors, such as age, sex, and lifestyle. Here, tHcy was compared to ratio-based biomarkers of total B-vitamin status to assess functionality and relation to CRC risk. In CRC patients and controls, the ratio-based markers outperformed tHcy as indicators of total B-vitamin status. Their association with CRC risk was similar to that of total B-vitamin status. Ratio-based biomarkers could fill a valuable role in assessments of functional B-vitamin levels and disease risk.

What's new?

A possible association between the insulin-like growth factor (IGF-I) and the risk of melanoma has been proposed, but with inconclusive results so far. In this prospective study, the authors found no evidence for an association between circulating IGF-I concentrations and melanoma risk. Although details on major risk factors like sun exposure were missing, the large sample size with more than 1000 incident melanoma cases underscores the relevance of the finding.

What's new?

Studies showing a relationship between increased cancer risk and weight gain and obesity in adulthood have focused primarily on Western countries. Compared to Western women, however, Asian women generally have lower rates of overweight and obesity. Nonetheless, in the present study, weight gain since age 20 was associated with increased risk of obesity-related cancers in Japanese women. Risk was elevated particularly for colon cancer, postmenopausal breast cancer, and endometrial cancer. No significant associations were found for Japanese men. The results highlight the importance of maintaining standard body weight in adulthood for the prevention of obesity-related cancers in Japanese women.

What's new?

More than four-fifths of patients with pancreatic cancer present with locally advanced, inoperable (LAPC) or metastatic (MPC) disease at diagnosis. Beyond clinical trials, relatively little data is available on survival outcomes for these patients. Here, real-world data, derived from an unselected cohort of 1,174 patients enrolled between 2014 and 2017 in a prospective study in Germany, show that the vast majority of first-line therapies given to LAPC/MPC patients consisted of either gemcitabine monotherapy, nab-paclitaxel plus gemcitabine, or FOLFIRINOX. About 40 percent of the patients received second-line therapy. Overall cohort survival was comparable to that reported for randomized clinical trials.

What's new?

Statins are widely used to lower blood cholesterol and reduce risk for cardiovascular diseases, but attention has recently focused on a role in cancer prevention or therapy. Data from existing studies on ovarian cancer prevention by statins are mixed, however. In this large case–control study spanning 16 years, statin use was associated with a significantly reduced risk for epithelial ovarian cancer, especially of mucinous histology. The association was not confounded by risk factors for ovarian cancer, indications for statin use, or medications used concomitantly. It is noteworthy that the association became apparent within a decade of the introduction of statins.

What's new?

Breast ultrasound can be a useful addition to mammogram for breast cancer screening, in certain cases. Currently, mammography is considered the most sensitive screening technique for early breast cancer detection, but dense breast tissue can make it harder for mammography to detect cancer. These authors compared mammography, ultrasound, and MRI for cancer diagnosis among various risk groups. For women with BRCA mutations, MRI gave the best results, with 94% sensitivity. In high risk patients, mammogram combined with twice-yearly ultrasound achieved 100% sensitivity. In women considered intermediate risk, however, mammogram without ultrasound provided sufficient sensitivity.

What's new?

Do cadmium and lead cause breast cancer? These two notorious toxic metals tend to linger in the body, and both are classified as carcinogens. Ubiquitous environmental contaminants, they accumulate in women particularly, due to their lower iron levels. Yet no definitive link has been demonstrated between cadmium or lead and breast cancer. Here, the authors analyzed three case–control studies. Across the three studies, a wide range of exposure levels was represented, and each study included a large number of participants. The meta-analysis revealed no association between high levels of cadmium or lead and breast cancer risk.

What's new?

Evaluations of organized screening programmes for cervical cancer (CC) in Europe remain inadequate. Here the authors report a 40% decrease in annual CC incidence following the introduction of a regional screening programme in 1998. Annual CC incidence rates expected in the absence of screening were robustly determined by two different methods. The programme is now transitioning to screening for human papillomavirus infection.

What's new?

Mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are associated with poor outcome and reduced survival in different cancers. Here, subtypes of these mutations were investigated for their impact on survival specifically in melanoma. Among patients with stage I/II melanoma, those with the −138/−139 CC > TT TERT alteration, which occurs primarily in skin cancers, showed the poorest disease-free and melanoma-specific survival. The impact on survival was significantly worsened when the −138/−139 CC > TT TERT alteration was combined with BRAF/NRAS mutations. The findings could have implications for melanoma patients treated with MAP-kinase inhibitors, which interact with BRAF/NRAS signaling networks.

What's new?

Double-strand DNA breaks (DSBs) initiate gene amplification, a phenomenon associated with therapeutic resistance in cancer that involves two topographical structures, double minutes (DMs) and homogeneously staining regions (HSRs). Whether DSB repair pathways, particularly homologous recombination (HR), also influence gene amplification is unknown. Here, in methotrexate-resistant colon cancer cells, HR inhibition effectively reduced gene amplification, specifically the DM-form, by blocking DM formation and promoting DM exclusion via micronuclei. HR inhibition had no influence on the HSR-form of gene amplification. Loss of gene amplification by HR inhibition, through partial reversal of methotrexate resistance, may contribute to improved chemotherapeutic outcome.

What's new?

Melanoma is a leading cause of cancer death in adolescents and young adults (AYA) in Western countries. Little is known, however, about the contribution of genetic factors to AYA melanoma risk. Here, genomic analyses show that AYA melanomas, similar to adult cutaneous melanomas, have a high mutation burden, with mutations indicative of ultraviolet radiation (UVR) damage. AYA tumors further exhibited increased somatic mutation rates in key melanoma driver genes and had a higher proportion of non-UVR mutation signatures relative to adult melanomas. Germline variants identified in an AYA patient subset suggests a role for dysfunctional DNA maintenance in AYA melanoma susceptibility.

What's new?

Non-small cell lung cancer is a tumor with extensive histological heterogeneity caused by spatial and temporal genomic changes, posing major challenges for the treatment and prognosis of patients with lung adenocarcinoma. To date, however, little is known about epigenomic intratumor variability. In our study, the authors investigate the spatial variations of somatic DNA methylation and copy number aberrations in comparison with histological growth patterns of seven resected lung adenocarcinomas and six corresponding lymph node metastases. The results suggest that epigenomic variation contributes considerably to the molecular and phenotypic heterogeneity and evolution of lung adenocarcinomas and lymph node metastases.

What's new?

Chronic infection with oncogenic human papillomavirus (HPV) is strongly associated with uterine cervical cancer. Several commercial HPV-DNA tests are currently available, but HPV-mRNA may represent a more promising alternative target for cervical screening tests as it marks transcriptionally-active HPV infection. Here, the authors tested for HPV-mRNA and HPV-DNA in cytology samples biobanked up to 7 years before cervical intraepithelial neoplasia (CIN) 3+. Sensitivity of HPV-mRNA was non-inferior compared to HPV-DNA, regardless of cytology result in women <30 and ≥30 years of age. The finding could have important global public health implications by allowing more precise and specific HPV screening tests.

What's new?

The regions in the world with high cervical cancer burden are also the regions with a high burden of human immunodeficiency virus (HIV) infection. Here the authors report incidence rates of cervical abnormalities in HIV-infected women in India. HIV-infected women with human papillomavirus infection at baseline had a 57 times increased risk of developing cervical intraepithelial neoplasia during follow-up, underscoring the urgent need for regular cervical cancer screening in HIV treatment platforms.

What's new?

Inhibitors of the nuclear enzyme poly (ADP-ribose) polymerase (PARP) are promising agents for the treatment of non-small cell lung cancer (NSCLC). Whether their effectiveness is augmented by combination with other therapies, however, remains unclear. In this study, PARP inhibitors were found to act synergistically against NSCLC cells and xenografts when combined with gemcitabine. Synergistic DNA damage induced by the combination treatment was dependent on the stalling of replication forks by gemcitabine. The failure of replication forks to recover in the presence of PARP inhibition likely leads to an increase in double-strand DNA breaks, resulting in greater cancer cell death.

What's new?

Small-cell lung cancer (SCLC) is a highly aggressive and metastatic neuroendocrine carcinoma with no therapeutic improvement in decades. SSTR2 is canonically viewed as an inhibitory receptor on cell growth, but trials have shown poor clinical responses to agonists. This work shows that SCLC cell lines and primary tumors express high levels of SSTR2, and high SSTR2 expression is correlated with worse patient survival in SCLC. Furthermore, SSTR2 signaling rather serves as an important protumor survival signal in a subset of SCLC cell lines/tumor tissues, with loss of SSTR2 expression leading to profound effects on apoptosis with significant clinical implications.

What's new?

Metabolic syndrome (MeS) increases prostate cancer (PCa) risk and aggressiveness. Previously, the authors identified CTBP1, a transcriptional co-repressor of tumor suppressor genes, as a novel link associating both diseases. Here, they investigate the underlying mechanism based on aromatase and estrogen synthesis regulation. They found that CTBP1 and MeS modulate aromatase transcription, which elevates estrogen concentrations in prostate tumors. Additionally, MeS induces inflammation of the white adipose tissue, leading to a proinflammatory phenotype and increased serum estradiol concentrations which impact PCa growth. This study describes for the first time a novel CTBP1/CYP19A1/estradiol axis as an important link between MeS and PCa.

What's new?

The reprogramming of neutrophils into an immunosuppressive phenotype is known to occur in the solid tumor microenvironment. Our study shows that this phenomenon also exists in a hematological disease, wherein an increased percentage of circulating immunosuppressive neutrophils, namely the CD16^highCD62L^dim subset, was identified in chronic lymphocytic leukemia (CLL) patients. Cooperative effects of the soluble factors IL-10 and TGFβ, released from leukemic B cells, appear to play a role in neutrophil reprogramming into the CD16^highCD62L^dim subset. The findings shed light on the potential contribution of neutrophil reprogramming to the impaired immune response exhibited by CLL patients.

What's new?

Donor lymphocyte infusion (DLI) bears curative potential for leukemia patients due to the graft-versus-leukemia (GvL)-effect, but it may also cause life-threatening graft-versus-host disease (GvHD). A better understanding of specific T cell responses would help increase GvL potency without raising the risk of GvHD. Here, the authors assessed the frequency and diversity of leukemia-associated antigen (LAA)-specific cytotoxic T cells in 11 patients. An increase in specific CTL responses against several LAA following DLI was detected. The enhanced LAA diversity in T cell responses and the decreasing number of regulatory T cells may contribute to the clinical outcome of DLI treated patients.

What's new?

Immune checkpoint inhibitors (ICIs) block checkpoint proteins on immune cells and certain cancer cell types, thereby facilitating immune attack on cancer cells. Some cancer patients, however, readily develop resistance to ICIs. In the present study, the authors analyzed peripheral blood samples from patients with newly diagnosed, untreated metastatic melanoma, revealing that the loss of senescence markers on peripheral blood mononuclear cells is correlated with clinical response to ICI therapy. Affected surface markers included CD27, CD28, Tim-3 and CD57. The findings could have implications for the development of methods to identify ICI non-responders, helping avoid unnecessary toxicity.

What's new?

In prostate cancer survivors, rising PSA levels can presage a return of the tumor. Much research has gone into identifying biomarkers associated with biochemical relapse, but often these biomarkers aren't individually useful for predicting survival. In this study, the authors surveyed a variety of available biomarkers, to test how well they predicted metastatic relapse. While they found seven markers to be associated with biochemical relapse, only two functioned as key predictors of metastasis. The authors propose that biochemical relapse is not a good surrogate for metastasis.

What's new?

Lymph node metastasis (LNM) is the single most significant determinant of disease recurrence and prognosis in esophageal squamous cell carcinoma (ESCC). However, there currently is a paucity of reliable molecular signatures that can identify LNM is ESCC patients. Here, based on genome-wide methylation profiling of ESCC patients, the authors developed a comprehensive methylation signature to distinguish LNM cases. The lymph node metastasis-associated signature, or LNAS, showed high specificity in independent training and validation cohorts. In the training cohort, high LNAS risk score was further associated with worse disease-free survival. The novel signature could be clinically valuable, helping predict ESCC prognosis.

What's new?

Programmed death (PD)-1 immune checkpoint inhibitors are used clinically for the treatment of advanced nonsmall cell lung cancer (NSCLC). Little is understood, however, about associations between immune mediators and clinical outcome in anti-PD-1-treated NSCLC patients. Here, in two independent NSCLC cohorts, progression-free survival was significantly associated with decreasing levels of the cytokine CXCL2 and increasing levels of matrix metalloproteinase-2 (MMP2) after anti-PD-1 treatment. Over the course of anti-PD-1 therapy, these changes were associated with improved clinical outcome. CXCL2 and MMP2 can be measured by minimally invasive procedures, making them promising tools for clinical outcome monitoring in anti-PD-1-treated NSCLC patients.

What's new?

Epigenetic therapy induced by dietary components has strong potential in cancer prevention. Olive oil presents some chemopreventive activity in colon cancer, but its potential role in epigenetic therapy remains unclear. This study shows that olive oil prevents colon cancer by reducing the expression of inflammatory and angiogenic genes and enhancing apoptotic genes and miRNAs expression in a preclinical model. Moreover, the interface between DNA methylation and miRNA expression associates with transcriptional silencing of genes encoding for altered cellular pathways in colon cancer. Olive oil acts as a demethylating agent for tumor suppressor genes and hypermethylating agents for tumor promoter genes.

What's new?

In order to provide personalized therapy to patients with pathogenic BRCA1/2 variants, it's necessary to find them. Currently, patients are screened based on risk factors, such as family history. How many BRCA1/2 carriers are missed? What if everyone were screened? Here, the authors sequenced DNA from more than 5,000 Swedish breast cancer patients looking for pathogenic BRCA1/2 variants, and they found 92 carriers. Of these, only 35 had been identified by clinical screening. 60% of cancer-causing BRCA variants had not been detected. This is one of the largest population-based studies to date examining BRCA1/2 prevalence.