In a new study which recently published in the Journal Epidemiology, investigators reported that head and neck cancers (HNC) in young adults are more likely to be as a result of inherited factors rather than lifestyle factors such as smoking or drinking alcohol, after analyzing 25 case-control studies.

Annually, there is around 550,000 new cases of HNC diagnosed worldwide, with an increased incidence in young adults being reported.

In particular, reports indicate an increase in tumours affecting the tongue and oropharynx among young adults in Europe, the United States, India, and China.

Investigators pooled data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium to compare the role of major risk factors and family history in HNC for young adults (45 years of age or younger) and older adults (over 45 years of age). Participants were surveyed about their history of cigarette smoking, alcohol drinking, and diet, as well as family history of cancer. In total, there were 2,010 cases and 4,042 controls in young adults, and 17,700 cases and 22,704 controls in older adults.

The attributable fraction for smoking on the risk of HNC was 20% in young women, 49% in older women, 46% in young men, and 64% in older men. The attributable fraction for drinking alcohol on the risk of HNC was 5% in young women, 20% in older women, 22% in young men, and 50% in older men. Eating a diet rich in fruits and vegetables was shown to be inversely associated with the risk of HNC in both age groups.

The study showed that family history of any type of cancer was directly associated with HNC risk only among the older group, but a family history of early-onset cancer was associated with HNC risk only in young adults. The attributable fraction for family history of early onset cancer on the risk of HNC was 23% in young adults and 2% in older adults.

A researcher said: “To our knowledge, this is the largest study to evaluate the role of the major risk factors for HNC in young adults as well as to compare risks in younger and older patients. The large sample size allowed us to elucidate any differences in the role of risk factors in HNC in young adults according to age group, sex and cancer sub sites.

He added “Although they were less likely to be drinkers and/or smokers, alcohol consumption was a risk factor for HNC in young adults. However, a stronger association with heavy drinking was observed for the older group. Our results also indicate that the inverse association with fruit and vegetable intake is similar among young and older populations. Young adults were more likely to have been diagnosed with oral and oropharynx cancer than older adults. Also, early onset cancer in the family was associated with HNC risk only among young adults.

Key messages:

· Cigarette smoking and alcohol drinking were associated with a risk of HNC in younger adults (age 45 or less) and older adults (over 45), although in younger adults the association was weaker, probably due to shorter exposure.

· The protective effects of a diet rich in fruits and vegetables on HNC was consistent across younger and older people

· Family history of early onset cancers was associated with an increased risk of HNC in young adults, but not older ones

Reference:

Cohort Profile Update: The TRacking Adolescents’ Individual Lives Survey (TRAILS). International Journal of Epidemiology, 2014; DOI: 10.1093/ije/dyu225

Recently, Molecular Therapy published online a latest progress on HDAC inhibitors to treat breast cancer.

Histone deacetylase inhibitors (HDACi) are novel clinical anticancer drugs that inhibit HDAC gene expression and induce cell apoptosis in human cancers. Nevertheless, the detailed mechanism or the downstream HDAC targets by which HDACi mediates apoptosis in human breast cancer cells remains unclear. Here, the study shows that HDACi reduce tumorigenesis and induce intrinsic apoptosis of human breast cancer cells through the microRNA miR-125a-5p in vivo and in vitro. Intrinsic apoptosis was activated by the caspase 9/3 signaling pathway. In addition, HDACi mediated the expression of miR-125a-5p by activating RUNX3/p300/HDAC5 complex. Subsequently, miR-125a-5p silenced HDAC5 post-transcriptionally in the cells treated with HDACi. Thus, a regulatory loop may exist in human breast cancer cells involving miR-125a-5p and HDAC5 that is controlled by RUNX3 signaling. Silencing of miR-125a-5p and RUNX3 inhibited cancer progression and activated apoptosis, but silencing of HDAC5 had a converse effect. In conclusion, the research demonstrates a possible new mechanism by which HDACi influence tumorigenesis and apoptosis via downregulation of miR-125a-5p expression. This study provides clinical implications in cancer chemotherapy using HDACi.

Reference:

Tsung-Hua Hsieh, Chia-Yi Hsu, et al. HDAC Inhibitors Target HDAC5, Upregulate MicroRNA-125a-5p, and Induce Apoptosis in Breast Cancer Cells [J].Molecular Therapy, 2014.247.

The protein kinase C(PKC) family has been intensely investigated in the context of cancer since the discovery that it is a receptor for the tumor-prompting phorbol esters. This led to the dogma that activation of PKC by phorbol esters promotes carcinogen-induced tumorigenesis, yet targeting PKC in cancer has been unsuccessful. There is the research team from UCSD trying to figure out the reason. Their study was published in Cell.

The PKC family contains nine genes that have many targets and thus diverse cellular functions, including cell survival, proliferation, apoptosis, and migration. PKC has proved an intractable target in cancer therapeutics and is frequently mutated in human cancers.

In this study, to uncover whether loss or gain of PKC function contributes to cancer progression, researchers selected mutations throughout the primary sequence and family membership and assessed their functional impact. Specifically, they asked how these cancer-associated mutations alter the signaling output of PKC using their genetically encoded reporter, C kinase activity reporter(CKAR). Characterization of 46 these mutations revealed that most reduced or abolished PKC activity and none were activating.

Bioinformatic analysis of all PKC mutations revealed genes and tumor suppressors known to be regulated by PKC. Their data are consistent with PKC isozymes functioning generally as tumor suppressors, reversing the paradigm that their hyperactivation promotes tumor growth.

Reference:

Antal C E, Hudson A M, Kang E, et al. Cancer-Associated Protein Kinase C Mutations Reveal Kinase’s Role as Tumor Suppressor[J]. Cell, 2015.

Most patients inherit the syndrome through a maternal repeat expansion mutation that transcriptionally silences the FMR1 gene and results in loss of the gene product, FMRP. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation.

After sequencing 963 developmentally delayed males, we identified a patient with an R138Q missense mutation in the FMR1 gene.

The R138Q mutation does not impair FMRP’s postsynaptic function as a translation regulator, as evidenced by rescue of AMPA receptor trafficking, intact polyribosome association, and mRNA pull-down.  Expression of the mutant FMRP is unable to rescue structural defects at the neuro-muscular junction in fragile x mental retardation 1 deficient Drosophila.

We show that R138Q is a partial loss-of-function mutation that specifically impairs a presynaptic FMRP function while preserving the translation regulation capabilities of FMRP. Besides, the R138Q mutation also disrupts FMRP’s interaction with the large-conductance calcium-activated potassium (BK) channels that modulate AP width.

In summary, our study of the R138Q missense mutation in FMR1 provides a first step in opening the door of the domain-specific functions of FMRP in pre- and postsynaptic compartments, and their contribution to various elements of FXS pathophysiology.

One in two people will develop a cancer at some point in their lives, experts now estimate. Previous calculations that indicated cancer will affect just over one in three people were underestimating the scale of the disease, according to a new analysis by Cancer Research UK. However, because of advances in treatment and early detection, more people are now surviving cancer.

Two-thirds of the increase in risk can be attributed to the fact we are now living longer, and cancer is a disease that becomes more likely the older we get. The additional third is down to changes in lifestyle, CRUK said. The study calculates the lifetime risk of cancer for men born in the UK in 1960 is 53.5 per cent and for women 47.55 per cent, averaging at 50.5 per cent. The risk is likely to increase for people born after 1960, and CRUK said it was confident in predicting that this meant at least half the population can now expect to get cancer.

Recent estimates suggest that half of people who get cancer now survive the disease for 10 years or more – so it is projected that despite more cases, the number of deaths attributable to cancer will remain stable at around one in four.

Changes in lifestyle that have contributed to the increase in cancer risk include an increase in obesity, which is linked to a number of cancers and is projected to continue rising. Higher consumption of red and processed meats is also linked to a rise in bowel cancer. Other factors include an increase in the culture of using sunbeds and sunbathing, which has increased incidence of skin cancer, while women having babies later and breastfeeding less is also raising their chance of developing breast cancer. As well as this, more cancers are being detected by screening programmes.

Scientists at The Institute of Cancer Research, London, have uncovered several new genetic mutations that drive testicular cancer, and also identified a gene which may contribute to tumours becoming resistant to existing treatment. The finding, based on the whole-exome sequencing technology, published in the journal Nature Communications.

The research is the first to use state-of-the-art sequencing technology to look into the detail testicular germ cell tumours from 42 patients at the Royal Marsden NHS Foundation Trust, which make up the vast majority of testicular cancers and are the most common cancers in young men.

In the research, they uncovered a number of new chromosome duplications and other abnormalities that could result in the development of this cancer. For instance, they found defective copies of a DNA repair gene called XRCC2 in a patient who had become resistant to platinum-based chemotherapy, as well as verifying the link between XRCC2 and platinum resistance by sequencing an additional sample from another platinum-resistant tumour.

Although generally testicular cancer responds well to treatment, resistance to platinum-based chemotherapy is linked to a poor long-term survival rate. The research provides a clue to why around 3 percent of patients develop resistance to platinum chemotherapy, as well as new insights into testicular germ cell tumours generally.

A researcher, involved in this study, said ” we have identified new potential driver mutations for this type of cancer in the largest comprehensive sequencing study of testicular tumours published to date, and provided new evidence of a link between mutations in the gene XRCC2 and platinum treatment-resistant tumours. ”

He added, “we now need additional studies with a larger number of patients, focusing in particular on platinum-resistant tumours, to help our discoveries lead to new options for those unlucky men whose cancer progresses in spite of the best available treatments.

Another researcher said, ” survival rates for testicular cancer are generally very good, but a subset of men don’t respond to standard platinum chemotherapy, and the new research has identified a possible genetic cause for that drug resistance. Knowing which are the key genes driving a cancer’s development or helping it dodge the effects of chemotherapy is crucial to help us use current drugs more effectively and to design the next generation of drugs for personalized medicine.”

Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute myeloid leukemia (AML) cells through production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). The study performed a large-scale RNA interference (RNAi) screen to identify genes that are synthetic lethal to the IDH1R132H mutation in AML and identified the anti-apoptotic gene BCL-2.IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models.

This sensitization effect was induced by (R)-2-HG-mediated inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain (ETC); suppression of COX activity lowered the mitochondrial threshold to trigger apoptosis upon BCL-2 inhibition. The research indicate that IDH1/2 mutation status may identify patients that are likely to respond to pharmacologic BCL-2 inhibition and form the rational basis for combining agents that disrupt ETC activity with ABT-199 in future clinical studies.

Reference:

Steven M Chan, Daniel Thomas,et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia [J]. Nature medicine;2015.doi:10.1038/nm.3788.

Researchers from University of Brown have found that by decreasing or blocking specific protein level, two different types of cancer cells could be suppressed to metastasize in mice. This protein is common in human and other animals. The imbalance of the protein contributes to cancer metastasis. This study was published in Cancer Research.

Chitinase 3-like-1(Chi3L1) is the prototypic mammalian CLP. It was originally discovered in mouse breast cancer cells. It is now known to be expressed by a variety of cells including macrophages, neutrophis, epithelial cells, smooth muscle cells and chondrocytes and is stimulated by a number of mediators including IL-12, IL-6, IL-1β, and IFNγ. The Chi3L1 is induced in cancers and portends a poor prognosis, but whether it contributes to cancer progression is unknown.

In this study, scientists hypothesized that host Chi3L1 plays an essential role in the pathogenesis of malignant melanoma and that interventions that alter the induction Chi3L1 decrease the metastatic spread of this tumor. To test this hypothesis they characterized the ability of B16-F10 melanoma cells to stimulate Chi3L1 in wild type mice and their ability to generate pulmonary metastasis in wild type(WT) mice and mice with null mutations of Chi3L1.

Their studies highlight a novel host pathway in which Sema7a stimulates the production of Chi3L1 by interacting with β1 integrin and inhibits Chi3L1 by interacting with Plexin C1. They also demonstrate that the host Sema7a- Chi3L1-IL-13Rα2 axis plays a critical role in the generation of a metastasis-permissive pulmonary microenvironment leading to melanoma lung metastasis.

Reference:

Ma B, Herzog E L, Lee C G, et al. Role of Chitinase 3-like-1 and Semaphorin 7A in Pulmonary Melanoma Metastasis[J]. Cancer research, 2014: canres. 3339.2013.

Scientists from free University of Brussel have indicated that Twist1 could regulate the skin cancer‘s propagation and the function of cancer stem cells to suppress the deterioration process. They use transgenetic mice as the subjects, successfully identified the molecular of cancer’s initiation, propagation, and deterioration. This study was published in Cell Stem Cell.

The epithelial-to-mesenchymal transition(EMT) is a cellular process during which epithelial cells lose their adhesion properties and acquire mesenchymal features allowing their migration and invasion.Twist1, a basic-helix-loop-helix transcription factor, is one of the EMT-inducer prototypes. Twist1 deletion in mice leads to failure in neural tube closure associated with defects in the formation of the head mesenchyme and limb buds.

Mechanistically, Twist1 overexpression has been shown to rescue Myc-induced apoptosis through inhibition of p53. However, to what extent these different functions of Twist1 including its effect on EMT, stemness, proliferation, and apoptosis are functionally linked or whether these functions are independently regulated by Twist1 remians unknown.

In this study, using conditional deletion of Twist1 at different stages of skin tumorigenesis, researchers investigated the different functions of Twist1 and their interdependence during tumor initiation, maintenance, propagation, and malignant progression. They found that Twist1 is expressed at the earliest step of tumorigenesis and is essential for the initiation and maliganant progression of skin tumors in a gene-dosage-dependent manner. Conditional deletion of Twist1 in pre-existing tumors demonstrates the essential role of Twist1 in tumor maintenance. Twist1 inhibits oncogene-induced apoptosis in a p53-dependent manner, while the ability of Twist1 to promote tumor cell proliferation and propagation is regulated by a p53-in-dependent mechanism. Strikingly, these oncogenic functions of Twist are not dependent upon its ability to induce EMT.

Reference:

Beck B, Lapouge G, Rorive S, et al. Different Levels of Twist1 Regulate Skin Tumor Initiation, Stemness, and Progression[J]. Cell stem cell, 2015, 16(1): 67-79.