Cancer epigenetics: a perspective on the role of DNA methylation in acquired endocrine resistance

Epigenetic mechanisms, including DNA methylation, are responsible for determining and maintaining cell fate, stably differentiating the various tissues in our bodies. Increasing evidence shows that DNA methylation plays a significant role in cancer, from the silencing of tumor suppressors to the activation of oncogenes and the promotion of metastasis. Recent studies also suggest a role for DNA methylation in drug resistance. This perspective article discusses how DNA methylation may contribute to the development of acquired endocrine resistance, with a focus on breast cancer. In addition, we discuss DNA methylome profiling and how recent developments in this field are shedding new light on the role of epigenetics in endocrine resistance. Hormone ablation is the therapy of choice for hormone-sensitive breast tumors, yet as many as 40% of patients inevitably relapse, and these hormone refractory tumors often have a poor prognosis. Epigenetic studies could provide DNA methylation biomarkers to predict and diagnose acquired resistance in response to treatment. Elucidation of epigenetic mechanisms may also lead to the development of new treatments that specifically target epigenetic abnormalities or vulnerabilities in cancer cells. Expectations must be tempered by the fact that epigenetic mechanisms of endocrine resistance remain poorly understood, and further study is required to better understand how altering epigenetic pathways with therapeutics can promote or inhibit endocrine resistance in different contexts. Going forward, DNA methylome profiling will become increasingly central to epigenetic research, heralding a network-based approach to epigenetics that promises to advance our understanding of the etiology of cancer in ways not previously possible.

Approach to early-onset colorectal cancer:Clinicopathological,familial,molecular and immunohistochemical characteristics

AIM:To characterize clinicopathological and familial features of early-onset colorectal cancer(CRC) and compare features of tumors with and without microsatellite instability(MSI).METHODS:Forty-five patients with CRC aged 45 or younger were included in the study.Clinical information,a three-generation family history,and tumor samples were obtained.MSI status was analyzed and mismatch repair genes were examined in the MSI families.Tumors were included in a tissue microarray and an immunohistochemical study was carried out with a panel of selected antibodies.RESULTS:Early onset CRC is characterized by advanced stage at diagnosis,right colon location,low-grade of differentiation,mucin production,and presence of polyps.Hereditary forms represent at least 21% of cases.Eighty-one percent of patients who died during followup showed a lack of expression of cyclin E,which could be a marker of poor prognosis.β-catenin expression was normal in a high percentage of tumors.CONCLUSION:Early-onset CRC has an important familial component,with a high proportion of tumors showing microsatellite stable.Cyclin E might be a poor prognosis factor.

Heat shock factor 1 is a direct anti-amyloid factor:connecting neurodegeneration and uncontrolledgrowth

Worldwide,more than 40 million people are afflicted with Alzheimer's disease(AD)(Esquerda-Canals et al.,2017).AD is a devastating neurodegenerative disroder characterized by progressive decline in cognitive abilities.A hallmark of AD and other neurodegenerative disorders in humans is the aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions(Iadanza et al.)。

Cervical cancer:a tale from HPV infection to PARP inhibitors

Globally,cervical cancer(CxCa)ranks 4th common cancer among females and led to 569,847 incidences and 311,365 deaths in 2018.80%of CxCa cases occur due to persistent infection with a high-risk subtype of human papillomavirus(HPV-16 and 18).Smoking,high par-ity,and co-infection with type 2 herpes simplex or HIV are other known risk factors for CxCa.Major histological subtypes are squamous(70%)and adenocarcinoma(25%).Presently,concur-rent radiation plus cisplatin(CDDP)-based chemotherapy is the standard treatment for CxCa patients.However,CDDP resistance and toxic side effects limit its efficacy,leading to a poorer response rate and an expected overall survival ranging from 10 to 17.5 months.Reduced drug uptake,increased DNA damage repair,increased CDDP inactivation,and overexpressed Bcl-2 or caspase inhibition,are primarily accountable mechanisms for CDDP resistance and improving CDDP’s efficacy remains the major challenge.Poly(ADP-ribosyl)polymerase-1,an effective mediator of nucleotide excision repair pathway,is involved in DNA repair as well as maintaining genomic stability and is significantly expressed in malignant lymphomas,hepa-tocellular-,cervical-and colorectal carcinoma,which has been approved effective in mainte-nance therapy and may serve as an effective target to enhance CDDP sensitivity in CxCa.Here,we summarize the etiology and epidemiology of and treatment for CxCa,the mechanism responsible for chemotherapy resistance,PARP inhibitor as a possible therapy for CxCa,and other possible chemotherapeutic options for CxCa treatment.

遗传性非息肉性结肠直肠癌综合征的风险:发病年龄推迟

Background & Aims: Mutations in the mismatch repair genes cause hereditary nonpolyposis colorectal cancer (HNPCC) syndrome and convey high lifetime cancer risks for colorectal (CRC) and endometrial cancer. Currently, cancer risks for individuals with HNPCC are based on data from clinically ascertained families. The purpose of this study was to re-examine the penetrance in HNPCC using a comprehensive dataset from a geographically defined region. Methods: A combined dataset of 70 HNPCC families ascertained by traditional high-risk criteria and by molecular screening comprising 88 probands and 373 mutation-positive family members was used. Statistical methods were modified survival analysis techniques. Results: In mutation-positive relatives (excluding probands), the median age at diagnosis of CRC was 61.2 years (confidence interval [CI], 56.3- 68.0 y). The lifetime risk for CRC was 68.7% (CI, 58.6% - 78.9% ) for men and 52.2% (CI, 37.6% - 66.9% ) for women. Considering only probands, the median age at diagnosis of CRC was 44.0 years (CI, 41.0- 46.3 y). Median age of onset of EC was 62.0 years (CI, 55.9 y to an upper limit too high to calculate)with a lifetime cancer risk of 54% (CI, 41.9% - 66.1% ). Conclusions: A markedly later age of onset for CRC at 61 y than previously reported (? 44 y) is suggested, resulting mainly from a more rigorous method of analysis in which all gene-positive individuals (both affected and unaffected with cancer) are considered. Lifetime cancer risks may be lower for CRC and endometrial cancer than presently assumed. If confirmed, these data suggest a need to alter counseling practices, and to consider HNPCC in older individuals than before.

Research highlights from ACACR members

Dr.Chuan He at The University of Chicago and his collaborator at the ShanghaiTech University found that N6-methyladenosine(m6A)facilitates hippocampus-dependent learning and memory through YTHDF1,a m6A binding protein that enhances protein synthesis in a neuronal-stimulusdependent manner.https://www.nature.com/articles/s41586-018-0666-1.