RESUMO
In addition to mutations in genes, aberrant enhancer element activity at non-coding regions of the genome is a key driver of tumorigenesis. Here, we perform epigenomic enhancer profiling of a cohort of more than forty genetically diverse human colorectal cancer (CRC) specimens. Using normal colonic crypt epithelium as a comparator, we identify enhancers with recurrently gained or lost activity across CRC specimens. Of the enhancers highly recurrently activated in CRC, most are constituents of super enhancers, are occupied by AP-1 and cohesin complex members, and originate from primed chromatin. Many activate known oncogenes, and CRC growth can be mitigated through pharmacologic inhibition or genome editing of these loci. Nearly half of all GWAS CRC risk loci co-localize to recurrently activated enhancers. These findings indicate that the CRC epigenome is defined by highly recurrent epigenetic alterations at enhancers which activate a common, aberrant transcriptional programme critical for CRC growth and survival.
Assuntos
Neoplasias Colorretais/genética , Elementos Facilitadores Genéticos/genética , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica , Loci Gênicos/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Conjuntos de Dados como Assunto , Epigenômica/métodos , Feminino , Humanos , Camundongos , Camundongos Nus , Mutação , Análise Serial de Tecidos , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In recent studies, patients have reported an increased use of complementary and alternative medicine (CAM). Acupuncture is a popular complementary therapy for patients with cancer. This article will provide current cancer treatment providers with information on acupuncture as well as the research conducted on cancer symptoms and side effects of cancer treatments. Antiemetic studies are the most prevalent and contain the most promising results. Several studies have found that acupuncture significantly reduces the number of emesis (vomiting) episodes for patients receiving chemotherapy. While studies on pain control vary due to the heterogeneity of pain, there are few studies investigating pain caused from cancer and the removal of cancerous tumors. These studies, while promising, provide basic results that need further investigation for more definitive results. Although relatively few studies have been done on anxiety and depression, several researchers have found acupuncture to be just as effective as or more effective than antidepressants for patients without cancer. Studies on breathlessness, while small, have shown acupuncture to have a significant positive effect on chronic obstructive pulmonary disease, breathlessness associated with end-stage cancer, and asthma. Researchers studying xerostomic individuals who have received salivary gland irradiation found significant positive results in salivary flow rates compared to baseline. Patients with hot flashes due to hormonal imbalance may benefit from the use of acupuncture. A recent pilot study showed improvement of chronic postchemotherapy fatigue following acupuncture treatments. Many individuals with cancer have turned to acupuncture because their symptoms persisted with conventional treatments or as an alternative or complement to their ongoing treatments. Despite the immense popularity in the community, few large randomized trials have been conducted to determine the effects acupuncture has on cancer symptoms and side effects of treatments. A majority of the current studies have shown beneficial effects that warrant further investigation with large trial sizes.