抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

/pdf/signatures-of-mutational-processes-in-human-cancer-j3duru54oq.pdf

Signatures of mutational processes in human cancer

Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of “hills” (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these “driver gene” mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.

/pdf/cancer-genome-landscapes-qmge4i5y2h.pdf

Cancer Genome Landscapes

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients' lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.

/pdf/integrated-genomic-analyses-of-ovarian-carcinoma-hbamiwnq4e.pdf

Integrated genomic analyses of ovarian carcinoma

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.

Resistance to chemotherapeutic agents represents a chief cause of mortality in cancer patients with advanced disease. Gene amplification has been shown to be one of the molecular mechanisms for tumors to escape the effect of chemotherapeutic drugs. The amplification and subsequent overexpression of the chemoresistant gene product are likely the results of tumor cell clonal expansion under the selective pressure of chemotherapeutic agents. In the past few decades, researchers have correlated the amplification of several target genes to drug resistance status in in vitro cell culture models. Although it is possible for gene amplification to be a widespread mechanismof chemore-sistance in cancer patients, only a few well-studied examples are presently available. Therefore, the future application of new advances in molecular genetic technology holds promise for the discovery of novel amplified chemoresistant genes, which may significantly affect our understanding of how tumors become chemoresistant as well as provide a molecular platform for customized treatment of cancer patients.

Amplification in DNA Copy Numbers as a Mechanism of Acquired Drug Resistance

Chromatin softening and nuclear envelope breaching potentiates killing of chemoresistant cancer cells

In accordance with one or more embodiments, the present invention provides a compound of formulas I, II, and III, for use in methods of inhibition of PBX1-DNA interaction in a mammalian cell or population of cells, and for use in the treatment of medical conditions including but not limited to cancers, developmental disorders, inflammatory disorders, autoimmune diseases, or neuro-degenerative disorders

Small molecule compounds targeting pbx1 transcriptional complex

Ovarian epithelial cancer is a heterogeneous group of neoplastic diseases that can be broadly classified as type I and type II tumors. While type II ovarian cancer is composed of mostly high-grade serous carcinoma (HGSC), the most common type of ovarian cancer, type I ovarian cancers, includes several histologic subtypes and each of them only constitutes a small percentage of ovarian cancer. These rare ovarian cancers are divided into three groups: (1) endometriosis-related tumors which include endometrioid, clear cell, and seromucinous carcinomas, (2) low-grade serous carcinomas, and (3) mucinous carcinomas and malignant Brenner tumors. They usually present at early stages which are amenable for curable surgical resection. They grow slowly and are always associated with precursor lesions. Molecularly, the rare (type I) tumors are characterized by frequent somatic mutations involving PTEN , CTNNB1 , ARID1A , KRAS , BRAF , ERBB2 , PIK3CA , and mismatch repair genes, which are uncommon in the conventional ovarian cancer (i.e., HGSC). The presence of mutations provides an opportunity for targeted therapy using inhibitors that inactivate individual molecular pathways. In this chapter, we will briefly describe the clinicopathological features of representative type I tumors and summarize the most recent advances in elucidating their molecular pathogenesis. Lastly, we will discuss the ongoing and newly proposed therapeutic intervention to treat these rare types of ovarian cancer.

Updates on Rare Epithelial Ovarian Carcinoma

The instant invention provides cancer markers and methods of prognosis and diagnosis based on detection and/or quantitation of these markers. The invention further provides compositions for the treatment of cancer.

Ie Ming Shih

Papers

Amplification in DNA Copy Numbers as a Mechanism of Acquired Drug Resistance

Chromatin softening and nuclear envelope breaching potentiates killing of chemoresistant cancer cells

Small molecule compounds targeting pbx1 transcriptional complex

Updates on Rare Epithelial Ovarian Carcinoma

Nac-i as a prognostic marker and a target for therapeutic target in human cancer