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.

Clinician to Clinician: Have you ruled out a placental site nodule?

Ovarian cancer is associated with a high morbidity and mortality, and is the leading cause of gynecologic cancer-related death in the US. In recent years, the molecular pathophysiology of ovarian tumors has been better elucidated, allowing for the distinction of two tumor types: the more indolent type I tumors (encompassing endometrioid, clear cell, low-grade serous, and mucinous carcinomas) and the highly aggressive type II tumors (encompassing high-grade serous carcinomas and malignant mixed mullerian tumors). Type I tumors are related to abnormalities in the MAPK signaling pathway (KRAS and BRAF mutations), the PI3K/Akt2/PTEN pathway, and the Wnt/beta-catenin pathway, as well as mutations in other genes such as ARID1a, PPP2R1A, and HNF1-beta. Type II tumors, in contrast, are characterized by mutations in p53, as well as inactivation of BRCA1/2 and mutations in genes such as Notch3, Rsf-1, and NAC1. In this chapter, we discuss the characteristics and frequency of these molecular abnormalities, with an emphasis on their implications for diagnosis and treatment.

Molecular Pathology of Ovarian Cancer

Background The paradigm shift localizing the origin of ovarian high-grade serous carcinoma (HGSC) to the fallopian tube underscores the rationale for meticulous microscopic examination of salpingectomy specimens. The precursor, termed "serous tubal intraepithelial carcinoma," is often a focal lesion, which poses difficulties for histologic diagnosis. Methods The authors describe a method to examine exfoliated epithelial cells from fallopian tube fimbria by gentle brushing, thereby enabling thorough sampling of the mucosal surface. Fimbrial brushings were collected from 20 fresh salpingectomy specimens from 15 patients, including 5 who had pathologically confirmed ovarian HGSC. Samples taken only from tubes that were grossly negative for tumor were processed for Papanicolaou staining, p53 immunocytochemistry, and tumor protein 53 (TP53) mutation analysis. Results Cells with malignant cytomorphologic features were identified only in tubal brushings from patients with ovarian HGSC. In all cases, atypical/malignant cells on cytology corresponded to lesions with similar morphology and immunostaining pattern in permanent sections, demonstrating the sensitivity of the technique while providing reassurance that specimen integrity was not disrupted by the procedure. Targeted next-generation sequencing confirmed the presence of TP53 mutations in fimbrial brushings from HGSC, but not in benign samples, and demonstrated concordance with the immunostaining pattern. Identical mutations were observed in matched lesions microdissected from formalin-fixed tissue sections. Conclusions The described technique enables cytologic evaluation of the fallopian tube fimbria for a diagnosis of serous tubal intraepithelial carcinoma, serving as a complement to histology while offering distinct advantages with respect to the procurement of cellular material for ancillary testing and research.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncy.22110

Cytomorphologic and molecular analyses of fallopian tube fimbrial brushings for diagnosis of serous tubal intraepithelial carcinoma

A quantum dot based nanoassay for quantifying gene copy number with ultrahigh resolution

: The purpose of this study is to elucidate the pathogenesis of serous carcinoma by identifying the molecular genetic changes and preferentially expressed genes of different histological types of serous neoplasms. We hypothesize that the development of serous carcinoma proceeds along two main pathways: one is rapid progression from ovarian surface epithelium to high-grade serous carcinoma without well-established morphological precursors ("de novo" pathway) and the other is a gradual development from borderline tumors to non-invasive micropapillary serous carcinomas then to low- grade carcinomas (stepwise pathway). The first pathway results in a high-grade neoplasm (conventional serous carcinoma) and the second leads to the development of a low-grade indolent tumor. Both types of carcinomas and the putative precursor lesions of invasive MPSC are characterized by distinctive molecular genetic alterations and specific gene expression. We identified that mutations in KRAS/BRAF/ERRB2 genes characterized the development of low- grade serous carcinomas. Expression of HLA-G apoE and membralin molecules were confined to high-grade serous carcinomas. This project designed to test our proposed model of diverse pathways in the pathogenesis of ovarian serous carcinoma provides an etiologic basis for the other two projects.

Ie Ming Shih

Papers

Clinician to Clinician: Have you ruled out a placental site nodule?

Molecular Pathology of Ovarian Cancer

Cytomorphologic and molecular analyses of fallopian tube fimbrial brushings for diagnosis of serous tubal intraepithelial carcinoma

A quantum dot based nanoassay for quantifying gene copy number with ultrahigh resolution

Pathogenesis of Ovarian Serous Carcinoma as the Basis for Immunologic Directed Diagnosis and Treatment