ESMO│精准医疗词汇表

纳兰烙烙

2017年11月13日，欧洲肿瘤学学会（ESMO）发布了第一版精准医疗词汇表。“精准医学是一个新领域，相关术语是在缺乏定义的情况下发展出来的”，共同作者之一的Fabrice André（法国Gustave Roussy研究所）解释到，“这种尴尬局面已经开始产生一些困惑，特别是在科学文献的报道中，因为同样的词汇会根据用的人不同而有不同的含义”。

经ESMO成员和ESMO转化研究和个体化医疗工作组筛选，该词汇表包括43个的经常被误解或缺乏明确定义的术语。在指定定义前，工作组会和相关领域专家商讨并组织讨论。“我们认为，报告清晰花不仅对科学界，对患者也很重要”，André表示，“两个医生对同一个词汇有两种不同的定义已然是现实问题”。

该词汇表分为5个主题。分子改变主题的可靶向的基因组改变定义为“一种编码某种适用于现存药物或可合成药物蛋白的基因组改变（例如，大多数激酶都是可靶向的）“。肿瘤特征范围内的肿瘤间异质性（定义为”不同个体的癌症在基因组学，表观基因组学，转录，病理或临床上的差异“）。相比个体化医疗，工作组更倾向于精准医疗这个术语，虽然他们也声明这两个词汇在技术上是可以相互替换的。

“考虑到分子医学目前的现状，我们认为使用精准医学更加恰当“，André表示。他指出，现在这个领域仍然主要关注于精确的判断哪个患者应该使用哪种药物，而不是根据每个特定的患者开出针对性的疗法。

Rajesh Chopra（伦敦癌症研究所）表示欢迎这份词汇表。“特定术语的标准化非常有用；这份词汇表朝着正确方向迈出了一大步”。但是，他也警告不能把每个定义视作不可变的。词汇表应该周期性修改，并在数年之后有所增补。“如果我们想把这个领域推动向前，我们必须写下相关术语的定义”，André总结到，“医学科学绝不是一个口头传统可以主导的领域”。

精准医学词汇表

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决定机制

Mechanisms of decision

精准医学（优选）/个体化医疗

Precision medicine（preferred term）/ Personalised medcine

A healthcare approach with the primary aim of identifying which interventions are likely to be of most benefit to which patients based upon the features of the individual and their disease. In cancer, the term usually refers to the use of therapeutics that are expected to confer benefit to a subset of patients whose cancer displays specific molecular or cellular features (most commonly genomic changes and gene or protein expression patterns). Nevertheless, the term also includes the use of prognostic markers, predictors of toxicities and any parameter such as environmental and lifestyle factors that leads to treatment tailoring. Characterisation approaches in the future are expected to encompass a wider range of technologies such as functional imaging.

药物基因组学

Pharmacogenomics

A component of precision medicine—the study of how genomic variation within the individual or their disease (including gene expression, epigenetics, germline and somaticmutations) influences his/her response to drugs. In pharmacogenomics genomic variation is correlated with pharmacodynamics and pharmacokinetics. The aim of pharmacogenomics is to optimise drug therapy by maximising therapeutic effect and minimising adverse effects.

分层医学

Stratified medicine

The use of a molecular assay to define subpopulations, rather than individuals, who are likely to benefit from a treatment intervention.

分子肿瘤委员会

Molecular tumour board

A molecular tumour board is a specific type of multidisciplinary tumour board. In common with a classical multidisciplinary board it aims at providing clinical recommendations. A molecular tumour board, however, deals not only with the classical radiological, clinical and standard biological data of the patient, but also with modern molecular diagnostic tests. Its composition therefore goes beyond that of multidisciplinary boards, encompassing molecular biologists, geneticists and bioinformaticians.

分子改变的特征

突变/基因组突变

Mutation/genomic mutation

A permanent alteration in the DNA sequence that may be somatic (acquired during an individual’s lifetime) or germline (inherited). Alterations encompass point mutations, structural variants and copy number changes (all described below).

癌症基因

Cancer gene

Cancer genes are mutated forms of normal cell genes that through mutation can promote cancer development and progression. Cancer genes are broadly separated into oncogenes and tumour suppressor genes. Oncogenes promote cellular proliferation through either an increase in gene expression or through mutations that result in an increase in oncogene encoded protein activity. In contrast, tumour suppressor genes act to oppose the processes that can drive cancer progression, such as cellular proliferation therefore, it is reduced expression or inactivation of the tumour suppressor gene protein product that contributes to carcinogenesis. By definition, cancer genes are under positive selection in a tumour and the statistical analysis of selection in genomic sequences from over 7000 cancers has identified around 200 cancer genes, but it is predicted that many more remain to be discovered.

驱动突变

Driver mutation

A genomic mutation that falls within a cancer gene (or its regulatory regions) and, by altering the cancer gene’s function or activity, provides a critical role in the development and/or maintenance of the tumourmalignant phenotype, including cancer initiation, progression, maintenance or growth. An individual tumour may have several driver mutations. Recent estimates indicate that the average cancer has around 4 driver mutations but this varies between cancer types, ranging from one in thyroid and testicular cancers to more than 10 in endometrial and colorectal cancers

伴随突变

Passenger mutation

A somatic mutation within either a coding or non-coding region of the genome that does not confer a selective growth advantage under a given set of selective pressures. Notably, this is an emerging field and some variants currently considered to be passengermutations might be classified as driver mutations in the future when larger numbers of cancers are analysed or more functional data is available. Hundreds to thousands of passenger mutations are seen in most cancers and can reveal the processes underlying tumour aetiology and evolution. Passenger mutations are also seen in all normal cells and reflect exposure to intrinsic and extrinsic processes.

癌基因依赖

Oncogene addiction

Cancer cells harbour many genetic alterations and some of these occur in genes that are known to drive tumourigenesis (e.g. the BCR–ABL fusion gene in chronic myeloid leukaemia). The term oncogene addiction is used when a tumour becomes dependent on the expression and function of these driver genes and its ablation negatively impacts tumour maintenance and progression.

致病性变异

Pathogenic variant

A mutation that may be inherited (germline) or acquired (somatic) and predisposes an individual to a specific disease. Pathogenic variants may not be fully penetrant, i.e. the individual may not display the disease trait. For example, a female with a germline BRCA1 mutation has an 80% risk of developing breast cancer in her lifetime.

缺失性变异

Deleterious variant

In cancer this is used to describe a mutation that falls within a cancer gene and is predicted to inactivate or impair the encoded protein’s function.

可靶向基因组改变/可用药基因组改变

Targetable genomic alteration/druggable genomic alteration.

A genomic alteration that encodes an altered protein against which a drug exists or can be synthesised (for example, most kinases are targetable).

可行动基因组改变

Actionable genomic alteration

Includes both targetable alterations and genomic alterations that cannot be directly targeted but that lead to dysregulation of a pathway in which there are possible targets (for example, alterations of the PTEN tumour suppressor gene can be targeted with PI3K/AKT inhibitors).

点突变

Point mutation

Focal mutations in genomic DNA including single or double nucleotide substitutions.

插入/缺失突变

Insertion/deletion mutations

Insertions and deletions of (referred to as ‘indels’) that are typically small (1–5 bp) and less frequently medium, from 100 bp up to 30 kb or long (more than 30 kb). If the number of nucleotides in the insertion/deletion is not divisible by three, and occurs in a protein coding region, it is also named frameshift mutation.

结构性改变（优选）/基因组重排

Structural variant (preferred)/genomic rearrangement.

Changes in the orientation, location or number of copies of segments of genomic DNA. Usually refers to DNA segments of ～1 kbp or larger and includes inversions, translocations, deletions and duplications.

拷贝数变化（生殖系）

Copy number variation (germline)

Usually refers to germline copy number variants that contribute towards inter-individual genomic variability and may predispose to various inherited medical disorders. Copy number variation typically consists of deletions or variable number of copies of duplicated DNA segments that may contain as few as two to three nucleotides or entire genes.

拷贝数变化（体细胞性）

Copy number alteration (somatic)

Defines a change in copy number that has arisen in somatic cells including cancer cells. Encompasses gains and losses of chromosomal segments or whole chromosomes/chromosome arms in addition to high-level amplifications and focal deletions.

基因扩增

Gene amplification

A copy number increase of a restricted chromosomal region. Amplification is sometimes defined as a magnitude of gain that is more than twice the cancer ploidy and in some cancers amplicons may contain tens or hundreds of copies of an oncogene. Possible mechanisms generating amplification include extra-replication and recombination, breakage-fusion bridge cycles, double rolling-circle replication, and replication fork stalling and template switching.

拷贝数增多

Copy number gain

Gain of a chromosomal segment or even whole chromosome/chromosome arm resulting in a regional copy number that exceeds the background genome ploidy.

同源性缺失

Homozygous deletion

Bi-allelic loss of a segment of DNA arising through independent overlapping deletions involving both chromosomes.In contrast to heterozygous deletions where a single allele is deleted.

肿瘤特征

Tumour characteristics

肿瘤间异质性

Intra-tumour heterogeneity

The coexistence, within an individual cancer, of multiple sub-clonal populations of cancer cells that differ in their genomic, epigenomic, transcriptional, morphological or behavioural features. Intratumour heterogeneity includes ‘temporal heterogeneity’ whereby sub-clonal structure varies over time (including during treatment exposure) and ‘spatial heterogeneity’ whereby cancer sub-clones can show spatial variegation within a single primary tumour or metastatic deposit, between a primary tumour and metastatic deposit(s) or between multiple metastatic deposits.

肿瘤内异质性

Inter-tumour heterogeneity

Genomic, epigenomic, transcriptional, pathological or clinical differences between individuals’ cancers.

克隆演化

Clonal evolution.

The mechanism by which a cancer develops from a once normal cell, through a reiterative process of mutation accumulation, clonal selection and clonal expansion. Mutation accumulation may be gradual and/or occur in a punctuated fashion.

癌症克隆

Cancer clone.

Cancer cells derived from the same ancestral cell. Clonally related cancer cells share all somaticmutations that were present within the most recent common ancestor—a term that refers to the last cell that is inferred to have existed during cancer evolution before sub-clonal diversification.

癌症亚克隆

Cancer sub-clone

The progeny of a mutant cell arising within a cancer clone. What distinguishes a cancer sub-clone from the cancer clone is that only a fraction of the cancer cells present in the tumour derive from the ancestral cell of a sub-clone.

循环肿瘤细胞

Circulating tumour cells

Cells that have been shed from a tumour into body fluids (i.e. blood, cerebrospinal fluid) and can provide information about the molecular characteristics of the tumour of the patient.

无细胞循环肿瘤DNA

Cell free circulating tumour DNA.

DNA derived from tumour cells that is found extracellular, circulating in bodily fluids (i.e. blood, cerebrospinal fluid) that can provide information about the molecular characteristics of the tumour of the patient.

胞外囊泡

Extracellular vesicles

Cell-derived nano-sized vesicles generated by cell membrane shedding or vesicle exocytosis that carry tumour-derived nucleic acids and proteins and can provide information about the molecular characteristics of the tumour of

the patient.

临床试验和统计学

Clinical trials and statistics

篮形试验

Basket trial

Biomarker-based, randomised or non-randomised clinical trial that includes multiple histologies investigating a therapeutic intervention, such as a drug or a drug combination targeting a specific molecular aberration across different cancer types. An example is a clinical trial of the BRAF inhibitor vemurafenib in multiple non-melanoma cancer types all harbouring  BRAF V600 mutations [13]. Within the context of a basket trial, sub-baskets can be stratified by histology.

伞形试验

Umbrella trial

Biomarker-based, randomised or nonrandomised clinical trial that is histology-specific investigating different therapeutic interventions, such as different drugs or drug combinations, matched to different molecular aberrations in a single cancer type. An example is the FOCUS4 trial in patients with metastatic colorectal cancer that investigates multiple systemic therapies matched to specific molecular aberrations (EudraCT number: 2012-005111-12).

适应性试验

Adaptive trial

Clinical trial that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study. Analyses of the accumulating study data are carried out at prospectively planned time points within the study, can be carried out in a fully blinded manner or in an unblinded manner, and can occur with or without formal statistical hypothesis testing. An example is the I-SPY2 trial evaluating different neoadjuvant systemic regimens of novel agents in breast cancer (https://clinicaltrials.gov/ct2/show/ NCT01042379) (20 October 2017, date last accessed).

N-of-one trial

Clinical trial of a single subject investigating a specific therapeutic intervention, such as a drug or a drug combination.

Spider plot

A spider plot is a graphical representation of the longitudinal percent change from baseline in the sum of typically RECIST-based tumour measurements over the period of subject evaluation, in which a leg of the spider corresponds to a study subject. The time points corresponding to appearances of new lesions can be highlighted by particular symbols.

Circos plot

A circos plot is a circular figure that can be used to represent molecular aberration data, in which genomic positions are depicted as ribbons. Each ring corresponds to the molecular data of a patient sorted by the genomic positions. Different types of molecular aberrations can be depicted on different layers of the circle. They can be drawn for genome-wide aberrations or only in more selected genome regions such as a chromosome.

Waterfall plot

A waterfall plot is a figure that displays the maximum percent change from baseline in the sum of the diameters o target lesions of the patients included in a study as measured by RECIST 1.1 or other criteria. To calculate the change from baseline in the target lesion diameter, patients need to have had measurable disease at baseline and a post-baseline measurement. Different colours are often used to highlight particular response categories or other characteristics.

研究工具

Research tools

液体活检

Liquid biopsy

Fluid biological samples (i.e. blood, cerebrospinal fluid, urine, saliva) that contain markers (i.e. circulating cells, cell-free circulating DNA, RNA, miRNA, proteins) that can provide information about the molecular characteristics of the tumour of the patient.

患者来源的移植瘤模型

Patient-derived xenograft models

Animal model where derived clinical tumour specimens are implanted in immuno-deficient mice (or other preclinical animal species).

原位动物模型

Orthotopic animal models

Animal model where derived clinical tumour specimens are implanted in immuno-deficient mice (or other preclinical animal species) in the same anatomical location where the tumour from the patient was extracted.

人源化动物模型

Humanised animal mode

Animal model where derived clinical tumour specimens are implanted in immuno-deficient mice (or other preclinical animal species) in which elements of the human immune system have been reconstituted.

类肿瘤（肿瘤类器官）

Tumouroids (tumour organoids)

Cell cultures where derived clinical tumour specimens are cultured in vitro generating three dimensional molecular structures that can be passaged over time and that maintain some of the molecular characteristics of the original tumour. Tumouroids can be cultured from multiple cell lines (for example epithelial and stromal cells) to help mimic multicellular interactions within tumours.

原代培养

Primary cultures

Cell cultures where derived clinical tumour specimens are freshly cultured in vitro for a few passages.

器官型培养

Organotypic cultures

Tissue cultures where derived clinical tumour specimens are sliced preserving the tissue structure and intratumour heterogeneity and cultured for short periods of time.

同系动物模型

Syngenic animal models

Animal model where patient-derived tumour specimens from mice (or other preclinical animal species) are implanted in the same immuno-competent strain of mice where the tumour was originated.

来源：Dr. fIndi 精准医疗