Prognostic markers are

biomarkers In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...

used to measure the progress of a

disease A disease is a particular abnormal condition that adversely affects the structure or function (biology), function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical condi ...

in the patient sample. Prognostic markers are useful to stratify the patients into groups, guiding towards precise medicine discovery. The widely used prognostic markers in

cancers Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

include stage, size, grade, node and

metastasis Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

. In addition to these common markers, there are prognostic markers specific to different cancer types. For example

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

level,

progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

and

HER2 Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The ...

are markers specific to

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

patients. There is evidence showing that genes behaving as

tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...

s or

carcinogens A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and biologic agents such as viruse ...

could act as prognostic markers due to altered gene expression or

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

. Besides genetic biomarkers, there are also biomarkers that are detected in plasma or body fluid which can be metabolic or protein biomarkers.

Traditional markers

Traditional prognostic markers in

oncology Oncology is a branch of medicine that deals with the study, treatment, diagnosis, and prevention of cancer. A medical professional who practices oncology is an ''oncologist''. The name's Etymology, etymological origin is the Greek word ὄγ ...

include tumor size, staging, lymph node spreading status, and metastasis. Large tumor, late staging, presence of cancer cells in multiple distant lymph nodes, and observation of

often associate with poor prognosis.

Molecular markers

In recent years, advances in molecular techniques, genomics, cancer biology and sequencing technology have provided opportunities to discover and validate new biomarkers for prognosis, particularly molecular prognostic markers. The newly developed prognostic biomarker can roughly be divided into DNA,

epigenetic In biology, epigenetics is the study of changes in gene expression that happen without changes to the DNA sequence. The Greek prefix ''epi-'' (ἐπι- "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in ...

, RNA, signaling pathway, protein, and metabolic tumor biomarkers.

DNA markers

Carcinogenesis involves critical mutations on genes regulating cell cycle checkpoints which cause a normal cell to grow in an uncontrolled manner and thus DNA marker provide the first-hand information on carcinogenesis. DNA markers tend to be cancer type-specific, for instance, FLT3 mutations in acute myeloid leukemia, BRCA mutations in breast cancer, BRAF mutations in melanoma, and FGFR3 mutations in bladder cancer. Detection of cancer hotspot mutations are made feasible by the advance of next-generation sequencing (NGS) that offers high-throughput sequencing of target amplicons. Table1: DNA prognostic markers for common cancer types For liquid tumors, sufficient amount of DNA could be easily obtained since blood draw from patient is simple and noninvasive; for solid tumors, needle biopsy is often performed to collect tumor DNA, a process more invasive with limited DNA quantity for downstream analysis. An alternative DNA source is circulating tumor DNA (ctDNA). ctDNA primarily originates from apoptotic and necrotic tumor cells that release their fragmented DNA into the circulation. It is believed that the amount of ctDNA in plasma is correlated with tumor progression and thus it has the potential to be utilized as a cancer prognostic marker. Collection of ctDNA is less invasive compared to tumor biopsy in that only a blood draw is need. But the challenge lies in extraction of ctDNA from total blood, the DNA quantity obtained, and methods to analyze highly fragmented ctDNA.

Epigenetic markers

Epigenetics In biology, epigenetics is the study of changes in gene expression that happen without changes to the DNA sequence. The Greek prefix ''epi-'' (ἐπι- "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in ...

are inheritable changes in gene expression that are not caused by alterations in DNA sequence. One of the most frequently seen prognostic markers is

DNA methylation DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter (genetics), promoter, DNA methylati ...

, primarily methylation of CpG islands, where

cytosine Cytosine () (symbol C or Cyt) is one of the four nucleotide bases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attac ...

s in CpG dinucleotides can be methylated to form 5-methylcytosines. A panel of epigenetic methylation marker has been explored for prognosis of ovarian cancer, and it is reported that the panel exhibited high specificity and sensitivity (both above 70%) as a screen marker. Epigenetic markers have also shown promising potential as prognostic markers for bladder cancer.

RNA markers

While DNA sequence infers what the cells could possibly do, the expression profile indicates what is actually being done at a particular time point. Whether specific mRNA molecules exist and the degree at which they are expressed suggest whether a certain gene is “on” and its expression level. Therefore,

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

profiling could provide downstream transcriptional information about cancer in a more detailed and more timely manner. Technologies for mRNA profiling include RT-qPCR for highly sensitive analysis of few mRNA targets,

microarray A microarray is a multiplex (assay), multiplex lab-on-a-chip. Its purpose is to simultaneously detect the expression of thousands of biological interactions. It is a two-dimensional array on a Substrate (materials science), solid substrate—usu ...

s for multiplexing profiling up to whole transcriptome level, and next generation RNA sequencing, i.e.,

RNA-seq RNA-Seq (named as an abbreviation of RNA sequencing) is a technique that uses next-generation sequencing to reveal the presence and quantity of RNA molecules in a biological sample, providing a snapshot of gene expression in the sample, also k ...

, for analysis of all RNA molecules within a cancer cell (alternative splicing variants, mRNAs, noncoding RNAs and

microRNA Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcr ...

s). mRNA profiling panels have been established for breast cancer and other cancers as well. A set of 97-mRNA profile has achieved satisfactory molecular grading of breast cancer and has been commercialized as the MapQuant Dx Genomic Grade assay.

Protein markers

The technique used for identifying protein markers is

immunohistochemistry Immunohistochemistry is a form of immunostaining. It involves the process of selectively identifying antigens in cells and tissue, by exploiting the principle of Antibody, antibodies binding specifically to antigens in biological tissues. Alber ...

(IHC). IHC staining of the intended protein markers are performed on tumor tissues and stained tissue would demonstrate the presence and distribution of the intended protein markers. The advantage of this technology is that it could provide morphological information about protein expression levels and the procedures are standardized and of low cost. However, assessment of IHC-stained tissue is less quantitative and are subject to bias. Besides, the number of validated protein markers for a certain type of cancer is limited.

Metabolic markers

Metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s are potentially useful for predicting treatment response since they are the endpoint of many molecular pathways. For example, Sreekumar et al reported that the level of sarcosine, which is a derivative of glycine, in the urine of men is correlated with metastasis of

prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...

References

{{Reflist Cancer staging