genes biomarkers v2 Flashcards
(24 cards)
EGFR
Epidermal Growth Factor Receptor Named for its ligand (EGF); it’s a cell surface receptor that triggers growth signals. Predictive, Diagnostic Oncogene Encodes a receptor tyrosine kinase involved in cell growth and differentiation. Gain-of-function mutations lead to constitutive activation and uncontrolled cell proliferation. Predicts response to TKIs (e.g., erlotinib, gefitinib) in NSCLC.
KRAS
Kirsten Rat Sarcoma Viral Oncogene Homolog First discovered in rat sarcoma viruses; ‘Kirsten’ refers to the researcher. Predictive, Prognostic Oncogene Encodes a GTPase that transduces signals from membrane receptors to the nucleus. Gain-of-function mutations cause persistent activation, promoting cell proliferation. Indicates resistance to EGFR inhibitors; poor prognosis marker.
BRAF
B-Raf Proto-Oncogene, Serine/Threonine Kinase RAF family kinase involved in MAPK signaling; ‘B’ denotes the isoform. Predictive, Prognostic Oncogene Encodes a serine/threonine kinase in the MAPK/ERK signaling pathway. Gain-of-function mutations (e.g., V600E) result in constitutive kinase activity. V600E mutation predicts response to BRAF inhibitors; prognostic impact varies.
ALK
Anaplastic Lymphoma Kinase Discovered due to its role in anaplastic large-cell lymphoma. Predictive Oncogene Encodes a receptor tyrosine kinase involved in neuronal development. Gene fusions or mutations activate the kinase domain, leading to oncogenesis. ALK rearrangements predict response to ALK inhibitors (e.g., crizotinib).
HER2 (ERBB2)
Human Epidermal Growth Factor Receptor 2 Part of the ERBB family of receptors; HER2 is the second member identified. Predictive, Prognostic Oncogene Encodes a receptor tyrosine kinase in the EGFR family, mediating cell growth signals. Amplification or overexpression promotes uncontrolled cell proliferation. Amplification predicts response to trastuzumab; aggressive disease association.
BRCA1/2
Breast Cancer 1 and 2, Early Onset Identified as genes mutated in hereditary breast cancers; ‘early onset’ refers to young age at diagnosis. Predictive, Prognostic Tumor Suppressor Involved in DNA damage repair through homologous recombination. Loss-of-function mutations impair DNA repair, leading to genomic instability. Germline mutations predict response to PARP inhibitors; hereditary cancer risk marker.
TP53
Tumor Protein p53 p53 refers to its molecular weight (~53 kDa); it’s a crucial tumor suppressor. Prognostic Tumor Suppressor Encodes p53 protein, which regulates the cell cycle and induces apoptosis in response to DNA damage. Loss-of-function mutations disrupt cell cycle control and apoptosis. Associated with poor prognosis; limited targeted therapy options.
PIK3CA
Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha Encodes the catalytic subunit of PI3K, which phosphorylates phosphatidylinositols. Predictive Oncogene Encodes the catalytic subunit of PI3K, involved in the PI3K/AKT signaling pathway. Gain-of-function mutations activate the PI3K pathway, promoting survival and growth. Predicts response to PI3K inhibitors (e.g., alpelisib in HR+/HER2- breast cancer).
🔬 What PIK3CA Encodes
PIK3CA encodes p110α, the catalytic subunit of Class IA phosphatidylinositol 3-kinase (PI3K). This catalytic subunit works together with a regulatory subunit, usually p85 (encoded by PIK3R1), to form the functional PI3K enzyme complex.
⚙️ PI3K/AKT/mTOR Pathway
The PI3K complex is activated by signals from cell surface receptors, such as:
Receptor tyrosine kinases (RTKs) (e.g., EGFR, HER2)
G-protein-coupled receptors (GPCRs)
Integrins
Once activated, PI3K performs a crucial enzymatic step:
It phosphorylates the 3’ position of the inositol ring of phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3).
🧬 Downstream Effects
PIP3 acts as a second messenger that recruits and activates AKT (also called Protein Kinase B) at the plasma membrane. Activated AKT then phosphorylates a broad array of targets involved in:
Cell survival (anti-apoptotic signals)
Cell growth and proliferation
Glucose metabolism
Protein synthesis
Angiogenesis
Cell motility and cytoskeletal organization
Ultimately, the pathway culminates in activation of mTOR, a master regulator of protein synthesis and metabolism.
🛑 Negative Regulation
To keep this powerful pathway in check, PTEN (a tumor suppressor) dephosphorylates PIP3 back to PIP2, thereby turning off the signal. Loss of PTEN can mimic the effects of PIK3CA gain-of-function mutations.
📌 Summary
In normal cells, PIK3CA/p110α is:
A key signal transducer connecting extracellular growth factors to intracellular proliferation and survival programs.
Tightly regulated to avoid uncontrolled cell division.
To keep this powerful pathway in check, PTEN (a tumor suppressor) dephosphorylates PIP3 back to PIP2, thereby turning off the signal. Loss of PTEN can mimic the effects of PIK3CA gain-of-function mutations.
IDH1/2
Isocitrate Dehydrogenase 1 and 2 Enzymes in the Krebs cycle; mutated versions generate 2-hydroxyglutarate, an oncometabolite. Predictive, Diagnostic Oncogene Encodes isocitrate dehydrogenase enzymes involved in cellular metabolism. Gain-of-function mutations produce an oncometabolite (2-HG), altering epigenetic regulation. Helps tumor classification; predicts response to IDH inhibitors.
Great! Let’s break down IDH1 and IDH2, their normal function, and what happens when they mutate. These two genes are central to understanding metabolic reprogramming in cancer, especially in gliomas and leukemias.
🧬 What are IDH1 and IDH2?
IDH stands for Isocitrate Dehydrogenase.
These enzymes are part of the Krebs cycle (TCA cycle), which takes place in cells to produce energy.
Gene Location Where It Acts
IDH1 Chromosome 2 Cytoplasm and peroxisomes
IDH2 Chromosome 15 Mitochondria
⚙️ Normal Function
Both IDH1 and IDH2 catalyze the same biochemical reaction, just in different cellular locations:
Isocitrate → α-Ketoglutarate (α-KG)
Using NADP⁺, producing NADPH in the process.
🔑 Why it’s important:
α-KG is a key metabolite in multiple cellular processes.
NADPH is essential for:
Combating oxidative stress (protecting from reactive oxygen species)
Biosynthesis (lipids, nucleotides)
🧬 IDH1/2 Mutations in Cancer
Mutations in IDH1/2 are neomorphic — they give the enzyme a new function, not just a loss or gain of normal function.
🔄 What changes:
Mutant IDH1/2:
α-Ketoglutarate → 2-Hydroxyglutarate (2-HG)
2-HG is an oncometabolite, structurally similar to α-KG, but functionally disruptive.
☠️ Why is 2-HG bad?
2-HG inhibits α-KG-dependent dioxygenases, including:
DNA demethylases (TET enzymes)
Histone demethylases
This leads to:
Global DNA and histone hypermethylation
Blocked cell differentiation
Epigenetic dysregulation
Promotion of a stem-like, pre-cancerous state
🧫 Key Cancers with IDH1/2 Mutations
Gliomas (especially lower-grade and secondary glioblastomas)
Acute myeloid leukemia (AML)
Cholangiocarcinoma
Chondrosarcoma
🔬 Common Mutations
Gene Hotspot Mutation
IDH1 R132H (arginine to histidine at codon 132)
IDH2 R140Q, R172K (arginine to glutamine or lysine)
💊 Targeted Therapy
Drugs now specifically inhibit mutant IDH1/2:
Ivosidenib (IDH1 inhibitor) – FDA-approved for AML and cholangiocarcinoma.
Enasidenib (IDH2 inhibitor) – FDA-approved for relapsed/refractory AML.
These drugs reduce 2-HG levels and promote cell differentiation.
📌 Summary
Gene Normal Role Mutation Effect Cancer Impact
IDH1 Cytoplasmic isocitrate → α-KG + NADPH α-KG → 2-HG Glioma, AML
IDH2 Mitochondrial version of same reaction Same as above AML, glioma, cholangiocarcinoma
NTRK1/2/3
Neurotrophic Receptor Tyrosine Kinase 1, 2, and 3 Tyrosine kinase receptors for neurotrophins, crucial for neuron survival and growth. Predictive Oncogene Encode neurotrophin receptors involved in neural development. Gene fusions result in constitutively active TRK fusion proteins. Predicts response to TRK inhibitors; tumor-agnostic indication.
NRAS
Neuroblastoma RAS Viral Oncogene Homolog RAS family gene; discovered in human neuroblastoma cells. Predictive, Prognostic Oncogene Encodes a GTPase involved in transmitting growth signals. Gain-of-function mutations cause constitutive signaling and proliferation. Impacts therapy response; poor prognosis marker.
MET
MET Proto-Oncogene, Receptor Tyrosine Kinase MET refers to ‘mesenchymal-epithelial transition’; gene encodes the HGF receptor. Predictive Oncogene Encodes a receptor tyrosine kinase for hepatocyte growth factor (HGF). Mutations (e.g., exon 14 skipping) or amplification leads to persistent signaling. Exon 14 skipping mutations predict response to MET inhibitors.
RET
RET Proto-Oncogene (Rearranged during Transfection) Named after its discovery during transfection experiments; frequently rearranged in cancer. Predictive Oncogene Encodes a receptor tyrosine kinase involved in development and cell growth. Activating mutations or fusions lead to constitutive signaling. RET fusions predict sensitivity to selective RET inhibitors.
MSI-H/dMMR
Microsatellite Instability-High / Deficient Mismatch Repair Describes a phenotype of DNA repair failure leading to repeat instability; not a single gene but a defect in a repair system. Predictive, Diagnostic Tumor Suppressor (pathway) Mismatch repair genes correct DNA replication errors. Deficiency (via mutation or methylation) leads to microsatellite instability and high mutation burden. Predicts response to immune checkpoint inhibitors; Lynch syndrome screening tool.
ESR1
Estrogen Receptor 1 Encodes the alpha subtype of the estrogen receptor; mediates estrogen hormone effects. Predictive, Prognostic Oncogene (in context) Encodes the estrogen receptor, which regulates gene transcription in response to estrogen. Mutations lead to ligand-independent activation, causing endocrine therapy resistance. Mutations in the ligand-binding domain confer resistance to aromatase inhibitors; guide use of SERDs or alternative therapies.
MLH1
MutL Homolog 1 Human homolog of bacterial MutL gene, involved in mismatch repair system. Diagnostic, Predictive Tumor Suppressor Encodes a protein in the mismatch repair system. Promoter methylation silences expression, causing mismatch repair deficiency. Epigenetic silencing via promoter methylation (not a DNA sequence mutation) MLH1 methylation leads to loss of MLH1 protein expression, resulting in defective DNA mismatch repair (dMMR).
Tumors with MLH1 methylation show microsatellite instability-high (MSI-H) status.
Helps distinguish sporadic dMMR tumors (MLH1 methylation) from Lynch syndrome (germline MMR gene mutations).
MSI-H/dMMR tumors are highly responsive to immune checkpoint inhibitors (e.g., pembrolizumab).
Important in diagnostic workflows to determine if further germline testing for Lynch syndrome is needed.
So in clinical practice, MLH1 promoter methylation testing is often done after detecting dMMR/MSI-H, to help decide whether the tumor is sporadic or hereditary. It has major implications for both treatment and genetic counseling.
the hallmarks of cancer
https://www.cell.com/fulltext/S0092-8674(00)81683-9
https://aacrjournals.org/cancerdiscovery/article/12/1/31/675608/Hallmarks-of-Cancer-New-DimensionsHallmarks-of
PTEN
PTEN (a tumor suppressor) dephosphorylates PIP3 back to PIP2, thereby turning off the signal. Loss of PTEN can mimic the effects of PIK3CA gain-of-function mutations.
TERT
PIK3CA is the gene that encodes for the catalytic subunit p110α of phosphatidylinositol 3-kinase (PI3K), which plays a key role in the PI3K/AKT/mTOR signaling pathway. This pathway is involved in many cellular functions, including cell growth, proliferation, survival, and metabolism.
Key points about PIK3CA:
Mutations in PIK3CA are common in various cancers, such as:
Breast cancer
Colorectal cancer
Endometrial cancer
Head and neck squamous cell carcinoma
Common hotspot mutations include:
E545K (exon 9)
H1047R (exon 20) These mutations lead to constitutive activation of the PI3K pathway, promoting tumorigenesis.
Targeted therapies: Some cancers with PIK3CA mutations may respond to PI3K inhibitors. An example is alpelisib (Piqray), approved for hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer.
It is also relevant in liquid biopsy: PIK3CA mutations can be detected in circulating tumor DNA (ctDNA), which may help guide treatment decisions or monitor minimal residual disease.
Would you like more technical detail, a focus on diagnostics, clinical implications, or something else?
You said:
could you tell me more abou the normal function of PIK3CA
ChatGPT said:
Absolutely! Here’s a breakdown of the normal physiological role of the PIK3CA gene and the protein it encodes:
🔬 What PIK3CA Encodes
PIK3CA encodes p110α, the catalytic subunit of Class IA phosphatidylinositol 3-kinase (PI3K). This catalytic subunit works together with a regulatory subunit, usually p85 (encoded by PIK3R1), to form the functional PI3K enzyme complex.
⚙️ PI3K/AKT/mTOR Pathway
The PI3K complex is activated by signals from cell surface receptors, such as:
Receptor tyrosine kinases (RTKs) (e.g., EGFR, HER2)
G-protein-coupled receptors (GPCRs)
Integrins
Once activated, PI3K performs a crucial enzymatic step:
It phosphorylates the 3’ position of the inositol ring of phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3).
🧬 Downstream Effects
PIP3 acts as a second messenger that recruits and activates AKT (also called Protein Kinase B) at the plasma membrane. Activated AKT then phosphorylates a broad array of targets involved in:
Cell survival (anti-apoptotic signals)
Cell growth and proliferation
Glucose metabolism
Protein synthesis
Angiogenesis
Cell motility and cytoskeletal organization
Ultimately, the pathway culminates in activation of mTOR, a master regulator of protein synthesis and metabolism.
🛑 Negative Regulation
To keep this powerful pathway in check, PTEN (a tumor suppressor) dephosphorylates PIP3 back to PIP2, thereby turning off the signal. Loss of PTEN can mimic the effects of PIK3CA gain-of-function mutations.
📌 Summary
In normal cells, PIK3CA/p110α is:
A key signal transducer connecting extracellular growth factors to intracellular proliferation and survival programs.
Tightly regulated to avoid uncontrolled cell division.
Let me know if you’d like a diagram, or a focus on what happens when this normal function goes wrong (like in cancer or overgrowth syndromes).
You said:
thanks! could you give me a similar info a bout TERT?
ChatGPT said:
Of course! Here’s a clear breakdown of the normal function of TERT and why it’s important:
🧬 What is TERT?
TERT stands for telomerase reverse transcriptase. It is the catalytic subunit of telomerase, the enzyme responsible for maintaining the length of telomeres.
Gene name: TERT
Protein product: hTERT (human telomerase reverse transcriptase)
Enzyme complex: Telomerase is made of hTERT + an RNA template (TERC) + accessory proteins.
🧪 Normal Function of Telomerase / TERT
🔁 Telomeres:
Telomeres are repetitive DNA sequences (TTAGGG in humans) at the ends of chromosomes.
They protect chromosomes from degradation or fusion.
Every time a cell divides, telomeres shorten a little.
🧰 What TERT Does:
TERT adds telomeric repeats back to the ends of chromosomes, using the RNA component (TERC) as a template. This happens through its reverse transcriptase activity, meaning it builds DNA from an RNA template.
👶 Where is TERT Active Normally?
TERT expression is low or absent in most normal somatic (body) cells, leading to gradual telomere shortening, which contributes to cellular aging and senescence.
However, TERT is active in:
Germ cells (e.g. sperm, egg precursors)
Stem cells
Activated immune cells
Embryonic cells These need more divisions and long-term renewal, so telomere maintenance is crucial.
🧓 What Happens Without TERT?
Telomeres shorten → DNA damage signals → Cell cycle arrest (senescence) or apoptosis
This acts as a tumor suppressor mechanism—cells stop dividing when they reach a “replicative limit” (the Hayflick limit).
🧫 TERT in Disease
TERT reactivation is a hallmark of ~90% of human cancers.
Tumor cells bypass senescence by reactivating TERT, allowing unlimited divisions.
This can happen through:
TERT promoter mutations (e.g., C228T and C250T), which increase TERT transcription.
Gene amplification or epigenetic activation.
📌 Summary
In normal physiology, TERT:
Maintains telomere length in cells that need long-term division.
Is highly regulated, turned off in most somatic cells.
Acts as a biological clock limiter — when it’s off, cells age; when it’s reactivated inappropriately, cells can become immortal (i.e., cancerous).
Great question! The notation -124C and -146C promoter mutations in TERT refers to specific point mutations in the promoter region of the TERT gene—not in the coding sequence, but in the regulatory DNA upstream of the gene that controls its expression.
Here’s what that means step by step:
🧬 TERT Promoter Mutations: -124C and -146C
These are shorthand names for two of the most common somatic mutations found in the TERT promoter in human cancers.
The full names of these mutations are:
C228T → located at -124 bp upstream of the transcription start site.
C250T → located at -146 bp upstream.
In older literature or some labs, these are often just called -124C>T and -146C>T, referring to the change from cytosine (C) to thymine (T) at those positions.
Both create de novo binding sites for ETS transcription factors (especially GABP), which leads to aberrant activation of TERT expression.
🧭 What “-124” or “-146” Means
These numbers are relative to the transcription start site (TSS).
So, -124 means 124 base pairs before the start of the TERT gene’s transcription.
These are in the promoter region, which controls how much and when the gene is transcribed.
🧫 Functional Consequences
In cells that normally have TERT silenced, these mutations:
Turn on the TERT gene inappropriately.
Allow cells to maintain telomeres → escape senescence → become immortalized.
Are non-coding mutations but very oncogenic—a rare example where a single point mutation in a promoter plays a major role in cancer.
🔍 Clinical Relevance
These mutations are found in several cancers, especially:
Glioblastoma
Melanoma
Bladder cancer
Thyroid cancer
Hepatocellular carcinoma
Their presence can help with:
Cancer diagnosis
Prognosis (often worse if present)
Monitoring via ctDNA in liquid biopsies
🧪 Summary
Mutation Position Change Effect
-124C>T C228T C → T Creates ETS binding site → ↑ TERT
-146C>T C250T C → T Same effect
These promoter mutations are a neat example of how non-coding mutations can have major functional and clinical impacts.
Want a visual diagram of how these mutations change transcription factor binding or how they’re used in diagnostics?
FGFR1
Absolutely — FGFR1 is another very interesting and clinically relevant gene. Here’s a full breakdown:
🧬 What is FGFR1?
FGFR1 stands for Fibroblast Growth Factor Receptor 1
It encodes a receptor tyrosine kinase that sits on the cell surface
Part of the FGFR family (FGFR1–FGFR4)
⚙️ Normal Function of FGFR1
FGFR1 binds to fibroblast growth factors (FGFs) — a family of signaling proteins involved in:
Embryonic development
Tissue repair
Angiogenesis (blood vessel formation)
Cell growth, survival, and migration
🧬 Signaling cascade:
When FGFR1 binds an FGF (with help from heparan sulfate), it:
Dimerizes (two FGFR1 molecules come together)
Autophosphorylates (activates its own tyrosine kinase domain)
Triggers several key pathways:
RAS/MAPK → cell proliferation & differentiation
PI3K/AKT → cell survival
PLCγ → calcium signaling
STAT → transcriptional regulation
🚨 FGFR1 in Disease
1. 🔁 Activating Mutations & Fusions
Found in various cancers, including:
Glioblastoma
Breast cancer
Lung cancer
Bladder cancer
Hematologic malignancies (e.g., 8p11 myeloproliferative syndrome)
Types of alterations:
Point mutations → constitutive activation
Gene fusions → common in hematologic malignancies (e.g., FGFR1–ZNF198)
Amplifications → overexpression
➡️ These alterations activate FGFR1 signaling without the need for FGF binding, driving uncontrolled cell growth.
- ❗ 8p11 Myeloproliferative Syndrome
A rare, aggressive blood cancer
Caused by FGFR1 translocations/fusions
Often progresses to acute leukemia
Fusions like BCR–FGFR1 or ZNF198–FGFR1 are seen
Poor prognosis unless treated with stem cell transplantation
- 🔬 Developmental Disorders
Germline mutations in FGFR1 are linked to:
Kallmann syndrome (delayed puberty + anosmia)
Congenital hypogonadotropic hypogonadism (CHH)
💊 Targeted Therapy
Several FGFR inhibitors have been developed — some approved, others in trials:
Drug Target Indication
Erdafitinib FGFR1-4 Bladder cancer (FDA-approved)
Pemigatinib FGFR2 (mainly) Cholangiocarcinoma (FGFR2 fusions)
Futibatinib Pan-FGFR Approved for FGFR2 fusion cholangiocarcinoma
⚠️ Resistance to FGFR inhibitors can develop via secondary mutations or bypass pathway activation.
📌 Summary
Feature FGFR1 Role
Normal function Receptor for FGFs, controls growth & repair
Signaling Activates RAS/MAPK, PI3K/AKT, PLCγ
In cancer Mutations, amplifications, or fusions → oncogenic
Therapies FGFR inhibitors (e.g., erdafitinib)
IDNAPTEX products
biomarkers and treatments
RAS family
Absolutely — here’s a clear and concise summary of the RAS family of genes and proteins, one of the most important families in cell signaling and cancer biology:
🧬 RAS Family Overview
RAS proteins are small GTPases — molecular switches that toggle between “on” (GTP-bound) and “off” (GDP-bound) states.
They regulate key signaling pathways that control:
Cell growth
Proliferation
Survival
Differentiation
Migration
🧑🔬 Major RAS Family Members
Gene Protein Chromosome Common in…
HRAS H-Ras protein Chr 11 Bladder, thyroid cancers
KRAS K-Ras protein Chr 12 Most frequently mutated RAS in cancer: lung, colon, pancreas
NRAS N-Ras protein Chr 1 Melanoma, AML, thyroid
All three code for similar proteins (~21 kDa) that localize to the inner plasma membrane and act early in many growth factor signaling cascades.
⚙️ How RAS Works: The Signaling Switch
Inactive: RAS is bound to GDP.
Activation: Growth factors (like EGF, PDGF) stimulate receptor tyrosine kinases → activate GEFs (guanine nucleotide exchange factors, e.g. SOS) → GDP is replaced by GTP.
Active: RAS-GTP triggers downstream signaling, notably:
RAF → MEK → ERK (MAPK pathway)
PI3K → AKT
Turn-off: GAPs (GTPase-activating proteins) stimulate RAS to hydrolyze GTP → GDP → inactive again.
🚨 RAS Mutations in Cancer
RAS mutations lock the protein in the GTP-bound “on” state, so it keeps signaling without external input.
These mutations are oncogenic (they drive cancer).
Hotspot mutations often affect codons 12, 13, and 61.
RAS Gene Common Mutation Effect Found in…
KRAS G12D, G12V, G13D Constitutive activation Pancreatic, colorectal, lung
NRAS Q61K, G13R Same Melanoma, AML
HRAS G12V, Q61L Same Rare — bladder, salivary gland
💊 RAS and Targeted Therapy
For a long time, RAS was considered “undruggable”, but recent breakthroughs have changed that:
KRAS G12C inhibitors:
Sotorasib (Lumakras) – FDA approved for NSCLC with KRAS G12C
Adagrasib (Krazati) – Also approved
Other mutation-specific and pan-RAS inhibitors are in clinical trials.
Still, resistance often develops, so combination strategies are under investigation.
🧪 RAS Testing in Oncology
NGS panels routinely test for KRAS/NRAS mutations in cancers like:
Colorectal (to predict resistance to EGFR inhibitors)
NSCLC (to identify G12C)
Pancreatic cancer (KRAS status is almost always mutated)
📌 Summary
Feature RAS Family
Genes KRAS, NRAS, HRAS
Protein type Small GTPase (molecular switch)
Function Controls cell growth and survival pathways
Cancer link Mutations lead to constitutive activation
Therapies G12C inhibitors, emerging mutation-specific drugs
Let me know if you’d like a visual map of RAS signaling, or a cancer-specific breakdown (e.g., how KRAS affects treatment in colon or lung cancer).
Main pathways in cancer
cells-10-00659-v2.pdf
