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Most cancers are caused by a combination of of causes and factors

Cancer arises from multiple “hits”

Mutations in critical genes
Changes in chromosome number and chromosome structure

Contributors to cancer

spontaneous errors that occur as cells divide
damage to DNA caused by harmful substances in the environment (tobacco smoke and UV rays)
inherited genetic errors from our parents
certain viruses, such as HPV, HIV, and hepatitis B and C
others

https://www.cancer.gov/about-cancer/understanding/what-is-cancer

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Demographics

World-wide in 2022

20 million cancer cases were newly diagnosed, and 9.7 million people died
By 2050, the number of cases is predicted to increase to 35 million based solely on projected population growth

In 2024 in the U.S.

About 125,070 deaths
Estimated 234,580 new cases
In 2021, an estimated 610,816 people living with lung cancer
Second most common cancer in men and women

Average age at diagnosis is 70
Death rate decreasing over time

60/100,000 in 1992
30/100,000 in 2022

https://seer.cancer.gov/statfacts/html/lungb.html

https://www.cancer.org/cancer/types/lung-cancer/detection-diagnosis-staging/survival-rates.html

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Cancer

Cancer is a multistep genetic and evolutionary process

Involves multiple, serial mutations and cycles of selection for cancer cells
Leads to progressively increasing capacity for proliferation, survival, invasion, and metastasis
Cancers are not genetically uniform

substantial intra-tumoral heterogeneity

DNA content and chromosome number are frequently not normal
Non-normal chromosome number (aneuploidy, polyploidy)

Cancers evolve solutions to selection pressures including therapies
Multiple oncogenes, along with mutated tumor suppressor genes, act in concert to cause cancer progression (more on that later)

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Cancer

characterized by numerous genetic mutations in a tumor mass
cells in a tumor mass are a collection of many different genetic diseases
DNA content and chromosome number are frequently not uniform

From tumor edge to center of the tumor for example

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What cancer cells do that normal cells do not:�cancer biology snapshot

grow in the absence of signals telling them to grow
ignore signals that normally tell cells to stop dividing or to die
invade into nearby areas and spread to other areas of the body
tell blood vessels to grow toward tumors
accumulate multiple changes in their chromosomes
rely on different kinds of nutrients than normal cells
hide from the immune system
trick the immune system into helping the cancer cells stay alive and grow

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Tumors and Cancers

Tumors and cancers arise from single cells that begin to proliferate abnormally

Tumors may be benign (not cancer) or cancerous (malignant)
Cancers divide without control and invade tissues (malignant)

Only malignant tumors are properly referred to as cancers
Cancers spread (metastasize) to other parts of the body through direct invasion or through the blood and lymph systems

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Benign vs. Malignant Tumors

Benign	Malignant
Grow slowly	Grow rapidly
Well-defined capsule	Not encapsulated
Not invasive	Invasive
Well differentiated	Poorly differentiated
Low mitotic index	High mitotic index
Do not metastasize	Can spread distantly (metastasis)

Mitotic index = rate of growth

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Classification and Nomenclature

Benign tumors

Named according to the tissues from which they arise, and include the suffix “-oma”

Lipoma (fat [lipid] cells)
Fibroma (fibrous connective tissue)
Neurofibroma (grow on or around nerves)
Schwannoma (nerve sheath cells, i.,e. Schwann cells)
Chondroma (cartilage cells called chondrocytes)

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Classification and Nomenclature

Malignant tumors

Named according to the tissues from which they arise
Broadly categorized as

Carcinomas

epithelial tumors

Adenocarcinomas

epithelial tumors from glandular epithelium

Sarcomas

connective tissue tumors

Lymphomas

lymphatic tissue

Leukemias

Tumors from blood-forming cell

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Cancer�mutations and chromosomal abnormalities

Cancer arises from the mutation of normal genes
It is thought that several mutations need to occur to give rise to cancer
Mutations can lead to larger changes effecting chromosomes
Mutations and chromosomal abnormalities are both hallmarks of cancer and are often interlinked
Both are directly involved to the uncontrolled cell growth that defines cancer

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Characteristics of Chromosomes in Cancer Cells: normal human cells have 46 chromosomes

Aneuploidy

The presence of an abnormal number of chromosomes

A defining characteristic of cancer
range of 40 to 60 chromosomes common, but can exceed 100

Genetic Instability

Persistent loss and gain of entire chromosomes and chromosomal arms
Large-scale structural rearrangements of chromosomes

Heterogeneity

Chromosome number is highly varied, even within the same tumor

Clinical significance

Associated with more aggressive tumors and worse clinical outcomes

Impact on genes

The extra or missing chromosomes in aneuploid cells can skew the activity of hundreds or thousands of genes
Promotes the survival and spread of cancer cells

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Chromosomal changes can be large or small

Deletion

Duplication

Inversion

Homologous�chromosomes

Reciprocal�translocation

Nonhomologous�chromosomes

structural changes and rearrangements

deletions
duplications
inversions
translocations

found in over 90% of solid tumors

https://www.researchgate.net/publication/8884476_Targeting_Aberrant_Signal_Transduction_Pathways_in_Lung_Cancer

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Mutations

Induced changes in the DNA sequence
these changes can alter the function of genes

which in turn can affect protein structure and function

which in turn can affect cell growth, division, and survival

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Mutations are a part of how normal cells live, but most are repaired

average 175 mutations per diploid genome per cell generation

Potentially millions of mutations per human lifetime

the average person has around 400 defects in his or her gene

the average person inherits around 100–200 new mutations from their parents
most of these are harmless and have no apparent effect on our health or appearance

https://pmc.ncbi.nlm.nih.gov/articles/PMC1461236/

https://www.cell.com/ajhg/fulltext/S0002-9297(12)00538-1

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Types of mutations

Point mutations

Changes in a single nucleotide in the DNA sequence.

Insertions or deletions

Addition or removal of DNA nucleotides.

Translocations

Rearrangements of DNA segments between chromosomes.

Amplifications

Duplication of DNA segments

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Several mutations are need to occur to give rise to cancer

Mutations lead to selection within the evolving tumor for “most survivable, cancerous” cells

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Mutations leading to cancer

Caused by a combination of factors

errors during DNA replication and cell division
environmental factors like exposure to carcinogens (such as tobacco smoke and UV radiation)
certain viruses (human papilloma virus, HPV)
inherited genetic changes from a parent (BRAC1/2)

Cancer predisposition

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Alleles and mutations

Alleles are alternative forms of a gene that determines a specific trait

Mutations in alleles do not necessarily affect the same nucleotide sequence

Normal chromosome

Two alleles in yellow

Point mutation changes amino acid from cysteine to arginine

Mono allelic mutation

One allele affected

Bi-allelic mutation

Two alleles affected

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Not all mutations are equal

“Driver mutations" confer a growth advantage
Driver mutations typically range between 2 and 10 depending on the specific cancer

The total number of mutations in a cancer cell can be much higher than the number of driver mutations

Range 1 to > 1600 mutations per cell (typical 10-40)

“Passenger mutations” are also present but do not directly contribute to cancer growth

https://pmc.ncbi.nlm.nih.gov/articles/PMC1867158/

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What cancer drivers are being mutated?

Significantly mutated genes (frequency in lung adenocarcinoma population)

Oncogenes (orange)
Tumor suppressors (red)

More on these later

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092285/

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Genetic changes that drive cancer progression: cancer “drivers”

affect three main types of genes

proto-oncogenes (found in normal cells)

Mutation of proto-oncogenes gives rise to oncogenes

promotes cell proliferation, inhibit apoptosis (programmed cell death), and increase angiogenesis (new blood vessel formation)

tumor suppressor genes

Typically associated with loss of function

Releases controls on cell proliferation and blocks apoptosis

DNA repair genes

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tumor suppressors and oncoproteins are often analogized to the brakes and accelerator of a car

https://www.biopharmatrend.com/post/546-predicting-a-patients-future-with-a-crystal-ball-comprised-of-cell-free-dna/

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Tumor suppressors and associated cancers

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Common Oncogenes and Associated Cancers

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Cancer arises as an abnormality in genomic control and affect cell processes

Oncogenes and tumor suppressors affect molecular pathways

signaling pathways that control cell proliferation

MAPK/ERK, PI3K/AKT/mTOR, and Wnt/β-catenin

apoptosis signaling pathways

intrinsic (mitochondrial) pathway and the extrinsic (death receptor) pathway

Both pathways converge on the activation of caspases (proteases)

DNA repair signaling pathways

direct reversal, base excision repair, nucleotide excision repair, mismatch repair, and double-strand break repair

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Oncogenes and tumor suppressors: �distinction in function

	Oncogenes	Tumor Suppressors
Origin	Mutated versions of normal genes called proto-oncogenes	Normal genes that lose their function due to mutation
Function	Stimulate excessive cell growth	Release controls on cell growth, DNA repair, and block cell death,
Mutation	A "gain-of-function" mutation activates the gene; only one copy needs to be mutated to have an effect (dominant)	A "loss-of-function" mutation inactivates the gene; both copies must be lost for the cell to become cancerous (recessive)
Therapeutic goal	Block or inhibit the overactive protein product of the oncogene	Restore the function of the suppressed protein or counteract the downstream effects of its loss

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Signaling pathway

A series of connected biochemical events where a signal is relayed through a chain of activated molecules to trigger a specific cellular response.
Protein pathways control growth, cell cycle division, metabolism, and cell death
Can be found at all cell compartment levels
Dysfunctional signaling pathways can lead to diseases, including cancer

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Comparative table of signaling pathways

Signaling Pathway	Function in Normal Cell	Effect of Oncogenes	Effect of Tumor Suppressors
Cell Cycle Regulation	Prevent uncontrolled division	Promotes uncontrolled proliferation by causing gain-of-function (GOF) mutations	Permits cell cycle progression by causing loss-of-function (LOF) mutations in cell-cycle inhibiting genes.
Apoptosis (Programmed Cell Death)	Ensures removal of old, damaged, or infected cells. Balances cell proliferation.	Inhibits cell death by promoting survival signals or interfering with apoptotic machinery.	Suppresses apoptosis
PI3K/Akt/mTOR Pathway	Mediates growth factor signaling o promote controlled cell growth, metabolism, and survival.	Constitutively activates the pathway, even without growth factor signals.	Acts as a negative regulator of the pathway.
Ras/Raf/MAPK/ERK Pathway	Mediates growth factor signaling o promote controlled cell growth, metabolism, and survival.	Maintains constant activation of the pathway, driving uncontrolled proliferation.	Acts as a negative regulator of Ras signaling.
Wnt/beta-catenin pathway	Controls cell-cell adhesion and promotes cell growth during development.	Leads to aberrant stabilization of beta-catenin promoting its nuclear localization and activation of target genes.	Acts as a negative regulator by promoting the degradation of
DNA Damage Response	Initiates cell cycle arrest or apoptosis to repair DNA damage, ensuring genomic stability.	Does not actively repair damage, but mutations can make cells insensitive to DNA damage checkpoints	Senses and repairs DNA damage by initiating cell cycle checkpoints and repair mechanisms.

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Key (but not the only) Signaling Pathways in Cancer

PI3K/Akt/mTOR Pathway

crucial for cell growth, proliferation, survival, and metabolism, and its dysregulation is found in many human cancers

MAPK (Ras-ERK) Pathway

fundamental component of cell growth regulation and is heavily involved in cancer.

Wnt/β-catenin Signaling

Aberrant activation promotes the transcription of genes involved in cancer

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Consequences of differences in the tumor suppressor TP53 gene expression level: normal vs with loss of function

Normal cell

Cancer cell

https://pmc.ncbi.nlm.nih.gov/articles/PMC7247559/

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Growth stimulatory pathway (oncogene associated)

EGFR, HER1, MET, ALK

KRAS

BRAF

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Oncogens and tumor suppressors can be in the same signaling pathway

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762943/

NF1

Growth stimulatory pathway (tumor suppressor)

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Overview of Cancer and its Biology, pt2

Computational Biology Working Group

MoComakers and DMV Petri Dish

10/17/2025

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Overview

Cancer, definition
Nomenclature

Tumor vs cancer, benign vs malignant

Chromosomal abnormalities and mutations
Tumor suppressors, proto-oncogenes and oncogenes
Signaling pathways
Tumor microenvironment
Metastasis and tumor “stages”
Tumor detection
Cancer therapy
Resistance to therapy

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The tumor cells live in a micro-environment that evolves: from initiation to metastasis

Each cell type in the tumor micro-environment generates signaling mediators that drives cell mobilization and activation

Growth factors
Chemokines
Cytokines
Hormones
Neurotransmitters

Extracellular Matrix Components

Collagen, fibronectin, laminin, and hyaluronan can act as signaling scaffolds.

Soluble Receptors and Decoy Molecules

Shed or secreted receptors can bind ligands and modulate signaling availability.

Metabolites and pH Modulators

Lactate, adenosine, and other metabolites secreted by cancer cells can reprogram immune cells and stromal components.

Acidic microenvironments promote invasion and suppress immune responses.

https://www.sciencedirect.com/science/article/pii/S1535610823000442

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The tumor cells live in a complex micro-environment with many different cell types

Cancer Cells
Immune Cells

T Lymphocytes
B Cells: Produce antibodies; roles in cancer are context-dependent.
Natural Killer (NK) Cells

Tumor-Associated Macrophages
Myeloid-Derived Suppressor Cells (MDSCs)

Inhibit T cell responses and promote tumor growth.

Cancer-Associated Fibroblasts
Endothelial Cells
Mesenchymal Stem Cells (MSCs):
Adipocytes

https://www.researchgate.net/publication/378155853_Patient-derived_organoids_a_promising_tool_for_breast_cancer_research

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The micro-environment evolves from cancer initiation to metastatic outgrowth

Changes in the micro-environment directly affect the biology of cancer cells
Can influence the types of therapy used to combat them

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Activation of signaling pathways in the cancer�microenvironment

Signal transduction pathways

networks of proteins that receive external signals (like growth factors) and translate them into internal cellular actions, such as cell division, growth, and survival

In cancers these signaling pathways be can permanently "switch on"

Permanent hyperactivation
Oncogenes are activated driving excessive signaling (growth)
Tumor suppressors are inactivated removing crucial "brakes" on cell growth

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Cancer stages and metastasis

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Tumor masses are biologically diverse

The center (core) and the periphery (edge) have significant differences in cellular composition, microenvironment, and genetic and metabolic activity
The core often contains inactive or necrotic cells, while the edge is typically more active and invasive
Therapies that target one part of the tumor may not be effective against another
This spatial heterogeneity is a major factor in tumor growth, resistance to treatment, and metastasis

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Metastatic cancer cells are also diverse and are a mixed population of cells

Cells vary genetically and phenotypically within a metastatic site
Vary from metastatic site to metastatic site

the most predominant genes that are changed in metastasis included tumor suppressors (TP53, CDKN2A, PTEN, PIK3CA, RB1)

DNA repair defects are common

https://www.nature.com/articles/s41392-020-0134-x

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Metastasis is the spread of cancer cells to other parts of the body

Detachment and Invasion:

Cells detach from the primary tumor and invade the surrounding tissue

Intravasation:

Cancer cells enter the bloodstream or lymphatic system

Dissemination:

Cells travel through the body, potentially settling in distant organs
They may adhere to the walls of blood vessels or lymphatic nodes

Extravasation:

Cancer cells exit the bloodstream or lymphatic system into the target tissue

Colonization:

Cancer cells establish a new tumor in the target tissue

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Cancer cells circulate as single units or in clusters

After arresting at secondary sites or becoming stuck in capillaries, circulating tumor cells extravasated and colonize their new niche

https://www.nature.com/articles/s41392-020-0134-x

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Gene alternations that drive metastasis are different from those that drive tumor development

Cancer development drivers
Frequently mutated genes TP53 (64.4%), EGFR (38.6%), KRAS (8.9%), and KEAP1 (14.9%),
Metastases drivers

Amplification of MYC, RICTOR, KDM2A, and NKX2-1, mutations in NPIPA2, WDR87, NPIPA1, C16orf3, and DDX11, and chromosomal arm 20p gain and 11p loss
metastatic seeding happened approximately 2.74 years before clinical detection (except for local lymph nodes)

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Typical Stages of Cancer Spread

Stage 1: Confined to organ of origin

Stage 2: Locally invasive

Stage 3: Spread to lymph nodes

Stage 4: Spread to distant sites

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Staging of lung cancer

https://www.lungcancercenter.com/lung-cancer/stages/

<walnut

Walnut-peach

<lime

> peach

https://visualsonline.cancer.gov/details.cfm?imageid=7200

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Histology of lung cancer

There are five main histologic growth patterns

This pattern is solid nests of neoplastic cells accompanied by mucinous cells

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Lung cancer histology, H&E

Small cell lung carcinoma

Non-small cell lung carcinoma

Chong S. Published Online: January 01, 2006

https://doi.org/10.1148/rg.261055057

https://librepathology.org/wiki/Non-small_cell_lung_carcinoma

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Where lung cancers arise

smoking

Non-small cell

Small cell

(non-small cell)

smoking

Non-small cell

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Lung cancer: time of detection and survival

Non-small cell lung cancer

Stage 3 (metastasized)

Small cell lung cancer

stage 3 or 4 (metastasized)
usually is diagnosed at a later stage than non-small cell lung cancer

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Where lung cancer can end up (metastases)

nearby lymph nodes or distant lymph node
brain
bones
liver
adrenal glands (small hormone glands just above the kidney)
other parts of the lung or the other lung

Kaplan-Meier curve of cancer-specific 5-year survival based on the site of metastases

https://www.jcancer.org/v10p3079.htm

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Screening for lung cancer

The only recommended screening test for lung cancer is low-dose computed tomography (also called a low-dose CT scan, or LDCT)

Sensitivity and specificity 88.9% and 92.6%

Lung cancer screening is recommended only for adults who are at high risk for developing the disease because of their smoking history and age
Radiation dose

CT radiation dose = 7 mSv, equal to about 2 years of background radiation
LDCT = 1.5 mSv, equal to about 6 months of background radiation
chest x-ray = 0.1 mSv, about the same as 10 days of background radiation

What a radiologist might see,

LDCT, axial, clinically symptomatic

https://www.sciencedirect.com/science/article/pii/S2352047716300077#fig0005

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2391122/

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CT, computerized tomography

uses a combination of X-rays and computer technology to produce images of the inside of the body
X-ray beam moves in a circle around the body allowing many different “views” of the same organ
X-ray information from the detectors is sent to a computer that processes the data and displays it in two-dimensional cross-sectional images or “slices”
Successive slices can be digitally “stacked” together and reconstructed to longitudinal images

3D image reconstruction also used

CT scan of the chest: sagittal, axial, coronal views

https://www.nibib.nih.gov/science-education/science-topics/computed-tomography-ct

DOI:10.1016/j.ijscr.2023.108804

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Diagnostic imaging for lung cancer

Chest x-ray

Least effective
Average size of tumor at diagnosis 2 cm
sensitivity 77% to 80%

Computed tomography (CT)

Most sensitive
False positives occur in between 12-14% of initial lung cancer CT scans

Magnetic resonance imaging (MRI) scan
Positron emission tomography

Uses a radioactive tracer

[¹⁸F]Fluorodeoxyglucose

Combined PET/CT

Used primarily for metastasis detection

https://introductiontoradiology.net/courses/rad/PETCT/Nonsmall.html

PET/CT sagittal, coronal views, NCSLC

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Treatment options for lung cancer

https://conquer-magazine.com/issues/2020/vol-6-no-2-april-2020/1240-treatment-of-non-small-cell-lung-cancer-a-guide-for-patients

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Treatment options change with cancer progression

treatment

Surgery

Surgery +

chemotherapy

Radiotherapy +

chemotherapy

Chemotherapy +/-

Targeted therapy

Limited disease

Extensive disease

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Common chemotherapy drugs used to treat lung cancers

NSCLC

Cisplatin
Carboplatin
Paclitaxel (Taxol)
Albumin-bound paclitaxel (nab-paclitaxel, Abraxane)
Docetaxel (Taxotere)
Gemcitabine (Gemzar)
Vinorelbine (Navelbine)
Etoposide (VP-16)
Pemetrexed (Alimta)

SCLC

Topotecan (Hycamtin)
Lurbinectedin (Zepzelca)
Docetaxel (Taxotere)
Paclitaxel (Taxol)
Gemcitabine (Gemzar)
Irinotecan (Camptosar)
Temozolomide (Temodar)
Vinorelbine (Navelbine)

For complete list of FDA approved drugs see https://www.cancer.gov/about-cancer/treatment/drugs/lung#2

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Classification of commonly used chemotherapeutics depending on their mechanism of action