Other Tumor Suppressor Genes

Slide 1 · Other Tumor Suppressor Genes

How loss of growth restraints drives neoplasia

APC • CDH1 • CDKN2A • TGF-β/SMAD • PTEN • VHL • STK11

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

By the end of the lecture, explain:

How APC regulates β-catenin stability and colonic epithelial proliferation.

How CDH1, CDKN2A and TGF-β signaling restrain growth or invasion.

How PTEN, VHL and STK11 control intracellular signaling and metabolism.

How inherited defects differ from additional somatic events in tumor evolution.

Slide 3 · Seven suppressors, several cellular brakes

Tumor suppressor activity

Growth-promoting signaling APC / PTEN

Cell adhesion CDH1

Cell-cycle arrest CDKN2A / TGF-β

Oxygen and metabolism VHL / STK11

Each mechanism restrains an aspect of the neoplastic phenotype.

Slide 4 · Tumor suppressors are functional restraints

The affected pathway matters as much as the gene.

Tumor suppressors influence one or more hallmarks of cancer.

Recurrent chromosomal deletions can disable suppressor loci.

Cancer genome sequencing continues to define the full set of suppressors.

The examples in this section illustrate distinct suppressive mechanisms.

Slide 5 · A hereditary allele predisposes; Additional loss initiates

APC illustrates the need to inactivate both copies.

Inherited mutant APC allele

Somatic loss of remaining allele

Adenomatous polyp develops

Further alterations permit carcinoma

Familial predisposition and subsequent tumor progression are not the same genetic event.

Slide 6 · Map each suppressor to its primary brake

Gene / pathway

Physiologic restraint

Loss-of-function consequence

APC

β-catenin turnover

Constitutive Wnt-like transcription

CDH1

Intercellular adhesion

Reduced cohesion; altered β-catenin

CDKN2A

RB and p53 checkpoint support

Easier cell-cycle progression

TGF-β / SMAD

Antiproliferative gene program

Escape from growth inhibition

PTEN

PI3K–AKT pathway brake

Excess progrowth signaling

VHL

Oxygen-dependent HIFα disposal

Persistent hypoxia-response signaling

STK11

Metabolic regulation

Altered metabolic control

Slide 7 · APC: The gatekeeper of colonic neoplasia

Loss of a growth-signal brake is an early lesion.

APC is a tumor suppressor on chromosome 5q21.

Germline loss-of-function variants underlie familial adenomatous polyposis (FAP).

Both APC copies must be lost for an adenoma to arise.

Further acquired alterations are needed for carcinoma progression.

Slide 8 · Familial adenomatous polyposis follows a two-hit pattern

FAP is autosomal dominant at the family level.

Germline APC loss of one allele

Second APC allele inactivated

Numerous colonic adenomas

Some progress toward carcinoma

The inherited phenotype is dominant, but an individual adenoma requires loss of both functional APC copies.

Slide 9 · The clinical phenotype of FAP

The colon develops an extensive adenoma burden.

Affected individuals often develop thousands of adenomas.

Polyps commonly appear during adolescence or early adulthood.

One or more adenomas almost invariably undergo malignant transformation without effective intervention.

The mechanism connects inherited susceptibility to sequential somatic changes.

Slide 10 · APC loss is common in sporadic colorectal tumors

Hereditary and sporadic tumors can converge mechanistically.

APC defects in 70%–80% of nonfamilial colorectal carcinomas and sporadic adenomas.

Acquired abnormalities may affect both APC alleles.

Convergence on a common growth-control pathway supports a central causal role for APC.

Inherited and acquired APC lesions differ in origin, not in the pathway disrupted.

Slide 11 · Wnt absent: The APC destruction complex is active

The resting colonic epithelium keeps β-catenin low.

No Wnt ligand at receptor

APC-containing destruction complex

β-catenin degradation

Low nuclear β-catenin activity

Proteasomal removal of β-catenin limits the transcription of progrowth genes.

Slide 12 · Why β-catenin must be regulated

Its abundance changes a transcriptional program.

β-catenin is both a signaling effector and a component of adhesion complexes.

A stabilized signaling pool can enter the nucleus.

With TCF, nuclear β-catenin increases expression of genes that drive epithelial cell growth.

The APC complex normally prevents inappropriate accumulation.

Slide 13 · Wnt present: The destruction complex is suppressed

Extracellular Wnt changes β-catenin fate.

Wnt binds a Frizzled receptor

Destruction-complex activity inhibited

β-catenin accumulates

β-catenin enters the nucleus

Physiologic Wnt signaling permits controlled activation of growth and differentiation programs.

Slide 14 · Nuclear β-catenin is a transcriptional activator

β-catenin + TCF

MYC expression increases

CCND1 / cyclin D1 increases

Other progrowth targets increase

These transcriptional targets provide a mechanistic link to colonic epithelial proliferation.

Slide 15 · APC loss creates ligand-independent signaling

The cell behaves as though Wnt is continuously present.

Biallelic APC loss

β-catenin not effectively destroyed

Persistent nuclear β-catenin–TCF

Excessive growth signaling

The upstream ligand is no longer required to maintain the β-catenin program.

Slide 16 · Normal Wnt response versus APC-deficient state

Intact APC

β-catenin is degraded without Wnt.

Signal increases transiently when Wnt activates the receptor.

Proliferation is responsive to its regulatory environment.

APC loss

Destruction complex cannot adequately dispose of β-catenin.

Nuclear β-catenin activity persists.

Growth appears Wnt-stimulated even in the absence of ligand.

Slide 17 · Activating β-catenin mutations can mimic APC loss

Different genetic lesions reach the same signaling endpoint.

β-catenin mutation blocks degradation

β-catenin stabilized

TCF-mediated transcription increases

Cellular growth promoted

Some colon tumors with intact APC carry β-catenin mutations that prevent its destruction.

Slide 18 · β-catenin dysregulation is not colon-specific

The pathway has relevance beyond colorectal cancer.

β-catenin is a proto-oncoprotein regulated by tumor suppressor APC.

Activating β-catenin mutations in approximately 20% of hepatocellular carcinomas.

The same transcriptional mechanism can operate in different tissues.

A pathway should not be equated with a single tumor site.

Slide 19 · An adenoma is not yet a carcinoma

APC loss is an initiating event, not a complete malignant genotype.

Loss of APC function

Adenoma formation

Additional genetic events

Malignant progression

Separating initiation from progression prevents over-attributing malignancy to a single suppressor defect.

Slide 20 · Applied mechanism: Numerous colonic adenomas

A young adult has an extensive colonic adenoma burden and relatives with colorectal neoplasia.

Which suppressor is the leading candidate, and why do adenomas still require a second event?

Pause and explain the molecular mechanism.

Slide 21 · E-cadherin: The epithelial adhesion restraint

Adhesion regulates both cohesion and growth signaling.

E-cadherin is a cell-surface adhesion protein encoded by CDH1.

Its cytoplasmic tail binds β-catenin.

Intact contacts help sequester β-catenin at the membrane.

Cell–cell contact therefore contributes to contact inhibition.

Slide 22 · Intact epithelial junctions sequester β-catenin

Physical contact limits the signaling pool.

E-cadherin adhesive contacts

β-catenin binds the cytoplasmic tail

β-catenin retained at the membrane

Proliferative signals restrained

The adhesion complex establishes a link between tissue architecture and transcriptional regulation.

Slide 23 · Wounding releases a transient proliferative signal

Loss of contact can be appropriate during repair.

Epithelial injury disrupts contacts

Less β-catenin is sequestered

Nuclear β-catenin signaling increases

Proliferation supports wound repair

This reversible response is physiologic when followed by re-formation of intercellular junctions.

Slide 24 · Healing restores contact inhibition

Re-establishing junctions ends the transient response.

Epithelial contacts re-form

E-cadherin binds β-catenin

Membrane sequestration is restored

Proliferative signaling falls

The same molecular circuit can support repair or drive dysregulated growth, depending on its control.

Slide 25 · CDH1 dysfunction has two consequences

Loss of functional E-cadherin

Less cell–cell cohesion → invasion potential

Altered β-catenin control → growth signals

Both effects can contribute to malignancy, although their relative importance varies by tumor.

Slide 26 · Why weaker adhesion favors dissemination

Cohesion is a physical barrier to invasion.

Reduced E-cadherin weakens epithelial cell–cell interactions.

Looser interactions may facilitate local invasion.

The same loss of cohesion can contribute to subsequent metastatic spread.

A loss of adhesion is not synonymous with metastasis by itself.

Slide 27 · CDH1 is a hereditary gastric-cancer susceptibility gene

An inherited adhesion defect can predispose to cancer.

Germline CDH1 loss-of-function variants are associated with familial gastric carcinoma.

Some sporadic gastric carcinomas also show loss of E-cadherin expression.

In sporadic cancers, reduced expression may follow mutation or indirect mechanisms.

An observed loss of protein expression does not alone specify the molecular cause.

Slide 28 · E-cadherin reduction spans multiple carcinomas

This is a recurring malignant epithelial phenotype.

Reduced cell-surface expression is common in several carcinomas.

Examples in the source include esophageal, colorectal, breast, ovarian and prostatic tumors.

The alteration may affect local tumor cell cohesion and β-catenin regulation.

Its presence is not unique to gastric carcinoma.

Slide 29 · APC and CDH1 converge on β-catenin

APC defect

Primary lesion: β-catenin destruction is impaired.

β-catenin–TCF transcription becomes persistently active.

Strong association with colorectal adenoma formation.

CDH1 defect

Primary lesion: Epithelial adhesion is reduced.

β-catenin sequestration at contacts may be weakened.

Both growth-control and invasion-related effects may occur.

Slide 30 · One CDKN2A locus encodes two suppressive proteins

CDKN2A gene

P16/INK4a restrains CDK4–cyclin D

P14/ARF restrains MDM2

These two products protect different checkpoint pathways: RB and p53.

Slide 31 · P16 maintains the RB restriction point

Cyclin-dependent kinase inhibition protects G₁/S control.

Functional p16/INK4a

CDK4–cyclin D activity restricted

RB phosphorylation reduced

G₁/S checkpoint reinforced

Loss of p16 weakens RB-mediated suppression of cell-cycle progression.

Slide 32 · P14/ARF supports the p53 pathway

MDM2 negatively regulates p53.

Functional p14/ARF

MDM2 activity inhibited

P53 destruction reduced

P53 pathway supported

Both products of CDKN2A act as restraints, but by distinct molecular routes.

Slide 33 · P16 contributes to cellular senescence

The checkpoint function extends beyond transient arrest.

P16-mediated suppression of cyclin-dependent kinase activity reinforces growth arrest.

The source also links p16 to induction of cellular senescence.

A lesion at CDKN2A can therefore disrupt multiple restraints on proliferation.

Do not assume that every CDKN2A alteration affects both products identically.

Slide 34 · Inherited CDKN2A defects predispose to melanoma

A hereditary checkpoint defect can define a cancer family.

Germline mutations are associated with familial forms of melanoma.

CDKN2A encodes two mechanistically distinct suppressors.

Loss of cell-cycle control increases the opportunity for clonal expansion.

Clinical association alone does not specify the effect of an individual variant.

Slide 35 · Sporadic CDKN2A alterations occur in diverse tumors

Examples cited in Robbins

Tumor type / context

Bladder

Carcinoma

Head and neck

Tumors of the region

Acute lymphoblastic leukemia

Hematolymphoid malignancy

Cholangiocarcinoma

Biliary epithelial carcinoma

Slide 36 · Loss of a suppressor is not always a deletion

Genetic mechanisms

Chromosomal deletion may remove a locus.

Inactivating sequence mutations may affect a protein.

These changes can abolish a functional brake.

Epigenetic mechanisms

Promoter hypermethylation may silence expression.

The DNA coding sequence need not be changed.

The text notes this mechanism for CDKN2A in some tumors.

Slide 37 · Two checkpoint arms meet at CDKN2A

P16/INK4a → RB

Restrains CDK4–cyclin D.

Limits RB phosphorylation.

Reinforces G₁/S arrest.

P14/ARF → p53

Inhibits MDM2.

Protects p53 from destruction.

Supports the p53 stress response.

Slide 38 · TGF-β receptors signal through SMAD proteins

Ligand-receptor engagement creates a transcriptional response.

TGF-β binds its cell-surface receptors

SMAD proteins phosphorylated

SMAD4-containing complex formed

Complex alters nuclear transcription

The normal program is antiproliferative in many epithelial, endothelial and hematopoietic cells.

Slide 39 · TGF-β signaling activates a growth-arrest program

Functional TGF-β–SMAD signaling

Cyclin-dependent kinase inhibitors ↑

MYC, cyclins and CDKs ↓

RB phosphorylation ↓

The shared functional endpoint is suppression of cell-cycle progression.

Slide 40 · Reduced RB phosphorylation enforces arrest

TGF-β ultimately converges on the G₁/S restriction point.

TGF-β / SMAD response

Antiproliferative gene-expression changes

Less RB phosphorylation

Cell-cycle arrest

Multiple growth-suppressive circuits converge on RB, even when their initiating receptors differ.

Slide 41 · TGF-β receptor lesions disable growth inhibition

Defects can occur at the receptor level.

Loss-of-function changes impair transmission of TGF-β signals.

The source notes receptor mutations in colon, stomach and endometrial cancers.

The resulting cell may resist a normally potent extracellular growth inhibitor.

Mutations in different pathway components can produce similar escape.

Slide 42 · SMAD4 loss is important in pancreatic carcinoma

The transcriptional response may fail despite ligand binding.

SMAD4 partners with phosphorylated SMAD proteins.

SMAD4-containing complexes regulate nuclear transcription.

Mutational inactivation of SMAD4 is common in pancreatic cancers.

The site of pathway interruption can be downstream of intact receptors.

Slide 43 · Tumors can escape downstream of intact SMADs

Target-gene defects can cancel the growth-arrest output.

TGF-β receptor signal persists

SMAD signaling may remain intact

P21 lost or MYC persistently expressed

Antiproliferative response bypassed

An apparently intact upstream pathway does not guarantee a functional growth-inhibitory response.

Slide 44 · TGF-β can suppress or favor tumor progression

Growth suppression

CDK inhibitors are upregulated.

Proliferation-driving genes are restrained.

RB-dependent cell-cycle arrest follows.

Context-dependent promotion

Growth suppression can be lost downstream.

Other TGF-β responses may persist.

These responses may support immune evasion or angiogenesis.

Slide 45 · The TGF-β paradox depends on genetic context

TGF-β pathway activity

Intact growth-arrest machinery → antiproliferation

Disabled growth-arrest output → other programs may persist

TGF-β cannot be classified as uniformly inhibitory or promotional in all tumor cells.

Slide 46 · PTEN antagonizes the PI3K–AKT growth pathway

A phosphatase acts as a molecular brake.

PTEN is a membrane-associated phosphatase.

Its gene lies on chromosome 10q23.

PTEN restrains signaling through the PI3K–AKT pathway.

Loss of function removes a negative regulator of cell growth and survival signaling.

Slide 47 · PTEN limits PI3K–AKT signaling

PTEN inhibits a pathway rather than acting as a downstream activator.

Upstream growth signaling

PI3K–AKT signaling

Proliferation / survival signaling

PTEN phosphatase

Inhibitory restraint

PTEN loss removes an inhibitory influence on PI3K–AKT signaling.

Slide 48 · PTEN inactivation has several molecular routes

A functional suppressor can be lost without one unique lesion.

Deletion may remove all or part of the gene.

Deleterious point mutations can disrupt function.

Epigenetic silencing may reduce expression.

These routes converge on reduced PTEN-mediated pathway restraint.

Slide 49 · Cowden syndrome links PTEN to hereditary neoplasia

A germline defect creates multiorgan susceptibility.

Germline PTEN mutations are associated with autosomal dominant Cowden syndrome.

The source describes benign skin appendage tumors.

Epithelial cancer risk is increased, especially breast, endometrial and thyroid cancers.

A syndromic phenotype may identify a particular pathway defect.

Slide 50 · APC and PTEN both restrain growth signals

APC

Suppresses β-catenin–TCF transcription.

Acts within the Wnt pathway.

Strongly linked to colorectal adenoma initiation.

PTEN

Opposes PI3K–AKT signaling.

Acts as a membrane-associated phosphatase.

Associated with Cowden syndrome and diverse cancers.

Slide 51 · VHL coordinates responses to ambient oxygen

The suppressor participates in regulated protein disposal.

VHL is located on chromosome 3p.

It forms part of a ubiquitin-ligase complex.

An essential target is hypoxia-inducible factor 1α (HIF-1α).

Oxygen availability determines whether HIF-1α can be recognized for degradation.

Slide 52 · Normoxia: Hydroxylation marks HIF-1α for removal

Oxygen-dependent recognition is the critical step.

Oxygen available

Prolyl hydroxylase modifies HIF-1α

VHL recognizes hydroxylated HIF-1α

Ubiquitination and degradation

When oxygen is present, VHL helps maintain low HIF-1α protein abundance.

Slide 53 · The VHL complex targets HIF-1α to the proteasome

Ubiquitin tagging connects recognition to degradation.

Hydroxylated HIF-1α

VHL-containing ligase complex

Ubiquitin chains attached

Proteasomal destruction

The mechanism is post-translational: HIF-1α is controlled by protein stability.

Slide 54 · Hypoxia: HIF-1α escapes VHL recognition

Low oxygen interrupts the hydroxylation step.

Oxygen scarcity

HIF-1α is not adequately hydroxylated

VHL recognition reduced

HIF-1α accumulates

An intact VHL gene does not trigger degradation when the required oxygen-dependent modification fails.

Slide 55 · Accumulated HIF alters nuclear gene expression

The hypoxia response couples oxygen sensing to transcription.

Stabilized HIF-1α

Complex with HIF-β

Nuclear transcription activated

Angiogenic and metabolic targets rise

This is the physiologic adaptive response to hypoxia; It also becomes oncogenic when deregulated.

Slide 56 · HIF activates angiogenic and metabolic effectors

Nuclear HIF complex

VEGF angiogenesis

PDGF mitogenic signaling

GLUT1 and glycolytic enzymes metabolic adaptation

The downstream programs support blood-vessel formation and altered energy handling.

Slide 57 · VHL loss produces a false hypoxia signal

HIF-1α persists even when oxygen is available.

Inactivating VHL mutations prevent normal HIF-1α ubiquitination.

HIF-1α can accumulate under normoxic conditions.

Angiogenic growth factors and metabolic programs are consequently elevated.

This constitutes loss of an oxygen-dependent tumor-suppressive brake.

Slide 58 · Three oxygen-sensing states

Intact VHL with normoxia

HIF-1α undergoes hydroxylation.

VHL recognizes and targets it for degradation.

Low HIF-mediated transcription.

Hypoxia or VHL inactivation

Hypoxia prevents the recognition modification.

VHL loss prevents degradation despite oxygen.

Both can lead to HIF accumulation.

Different upstream causes can yield a similar HIF transcriptional state.

Slide 59 · VHL-related tumors illustrate hereditary and somatic loss

Renal neoplasia is an important clinical association.

Germline VHL loss-of-function mutations predispose to hereditary renal cell carcinoma and other lesions.

Somatic VHL mutations also occur in a subset of sporadic renal cell carcinomas.

The shared mechanism involves persistent hypoxia-response signaling.

The exact lesion spectrum is developed in the organ-specific chapter.

Slide 60 · Applied mechanism: HIF remains high in room air

Tumor cells accumulate nuclear HIF-1α despite adequate oxygen delivery and express angiogenic factors.

Which tumor suppressor defect provides a direct explanation?

Pause and explain the molecular mechanism.

Slide 61 · STK11/LKB1 links tumor suppression and metabolism

The suppressor is a serine/threonine kinase.

STK11 is also known as LKB1.

It regulates several aspects of cellular metabolism.

The source emphasizes the breadth of its effects rather than one terminal effector.

Its inactivation reveals that metabolic regulation contributes to suppression of transformation.

Slide 62 · STK11 regulates multiple metabolic processes

Functional STK11 / LKB1

Glucose uptake and gluconeogenesis

Protein synthesis

Mitochondrial biogenesis

Lipid metabolism

A single metabolic regulator can coordinate several resources required for cell growth.

Slide 63 · Peutz–Jeghers syndrome is associated with STK11

Inherited metabolic regulation defects predispose to tumors.

Germline loss-of-function STK11 variants cause Peutz–Jeghers syndrome.

The syndrome is autosomal dominant.

Benign gastrointestinal polyps occur.

Risk of multiple epithelial cancers is increased, particularly gastrointestinal and pancreatic carcinomas.

Slide 64 · Sporadic STK11 loss broadens the mechanism

The pathway matters outside a hereditary syndrome.

Sporadic inactivating STK11 mutations occur in diverse carcinomas.

Metabolic adaptation is relevant to establishment and maintenance of the transformed state.

The source does not reduce STK11 function to a single metabolic substrate.

STK11 is one example of a metabolic tumor suppressor.

Slide 65 · What is interrupted when each suppressor is lost?

Defect

Normal functional brake

Immediate pathway effect

APC

β-catenin destruction

Nuclear β-catenin–TCF rises

CDH1

Cell adhesion and β-catenin retention

Cohesion falls; signaling changes

CDKN2A

RB/p53 checkpoint reinforcement

Proliferative restraints weakened

TGF-β/SMAD

Antiproliferative transcription

Growth-inhibitory response impaired

PTEN

PI3K–AKT restraint

Growth signaling rises

VHL

HIF-1α turnover

HIF targets rise in normoxia

STK11

Metabolic control

Multiple metabolic programs altered

Slide 66 · Inherited syndromes point to suppressor pathways

Syndrome / clinical setting

Gene

Mechanistic theme

Familial adenomatous polyposis

APC

Wnt / β-catenin

Familial gastric carcinoma

CDH1

Adhesion and signaling

Familial melanoma

CDKN2A

RB and p53 checkpoint support

Cowden syndrome

PTEN

PI3K–AKT

Hereditary VHL-related renal tumors

VHL

HIF regulation

Peutz–Jeghers syndrome

STK11

Metabolic regulation

Slide 67 · Not all suppressors are removed by the same mechanism

Loss of the gene or protein

Deletion or inactivating point mutation.

Can involve both alleles in a neoplastic cell.

Common mechanisms for APC and PTEN, among others.

Loss of the functional response

Epigenetic silencing can prevent expression.

Downstream gene defects may bypass an intact pathway.

Examples: CDKN2A silencing; TGF-β target-gene escape.

Slide 68 · Distinct lesions converge on cancer hallmarks

Tumor suppressor inactivation

Sustained growth signaling APC / PTEN

Reduced growth arrest CDKN2A / TGF-β

Loss of cohesion CDH1

Angiogenic/metabolic changes VHL / STK11

The phenotype is determined by the pathway lesion and the additional genetic context.

Slide 69 · Syndromic application: Skin lesions and epithelial cancers

A family shows benign skin appendage lesions and increased breast, thyroid and endometrial carcinomas.

Which suppressor and signaling pathway should be recalled?

Pause and explain the molecular mechanism.

Slide 70 · Syndromic application: Gastrointestinal polyps

Several relatives have gastrointestinal polyps with an inherited predisposition to gastrointestinal and pancreatic cancers.

Which metabolic tumor suppressor fits this pattern?

Pause and explain the molecular mechanism.

Slide 71 · Mechanism discrimination: Test the direct consequence

Finding

Most informative pathway

β-catenin escapes proteasomal destruction

APC / Wnt

Cells lose cohesion and β-catenin sequestration

CDH1 / E-cadherin

CDK4–cyclin D is insufficiently restrained

CDKN2A / p16

SMAD4-dependent antiproliferative output is lost

TGF-β / SMAD

PI3K–AKT growth signaling lacks its brake

PTEN

HIF-1α persists in normoxia

VHL

Metabolic regulatory kinase inactivated

STK11 / LKB1

Slide 72 · Integrated summary: The key distinctions

Tumor suppression is a family of mechanisms.

APC restrains β-catenin; CDH1 anchors junctions and helps regulate β-catenin availability.

CDKN2A protects RB and p53 checkpoints; TGF-β–SMAD induces growth arrest in susceptible cells.

PTEN limits PI3K–AKT; VHL limits HIF-1α; STK11 coordinates metabolic pathways.

Inherited predisposition requires additional cellular events; Tumors often converge on shared signaling outputs.

Slide 73 · Primary reading and scope

Source-based lecture, without external guideline updates.

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026).

Chapter 7, Neoplasia: “Other Tumor Suppressor Genes,” printed pages 264–267.

Original figures 7.28–7.30 are described in the source; this lecture uses independent, native editable schematics.

Tumor-specific diagnostic criteria, testing algorithms and management are outside this excerpt.