Enabling Replicative Immortality Module

Module enabling_replicative_immortality 3 disorders Pathograph 4

A conserved mechanism module for the fourth hallmark of cancer (Hanahan & Weinberg): the acquisition of unlimited replicative potential. Normal somatic cells can complete only a finite number of divisions because telomeres - the protective repeat caps on chromosome ends - shorten with each round of DNA replication, eventually triggering replicative senescence or crisis. This telomere clock is a powerful tumor-suppressive barrier. The conserved causal chain runs from progressive telomere attrition during clonal expansion through a proliferative crisis, to reactivation of a telomere-maintenance mechanism - in the great majority of cancers, transcriptional reactivation of the telomerase reverse transcriptase (TERT; via TERT promoter mutation, amplification, or rearrangement), and in a minority the recombination-based alternative lengthening of telomeres (ALT) - which stabilizes telomere length and confers unlimited proliferative capacity (replicative immortality). Individual disorder entries declare conformance via conforms_to, substituting the tumor-type-specific telomere-maintenance route (e.g., TERT promoter mutations in melanoma and glioblastoma, ALT in ATRX/DAXX-mutant tumors). This module is the immortality-enabling counterpart of the tumor-suppressive senescence captured in cellular_senescence and senescence_tumor_suppression.

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Pathophysiology Nodes

4 shared nodes are defined in this module.

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Cell Types

No cell types are annotated for this module.

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Biological Processes

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "enabling_replicative_immortality#Telomere Maintenance Reactivation"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should include the corresponding biological processes and causal edges, specialized to their tumor context. Key tumor-specific substitutions: melanoma and glioblastoma use TERT promoter mutations; pediatric/ATRX-DAXX-mutant tumors use ALT. The opposing tumor-suppressive reading of telomere attrition / senescence as a barrier is captured in cellular_senescence and senescence_tumor_suppression. Key conformance target: "enabling_replicative_immortality#Telomere Maintenance Reactivation".

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Used By Disorder Entries

Glioblastoma, IDH-Wildtype via TERT Promoter Activation → Telomere Maintenance Reactivation , Unlimited Replicative Potential → Replicative Immortality

Hepatocellular Carcinoma via Telomere Dysfunction and Genomic Instability → Replicative Senescence and Crisis Barrier

Leiomyosarcoma via Alternative Lengthening of Telomeres → Telomere Maintenance Reactivation

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.

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Pathophysiology

Progressive Telomere Attrition

trigger

Because conventional DNA polymerases cannot fully replicate chromosome ends (the end-replication problem), telomeres shorten with each cell division in cells lacking active telomerase. As a premalignant clone expands, telomeres erode toward a critically short length, which normally signals a DNA-damage response and engages the replicative-senescence or crisis barrier.

Telomere Maintenance via Telomere Lengthening GO:0010833 DECREASED

Downstream

Replicative Senescence and Crisis Barrier Critically short telomeres engage the senescence/crisis barrier that limits replicative potential.

Replicative Senescence and Crisis Barrier

effector

Critically short, uncapped telomeres are recognized as DNA double-strand breaks, activating p53/RB-dependent replicative senescence (the Hayflick limit) or, if those checkpoints are bypassed, a crisis state marked by chromosome end-to-end fusions and massive cell death. This barrier limits the number of divisions a lineage can complete and must be overcome for a clone to become immortal.

Replicative Senescence GO:0090399 INCREASED

Used by disorders

Hepatocellular Carcinoma as Telomere Dysfunction and Genomic Instability

Downstream

Telomere Maintenance Reactivation Rare clones that reactivate a telomere-maintenance mechanism escape the senescence/crisis barrier.

Telomere Maintenance Reactivation

central effector

A rare clone reactivates a telomere-maintenance mechanism, stabilizing telomere length and escaping the senescence/crisis barrier. In the great majority of human cancers this occurs through reactivation of telomerase (TERT) - via TERT promoter mutations, amplification, or rearrangement - while a minority use the recombination-based alternative lengthening of telomeres (ALT) pathway, frequently associated with ATRX/DAXX loss. This is the conserved central node disorder-specific lesions converge upon.

Telomere Maintenance via Telomerase GO:0007004 INCREASED

Used by disorders

Glioblastoma, IDH-Wildtype as TERT Promoter Activation

Leiomyosarcoma as Alternative Lengthening of Telomeres

Downstream

Replicative Immortality

Replicative Immortality

consequence

With telomeres stabilized, the cancer cell lineage acquires unlimited proliferative capacity - replicative immortality - decoupling division number from the telomere clock. This sustains the extensive clonal expansion required for macroscopic tumor growth and progression.

Cell Population Proliferation GO:0008283 INCREASED

Used by disorders

Glioblastoma, IDH-Wildtype as Unlimited Replicative Potential