L7 -Genetics of Leukaemia

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Last updated 2:34 PM on 10/4/26

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31 Terms

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what are the types of adult leukaemia

plus chronic myeloid leukaemia (CML) and T cell leukaemia

<ul><li><p>plus chronic myeloid leukaemia (CML) and T cell leukaemia </p></li></ul><p></p>

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At which stages of B-cell development can cancers arise, and what cancers are associated with them?

Cancers can arise at different stages of B-cell development: acute lymphoblastic/leukaemia from B-cell precursors,

Hodgkin lymphoma from germinal-centre B cells, multiple myeloma from plasma cells, and chronic lymphocytic leukaemia (CLL) from mature/memory B cells.

<p>Cancers can arise at different stages of B-cell development: <strong>acute lymphoblastic/leukaemia</strong> from B-cell precursors,</p><ul><li><p><strong>Hodgkin lymphoma</strong> from germinal-centre B cells, <strong>multiple myeloma</strong> from plasma cells, and <strong>chronic lymphocytic leukaemia (CLL)</strong> from mature/memory B cells.</p></li></ul><p></p>

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when are adult leukaemiad diagnosed

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How do constitutional and somatic genetic changes contribute to cancer risk?

The human genome contains >100 million polymorphisms, and DNA replication errors/mutations are an inevitable consequence of cell division.

These mutations accumulate differently in each cell, meaning each cell evolves differently and somatic mutations can contribute to cancer development.

<p>The human genome contains <strong>>100 million polymorphisms</strong>, and <strong>DNA replication errors/mutations are an inevitable consequence of cell division</strong>. </p><ul><li><p>These mutations accumulate differently in each cell, meaning <strong>each cell evolves differently</strong> and somatic mutations can contribute to cancer development.</p></li></ul><p></p>

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what is the natural history of chronic lymphocytic leukaemia

CLL is characterised by complex somatic genetics
clinical course of disease is very heterogeneous (because of genetics?)

<ul><li><p>CLL is characterised by complex somatic genetics</p></li><li><p>clinical course of disease is very heterogeneous (because of genetics?)</p></li></ul><p></p>

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How does the importance of constitutional vs somatic genetic variants change throughout cancer development?

Constitutional variants are present from birth and are more important in disease susceptibility/aetiology,

while somatic mutations accumulate over time and become increasingly important for disease progression, prognosis, diagnosis and treatment, enabling more tailored treatment.

<p><strong>Constitutional variants</strong> are present from birth and are more important in <strong>disease susceptibility/aetiology</strong>, </p><ul><li><p>while <strong>somatic mutations</strong> accumulate over time and become increasingly important for <strong>disease progression, prognosis, diagnosis and treatment</strong>, enabling more <strong>tailored treatment</strong>.</p></li></ul><p></p>

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Why do haematological cancers tend to run in families?

Familial clustering of haematological cancers may result from shared genetic factors and/or shared environmental exposures.

Different cancers can arise from different stages of haematopoietic cell development, including lymphoid and myeloid lineages.

<p>Familial clustering of haematological cancers may result from <strong>shared genetic factors and/or shared environmental exposures</strong>. </p><ul><li><p>Different cancers can arise from different stages of <strong>haematopoietic cell development</strong>, including lymphoid and myeloid lineages.</p></li></ul><p></p>

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How do risk alleles differ between monogenic and polygenic cancer?

Monogenic risk alleles are generally rarer and have higher penetrance

polygenic risk alleles are generally more common and have lower penetrance.

<ul><li><p><strong>Monogenic</strong> risk alleles are generally <strong>rarer and have higher penetrance</strong></p></li></ul><ul><li><p><strong>polygenic</strong> risk alleles are generally <strong>more common and have lower penetrance</strong>.</p></li></ul><p></p>

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How can AML be a monogenic disease?

Some individuals carry rare, high-penetrance germline variants that greatly increase their lifetime risk of AML

compared with ~0.5% risk in people without a high-penetrance variant.

<p>Some individuals carry <strong>rare, high-penetrance germline variants</strong> that greatly increase their lifetime risk of AML</p><ul><li><p>compared with ~0.5% risk in people without a high-penetrance variant.</p></li></ul><p></p>

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What evidence supports high-penetrance genetic variants causing AML?

High-penetrance variants are rare.
Some risk genes are also somatically mutated (e.g. CEBPA, RUNX1).
Some cause inherited syndromes where AML is a component (e.g. FANCA, TP53).
Strong familial recurrence is evidence that the variant is disease-causing.

<ul><li><p>High-penetrance variants are <strong>rare</strong>.</p></li><li><p>Some risk genes are also <strong>somatically mutated</strong> (e.g. <strong>CEBPA, RUNX1</strong>).</p></li><li><p>Some cause inherited syndromes where AML is a component (e.g. <strong>FANCA, TP53</strong>).</p></li><li><p><strong>Strong familial recurrence</strong> is evidence that the variant is disease-causing.</p></li></ul><p></p>

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What does the POT1 example show about genetic predisposition to cancer?

Rare POT1 (Protection of Telomeres 1) germline variants can predispose individuals to lymphoid and myeloid cancers.

The example shows a POT1 variant segregating in a family, with affected individuals developing cancers such as CLL and AML, demonstrating a monogenic inherited cancer predisposition.

<p>Rare <strong>POT1 (Protection of Telomeres 1) germline variants</strong> can predispose individuals to <strong>lymphoid and myeloid cancers</strong>. </p><ul><li><p>The example shows a <strong>POT1 variant segregating in a family</strong>, with affected individuals developing cancers such as <strong>CLL and AML</strong>, demonstrating a <strong>monogenic inherited cancer predisposition</strong>.</p></li></ul><p></p>

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Why is CLL considered a polygenic disease?

CLL risk is influenced by multiple common, low-penetrance alleles across different genes

Each allele contributes a small increase in disease risk, with their combined effects producing a higher overall genetic susceptibility.

<p>CLL risk is influenced by <strong>multiple common, low-penetrance alleles</strong> across different genes</p><ul><li><p>Each allele contributes a small increase in disease risk, with their <strong>combined effects</strong> producing a higher overall genetic susceptibility.</p></li></ul><p></p>

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What evidence shows that CLL is a polygenic disease?

43 loci carrying common variants account for ~25% of the heritable risk of CLL.

Each risk allele has a relatively small effect (e.g. IRF4 OR 1.54, C6orf106/ILRUN OR 1.20)
but the effects accumulate: carrying 8+ risk alleles is associated with an OR of 12.0 compared with having none.

<p><strong>43 loci</strong> carrying common variants account for ~<strong>25% of the heritable risk</strong> of CLL. </p><ul><li><p>Each risk allele has a relatively small effect (e.g. <strong>IRF4 OR 1.54</strong>, <strong>C6orf106/ILRUN OR 1.20</strong>)</p></li><li><p>but the effects <strong>accumulate</strong>: carrying <strong>8+ risk alleles</strong> is associated with an OR of <strong>12.0</strong> compared with having none.</p></li></ul><p></p>

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What is the role of IRF4 in CLL and Hodgkin lymphoma risk?

The IRF4 risk allele (rs872071) is associated with increased risk of CLL (OR 1.54) and Hodgkin lymphoma (OR 1.21).

IRF4 is important in B-cell development and differentiation, and the risk allele is associated with altered IRF4 mRNA expression in lymphocytes.

<p>The <strong>IRF4 risk allele (rs872071)</strong> is associated with increased risk of <strong>CLL (OR 1.54)</strong> and <strong>Hodgkin lymphoma (OR 1.21)</strong>.</p><ul><li><p>IRF4 is important in <strong>B-cell development and differentiation</strong>, and the risk allele is associated with altered <strong>IRF4 mRNA expression</strong> in lymphocytes.</p></li></ul><p></p>

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How do cancer risk loci, particularly in CLL, affect gene regulation?

Most GWAS risk variants map to non-coding regions and affect disease risk by altering gene regulation, including active promoters/enhancers and transcription factor (TF) binding sites such as IRF4, MYC, OCT2 and RUNX3.

These TFs regulate B-cell functions including BCR signalling, apoptosis and differentiation.

<p>Most GWAS risk variants map to <strong>non-coding regions</strong> and affect disease risk by altering <strong>gene regulation</strong>, including active <strong>promoters/enhancers</strong> and transcription factor (TF) binding sites such as <strong>IRF4, MYC, OCT2 and RUNX3</strong>. </p><ul><li><p>These TFs regulate B-cell functions including <strong>BCR signalling, apoptosis and differentiation</strong>.</p></li></ul><p></p>

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How can low IRF4 levels contribute to CLL cell survival?

Low IRF4 leads to increased BCR activation and CLL cell survival through phosphorylation of IKAROS and SYK.

The IRF4 risk allele (rs872071) is associated with increased CLL risk (OR 1.54).

<p><strong>Low IRF4</strong> leads to increased <strong>BCR activation</strong> and CLL cell survival through <strong>phosphorylation of IKAROS and SYK</strong>. </p><ul><li><p>The IRF4 risk allele (<strong>rs872071</strong>) is associated with increased CLL risk (<strong>OR 1.54</strong>).</p></li></ul><p></p>

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What is the genetic structure of acute myeloid leukaemia (AML)?

AML is a heterogeneous disease—a collection of diseases with a shared clinical phenotype but numerous different genetic pathways to transformation

including different mutations, chromosomal abnormalities and gene fusions.

<p>AML is a <strong>heterogeneous disease</strong>—a collection of diseases with a shared clinical phenotype but <strong>numerous different genetic pathways to transformation</strong></p><ul><li><p>including different mutations, chromosomal abnormalities and gene fusions.</p></li></ul><p></p>

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what is DNMTA3 in AML

DNMTA3 is an important gene in AML pathogenesis

the most commonly somatically mutated gene in AML

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what is the relevance of the HLA locus

the HLA locus carries risk alleles for numerous human cancers

HLA (rs3916765) OR 1.72, 95% CI 1.46-2.03 (risk allele frequency = 0.89)

Sub-type specific risk alleles

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what is HLA and

HLA antigens on specialized immune cells present peptides from foreign substances (e.g. viruses and bacteria) to effector cells of the immune system.

<p>HLA antigens on specialized immune cells present peptides from foreign substances (e.g. viruses and bacteria) to effector cells of the immune system.</p>

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why is HLA so important in cancer aetiology

The HLA complex is located within the 6p21.3 region of the short arm of chromosome 6 and contains >240 genes of diverse functions. Many of the genes encode immune system proteins