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Molecular Oncology > Day 6: MSI, serrated pathway, CRC subtypes > Flashcards

Day 6: MSI, serrated pathway, CRC subtypes Flashcards

HC15, 16

1
Q

Most DNA mutations are…

A

Due to polymerases: makes mistakes
> DNA replication
> rate mistakes 1 in 10^5

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2
Q

First line DNA mutations repair

A

Polymerase itself repairs it: proofreading
> recognize wobble structure because wrong matching of the nucleotides
> Proofreading goes right in 99%
> error rate 1 in 10^7

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3
Q

What happens if DNA cannot reverse anymore to repair DNA

A

No proofreading, quick death because cancer development

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4
Q

Second line DNA mutation repair

A

Mismatch repair (MMR)
> recognize mistakes (wobble structure / nick in DNA) by MMR machinery

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5
Q

MMR in E coli

A

Proteins which recognize mismatches recruit other proteins for unwinding and cleavage of the wrong DNA region and resynthesis

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6
Q

MMR in eukaryotes

A

More proteins involved than E. coli
> first: recognition wobble, recruiting proteins, unwinding and excision and resynthesis

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7
Q

Validity MMR

A

99%
> error rate 1 in 10^9
> 3 per cell cycle
> accumulate mutations, but most are silent

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8
Q

DNA MMR is essential to prevent …

A

cancer

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9
Q

In CRC, sequences can be observed as ….(length)

A

Shorter
> regions in DNA are missing
> deletions often in short repeat sequences

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10
Q

Microsatellites

A

Short repeat DNA sequences

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11
Q

Are all microsatellites the same length

A

No, various lengths and amounts of repeats per individual

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12
Q

Why are microsatellites more mutated and shortened in CRC?

A

Prone to replication mistakes
> coding and matching sequence if one of the repeats is looped out because mutation
> still wobble, but not that distorted in DNA helix, not recognized by DNA polymerase as mistake
> in next replication, extension or shortening of microsatellite

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13
Q

When MSI (microsatellite instability)

A

dMMR > deficient mismatch repair

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14
Q

DNA replication error in microsatellite when pMMR

A

Repaired

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15
Q

Lynch syndrome

A

Familial syndrome distinct from FAP
> CRC early age
> Hereditary Non-polyposis CRC
> Lynch tumors are right sided mostly (proximal)
> Often mucinous
> mutation in mismatch repair in the germline
> less aggressive than FAP (germline APC loss)

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16
Q

How many MSI patients have Lynch syndrome, and the rest?

A

Only 10%
> the rest: spontaneous MSI patients > inactivation of MLH1 by CpG island methylation (CIMP+)

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17
Q

Lynch patients often carry germline mutations in …

A

-MLH1
-MSH2
-MSH6
-PMS2
> dMMR
> only explains 20% of dMMR CRC

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18
Q

Spontaneous MSI

A

Inactivation MLH1 by CpG island methyaltion
> epigenetic silencing
> Condensed DNA
> No transcription of MLH1
> Both alleles
> Deficient for MLH1 and MMR

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19
Q

CpG sequences in MSI CRC

A

Heavily methylated
> genes for DNA methylation upregulated

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20
Q

When in sequence of development cancer dMMR in MSI tumors?

A

First step
> unknown what mediates the changed CpG methylation profile > maybe inflammation or microbiota

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21
Q

Which mutations are also common in MSI tumors

A

KRAS and BRAF mutations
> induced by dMMR > accumulate mutations

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22
Q

MSI tumors create big .. within the tumor and the involved mutations

A

Heterogeneity

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23
Q

Wnt activation has important role in transformation to hyperplasia in MSI tumors, how?

A

dMMR induces Wnt overactivation of pathway which is essential for hyperplasia
> Mostly b-catenin mutations instead of APC loss

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24
Q

Third hit in MSI cancers

A

First: MLH1
Second: b-catenin
Third: KRAS/BRAF
> activation pathway in almost all MSI tumors
> BRAF in spontaneous MSI
> KRAS mostly in Lynch Sydrome

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25
Q

dMMR when microsatellites in coding sequence

A

Creates deletion of part
> mostly results in frameshift > whole protein changed
> for example in Bax: insensitivity to intrinsic apoptosis pathway (one of Hallmarks of cancer, rest is slowly acquired due accumulation mutations in MSI)
> other MSI affected genes
- Bax, Fas, Casp-5, Axin2, IGF2R, PTEN

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26
Q

Pathways in cancer development

A

APC loss pathway
MSI pathway
Serrated pathway

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27
Q

Serrated adenoma

A

Has serrated (kartel achtig) structure instead of cystic

28
Q

Serrated pathway character

A

Fast growth, progression from first mutation to adenoma and cancer is faster than in FAP (APC conventional pathway)
> more frequent in women
> mostly right sided

29
Q

Serrated Polyposis Syndrome (SPS)

A
  • Epigenetically driven
  • At least five serrated polyps with 2 larger than 10 mm diameter
  • not familial mutations generally
  • first degree relative
30
Q

Common familial mutation for serrated pathway

A

RNF43 (inhibitor Wnt signalling via Frizzled)
> overactive Wnt pathway
> RNF43 is E3 ubiquitin ligase which ubiquitinates Frizzled to remove it from membrane
> after mutation, more sensitive for Wnt ligands (which are still required to thrive)

31
Q

Common mutations in serrated pathway

A

-First BRAF mutation mostly > hyperactive MAPK (Mek/Erk) parthay > survival and proliferation
-Association with CIMP profile (CpG island methylator phenotype)

32
Q

Senescence in serrated pathway

A

-Telomeres too short: senescence induced
> Hyperactivation oncogenic pathways: senescence
> or via DNA damage
> via TP53
> CIMP: escape senescence via tumor suppressors

33
Q

Nevi (moedervlekken) often carry .. mutation

A

BRAF, but senescence induced

34
Q

senescence when BRAF mutated

A

-Cell cycle inactivated in BRAF mutated cells
-p16ink4a > activated through oncogenic signals: tumor suppressor
> inhibits cells going from G1 to S phase by inhibiting cyclins
> pRB inactivated by cyclin/CDK (pRB inhibits cell cycle G1/S)
> senescence

35
Q

Escape senescence in serrated BRAF mutated tumor

A

CIMP genes include p16 (CDKN2A) and MLH1
> system escapes from senescence
> methylation p16INK4a after BRAF mutation

36
Q

Two fates with MLH1 after BRAF mutation and p16 silencing

A

-Mutated MLH1: MSI serrated CRC tumor
-Not mutated: MSS serrated CRC tumor
> later TP53 mutation as well

37
Q

Which one is more aggressive: MSI/MSS serrated CRC

A

MSS > less neo-antigens made > resistance against ICI

38
Q

Serrated adenomas formed when

A

BRAF mutation and p16 mutation

39
Q

BRAF mutants are resistant against the chemo and targeted:

A

Cetuximab (anti-EGFR) > upstream of BRAF
5-FU (when MSI)

40
Q

Serrated pathway

A

Normal mucosa
> CIMP+ and BRAF mutation
Adenoma
> Methylation p16INK4a (and or not MLH1)
> Loss TP53
MSI/MSS serrated CRC

41
Q

BRAF mutation but no CIMP

A

No spontaneous p16 inactivation > senescence
> traditional serrated adenoma
> CIMP-H: sessile serrated adenoma

42
Q

Serrated tumors and prognosis

A

Poor, MSI better than MSS
> tumor budding, invasive growth pattern

43
Q

HC16: MSS tumors and metastasis

A

Increased chance, less recognition by immune system, less neo-antigens

44
Q

Treatment stage 3 CRC

A

Surgery and adjuvant therapy like FOLFOX (5-FU + oxaliplatin)

45
Q

Toxicity Oxaliplatin

A

Neuropathy side effects which can become rationale to stop therapy

46
Q

Problem treatment CRC

A

One size fits all strategy, not all patients respond well to therapy > heterogeneity

47
Q

Stage 3 CRC has increased chance of … after surgery

A

Recurrence

48
Q

50% of patients get relapse with CRC stage … > …

A

stage 3 which shows heterogeneity after therapy
> who need adjuvant therapy to prevent relapse, because chemotherapy is long, expensive and has side effects!

49
Q

Stage 4 CRC treatment

A

Not well treatable, chemotherapy and targeted therapy used

50
Q

Adjuvant therapy response for recurrence in stage 3 CRC

A

Improvement
50% > 30%

51
Q

Personalized medicine in cancer: detect profiles

A
  • Look for mutations in cancer: DNA profiles
  • Look for MSI features
  • Look for gene expression differences: RNA seq, immense differences between subtypes in gene expression > coupled to routes in development CRC
52
Q

CCS classification CRC

A

Based on gene expression profiles
> linked to development routes CRC
> Unsupervised classification > find best seperation in subgroups > generate classifier
> CCS1, CCS2, CCS3

53
Q

Molecular characterization subtypes

A

CCS1: KRAS and TP53 mutated > Chromosomal instable tumors
CCS2: MSI and CIMP and BRAF > MSI tumors
CCS3: KRAS, BRAF, TP53 > ??

54
Q

Gene set enrichment analysis with CCS and adenomas

A

Take top X genes expressed in serrated adenomas and FAP adenomas (APC loss route) and compare with gene expression in CRC
> CCS1: Tubular adenomas (FAP, APC route)
> CCS3: Serrated adenomas (BRAF loss first)

55
Q

Survival CCS1 and CCS3 in stage 2 CRC

A

Better CCS1 and worst CCS3
> more recurrence in CCS3

56
Q

Different researchers came with own subtype classification: towards consensus subtyping

A

Different methods used
> 4 consensus molecular subtypes made
> Network analysis of all patients and subtype calls per research group used
> each group classified each dataset to make big matrix
> CMS1-4

57
Q

Molecular features CMS

A
  • No mutation specific associations
  • CMS1: MSI tumors (MSI-H and CIMP-H)
  • CMS1 least copy number counts but most mutations
  • CMS3 most KRAS mutant
58
Q

CMS features

A
  • CMS1: MSI, immune infilitrated (serrated)
  • CMS2: canonical (tubular adenoma, CIN+)
  • CMS3: Metabolic (tubular, KRAS mutated)
  • CMS4: mesenchymal (CCS3, serrated adenoma, high density stromal cells)
59
Q

CMS clinical features

A

CMS4 has worst survival rate (serrated with MSS likely)
> recurrence and metastasis: bad prognosis

60
Q

Goal with subtyping

A

Stratification based on gene expression based markers to improve treatment

61
Q

Which (CMS2 or CMS4) has the worst survival in cell line models

A

CMS2 > from the APC vogelgram pathway
(CMS4 is mesenchymal with a lot of stroma)

62
Q

Which CMS (2/4) reacts best to chemotherapy when transplanted to mice?

A

CMS2

63
Q

Why is immunotherapy a good option for MSI cancer

A

Mutated proteins (frameshifts induced due dMMR) > more neo-antigens made
> due extension or shortening of microsatellites
> proteins made which should not exist: on MHC1 > recognized by immune cells
> neo-antigens perfect targets for immunotherapy: T-cells which recognize them are present but tumor has developed immune escape for example through immune checkpoint

64
Q

CD8+ marker higher in MSI/MSS?

A

MSI, more immune infiltration
> immune system in alarm phase but cannot clear tumor: immune checkpoint
> immunotherapy: immune checkpoint inhibitors

65
Q

Personalized neo-adjuvant therapy

A

Give immunotherapy before surgery in MSI patients
> 97% have no tumor when surgeon should operate
> tumor disappears completely

Molecular Oncology (7 decks)

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