microsatellite instability in sporadic colorectal cancer a retrospective study
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Microsatellite Instability in Sporadic Colorectal Cancer: A Retrospective Study. Kimberley Slowther Trainee Project West Midlands Regional Genetics Laboratory. Colorectal Cancer. 35,000 diagnosed per year Treatment and prognosis depend upon tumour stage. Causes of CRC. Sporadic 75%.

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microsatellite instability in sporadic colorectal cancer a retrospective study

Microsatellite Instability in Sporadic Colorectal Cancer: A Retrospective Study

Kimberley Slowther

Trainee Project

West Midlands Regional Genetics Laboratory

colorectal cancer
Colorectal Cancer
  • 35,000 diagnosed per year
  • Treatment and prognosis depend upon tumour stage
causes of crc
Causes of CRC

Sporadic

75%

Familial

19%

Rare

Syndromes

<1%

HNPCC

5%

FAP

1%

genetic pathways in crc
Genetic Pathways in CRC
  • Microsatellite Instability (MSI-H)
    • Deficiency in DNA mismatch repair (MMR)
      • HNPCC (MSH2, MLH1, MSH6, PMS2)
      • 15% sporadic (hypermethylation of MLH1 promoter)
  • Chromosomal Instability (CIN)
    • APC, TP53, KRAS, Loss of Heterozygosity, aneuploid DNA content
  • CpG Island Methylator Phenotype (CIMP)
    • Methylation of CpG islands in promoter regions of tumour suppressor genes
      • Sporadic CRCs demonstrating MSI are a subset
comparison of sporadic msi h with hnpcc tumours
Comparison of Sporadic MSI-H with HNPCC Tumours
  • Both are MSI-H and proximally located
  • BUT Sporadic MSI-H:-
    • Greater predilection for the proximal colon
    • Higher frequency of BRAF mutations
    • Lower frequency of KRAS mutations
    • More age related
    • More common in females
    • Originate from serrated polyps
      • HNPCC tumours originate from adenomas
ras raf mek erk pathway
RAS-RAF-MEK-ERK Pathway

Regulates growth, differentiation and apoptosis

KRAS

  • GTPase
  • 90% mutations in codons 12 and 13
  • 30-40% sporadic MSS CRC
  • 40% HNPCC

BRAF

  • Serine-threonine specific kinase
  • 40% sporadic MSI-H tumours
  • Not present in HNPCC
  • Common mutation (90%) is V600E
msi and prognosis
MSI and Prognosis
  • MSI in CRC is a positive prognostic indicator
    • Better five-year rate of overall survival than MSS tumours
    • Less likely to metastasise
    • Why?
      • Enhanced mutation rate induces a burden not compatible with tumour cell survival
      • Abnormal peptides produced elicit antitumour immune responses that limit tumour growth
treatment of crc
Treatment of CRC
  • Dictated by stage
      • Stage I: surgery alone
      • Stage II, III+IV: adjuvant therapy
      • Less clear cut with Stage II
        • Patients reviewed on individual basis
    • Chemotherapy Drugs
      • 5-fluorouracil/folinic acid (5FU/FA) to Stage II and III patients
      • 5FU/FA and Oxaliplatin to Stage IV and fitter Stage II and III patients
msi and chemotherapy
MSI and Chemotherapy
  • Resistance of MSI-H CRC to 5FU is well documented
    • MSS patients have increased survival with 5FU
    • MSI-H patients do not have improved survival following treatment
    • Why have 5FU treatment if there is no benefit?
  • Oxaliplatin therapy not affected by loss of MMR
  • Information about MSI status could impact treatment:-
    • Decision of whether or not to opt for adjuvant therapy
    • Allocation patients to oxaliplatin therapy
project aim
Project Aim

Investigate whether microsatellite

analysis of sporadic colorectal cancer

would be a valuable service to offer in

future in order to tailor patient

treatment

methods
Methods
  • MSI status of patients with locally advanced, treatable sporadic (absence of family history) CRC
      • 41 – Department of Surgery Epithelial Research Group
      • 32 – Department of Histopathology
    • 7 microsatellite markers
      • MSI-H if instability present at 2 or more markers
      • MSI-L if instability present at 1 marker
  • Analysed MSI data in relation to:-
    • Age at diagnosis
    • Gender
    • BRAF exon 15 mutation
    • KRAS codon 12 and 13 mutation (41/73)
    • Tumour site
    • Tumour differentiation
results microsatellite status and age
Results: Microsatellite Status and Age

Plus-minus values are means ±SD.

  • On average patients demonstrating MSI in their tumours were younger but this was not statistically significant
  • Of the 14 patient samples demonstrating MSI, 7 were older than 70 at diagnosis
    • Usually opt not to be treated with adjuvant therapy; MSI status could be used to help make this decision
results microsatellite status and gender
Results: Microsatellite Status and Gender
  • More female samples demonstrated MSI-H but this was not statistically significant
results microsatellite status and tumour differentiation
Results: Microsatellite Status and Tumour Differentiation
  • MSI-H tumours more poorly differentiated than MSS or MSI-L tumours
results microsatellite status and tumour site
Results: Microsatellite Status and Tumour Site
  • MSI-H associated with localisation of tumour to the proximal colon
results microsatellite status and braf kras mutations
Results: Microsatellite Status and BRAF/KRAS Mutations
  • KRAS mutations and BRAF mutations were mutually exclusive
  • MSS and MSI-L tumours had a higher frequency of KRAS mutations
  • MSI-H tumours higher frequency of BRAF mutations
discussion
Discussion
  • What are the benefits of MSI analysis for sporadic CRC?
    • Improved patient care
      • MSI-H not given unnecessary treatment (5-FU)
      • MSI-H allocated to more effective treatments (Oxaliplatin)
    • ? Cost Benefit
      • Reduced chemotherapy?
  • Perhaps not all tumours were sporadic
    • Ethical Implications
      • Possibility that HNPCC patients included
        • Only 14% MSI-H samples contained BRAF mutations
      • Recommend that patients are counselled
future developments
Future Developments
  • Prospective study
    • Treatment vs no treatment
      • ? Unethical
      • Complicated by wide use of oxaliplatin
    • Oxaliplatin vs 5FU
      • In the future just offer oxaliplatin therapy to MSI-H patients
conclusion
Conclusion
  • Techniques available to put a system into place to offer MSI analysis of sporadic colorectal tumours
  • Tailor patient treatment depending upon tumour stage, microsatellite status and age
acknowledgements
Acknowledgements
  • West Midlands Regional Genetics Laboratory
    • Fiona Macdonald
    • Jennie Bell
    • Kerry Wall
  • University of Birmingham Department of Surgery Epithelial Research Group
    • Dion Morton
    • Germaine Caldwell
  • University Hospital of Birmingham Histopathology Department
    • Philippe Taniere
    • Brendan O’Sullivan
    • Graham Caine
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