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


Microsatellite instability

Normal

Normal

Tumour

Tumour

Microsatellite Instability


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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