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Cascade genetic testing for mismatch repair gene mutations

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Abstract

Mismatch repair gene mutation carriers have a high risk of developing colorectal cancer, and can benefit from appropriate surveillance. A combined population based ascertainment cascade genetic testing approach provides a systematic and potentially effective strategy for identifying such carriers. We have developed a Markov Chain computer model system which simulates various factors influencing cascade genetic testing; including demographics, uptake, genetic epidemiology and family size. This was used to evaluate cascade genetic testing for mismatch repair gene mutations in theory and practice. Simulations focussed on the population of Scotland by way of illustration, and were based on a 20-year programme in which index cases were ascertained from colorectal cancer cases aged <55 years at onset. Results indicated that without practical barriers to cascade genetic testing, 545 (95% CI = 522, 568) carriers could be identified; 42% of the population total. This comprised approximately 140 index cases, 302 asymptomatic relatives and 104 previously affected relatives. However, when realistic ascertainment and acceptance rates were used to inform simulations, only 257 (95% CI = 246, 268) carriers, about 20% of the carrier population, were identifiable. Of these approximately 112 were index cases, 108 were asymptomatic relatives, and 37 were previously affected relatives. This contrast emphasises the importance of ascertainment and acceptance rates. Likewise the low number of index cases shows that case identification is a limiting factor. In the absence of robust data from epidemiological studies, these findings can inform decisions about the use of cascade genetic testing for mismatch repair gene mutations.

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Abbreviations

MMR:

Mismatch repair

CRC:

Colorectal cancer

CGTM:

Cascade Genetic Testing Model

GPM:

Genetic Population Model

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Acknowledgements

This work was funded by the Chief Scientist Office of Scotland, grant no. CZH/4/145. The University of Edinburgh acted as sponsor, with vital collaboration from Heriot-Watt University. In addition to the work carried out by the authors, we acknowledge the expert input from Kenneth MacLeod regarding computer programming, and the support provided by Rosa Bisset.

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Correspondence to R. J. Mitchell.

Appendix 1

Appendix 1

Key input data to Genetic Population Model

Input data

Point estimate (if applicable)

Source/reference

Comments on data accuracy/quality

Generalisability

Population size

5,094,800 (2005)

GROS

Robust estimate based on census data

Scotland is a relatively small country but data may be extrapolated to populations with similar demographics

Demographic structure

 

GROS

Robust estimate

Scotland has a demographic structure that is typical of an aging population in a developed country

Deaths (historical data)

 

GROS

Robust national data

Scotland is broadly representative of developed countries with respect to mortality rate

Deaths (projections)

 

GAD

Projections only

The projected continuation of decreasing mortality rates for Scotland is typical of developed countries

Births

 

GROS

Robust national data

Fertility in Scotland, as with many developed countries, has decreased during the latter part of the 20th century

Births (projections)

 

GAD

Projections only

The projected continuation of decreasing fertility rates for Scotland is typical of developed countries

Disease incidence

 

ISD

Disease incidence has been recorded with a high degree of accuracy since the 1960s; earlier data is of poor quality

Scotland has a relatively high incidence of colorectal cancer, but incidence is comparable with other countries in which the disease is a public health issue

Disease incidence (projections)

 

ISD

Projections, based on current trends and demographic projections

The increasing incidence projected for Scotland is reflected in many other populations

Penetrance of MMR gene mutations

To age 70:

males: 80%

females: 40%

Scientific literature

Limited sources of data, various methods, wide confidence intervals

There is currently no evidence of population variations since differences in published estimates are likely to be due to methods used and lack of statistical power. However, penetrance may vary according to the precise mutation involved and numerous other factors, and may therefore vary by population

Prevalence of MMR gene mutations

1:3,139 (95% CI 1:1,247, 1:7,626)

Scientific literature

One source of data only, wide confidence intervals

Prevalence data are scarce, and the single published estimate relates to Scotland. Prevalence is likely to vary by country, particularly when common founder mutations are present in the population (e.g. Finland), but there is no evidence to suggest that Scotland is not representative in this respect

Disease survival

 

ISD

Robust national data

In terms of survival, Scotland is representative of countries with modern health care systems

Family structure

 

ONS

Data on frequency distribution of children as well as completed family size is limited to one reliable source

Family structure may vary across populations according to cultural, social and demographic trends. However, Scotland has a stable population which is useful for comparisons, and the observed trend of decreasing family size leading to stabilizing or decreasing population is common

  1. GROS = General Register Office Scotland, GAD = Government Actuary’s Department, ISD = Information Services Division Scotland, ONS = Office of National Statistics, CI = Confidence interval

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Mitchell, R.J., Ferguson, R.K., Macdonald, A. et al. Cascade genetic testing for mismatch repair gene mutations. Familial Cancer 7, 293–301 (2008). https://doi.org/10.1007/s10689-008-9192-x

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  • DOI: https://doi.org/10.1007/s10689-008-9192-x

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