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The changing face of familial colorectal cancer
Ayan Banerjea, Sue Clark and Sina Dorudi
BMJ 2005;330;2-3
doi:10.1136/bmj.330.7481.2
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Editorials
“minimalists who still hankered after the old style of
medicine . . . to do the least possible consistent with
good appearances.”3
The root of the reactionary culture, concludes
Dame Janet, is the fact that elected members (all
doctors) control the council. They see it as their job to
represent doctors rather than regulate them. Dame
Janet wants more medical members appointed rather
than elected, something that is unlikely to please rank
and file doctors who have rebelled in the past over
“taxation without representation.”
The old guard or minimalists are not entirely
philosophically bankrupt. They can gain some comfort
from another woman with an incisive mind, Onora
O’Neill. In her Reith lectures she argued that attempts
to replace trust with accountability may have gone too
far: “The efforts to prevent the abuse of trust are
gigantic, relentless, and expensive; their results are
always less than perfect.”4 There can never be so much
transparency that trust is no longer necessary, and the
challenge is to arrive at the correct balance of trust,
transparency, and accountability.
The government will respond to Dame Janet’s
report early this year, but if the GMC wants to improve
its performance—and survive—it will need to accept
many of Dame Janet’s proposals. This will mean
overhauling fitness to practise procedures that have
only just started, strengthening revalidation processes,
and yet again changing its constitution. Does it have
enough stomach for the battles ahead or will
expediency again prevail? I doubt its ability to reform,
but I’ll be happy to be wrong.
Richard Smith chief executive
UnitedHealth Europe, 10 Greycoat Place, London SW1P 1SB
(richardswsmith@yahoo.co.uk)
Competing interest: RS wrote a series of articles in the BMJ
highly critical of the GMC in the late 1980s.
1
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4
Shipman inquiry. Safeguarding patients: lessons from the past—proposals for
the future. 5th report. www.the-shipman-inquiry.org.uk/fifthreport.asp
(accessed 13 Dec 2004).
Friedson E. Professionalism reborn: theory, prophecy, and policy. Cambridge:
Polity Press, 1994.
Irvine D. The doctor’s tale: professionalism and public trust. London: Radcliffe,
2003.
O’Neill O. A question of trust. Cambridge: Cambridge University Press,
2002.
The changing face of familial colorectal cancer
Young patients with colorectal cancer should be assessed for genetic predispositions
2
DAVID M MARTIN/SPL
C
olorectal cancer is predominantly a disease of
elderly people in the developed world. The
annual incidence of more than 35 000 cases in
the United Kingdom means that many people have at
least one affected relative. Colorectal cancer in elderly
relatives may be due to shared environmental
exposure rather than a true genetic predisposition,
although the risk of developing colorectal cancer rises
with the number of relatives affected. Genetic factors
may have a role in up to 30% of cases,1 but only a small
proportion (less than 5%) of colorectal cancers arise in
families with strong histories in which tumours
develop at a young age (less than 50 years) and represent truly high risk inherited predispositions. Even so,
more than 1500 families per year need to be
counselled and screened.
Most hereditary colorectal cancers are attributable
to two recognised syndromes. Familial adenomatous
polyposis usually has a clear phenotype, characterised
by numerous (more than 100) adenomatous polyps in
the large bowel by the second to third decades of life,
which inevitably progress into cancers. This autosomal
dominant condition, caused by APC gene mutations,
has been a paradigm for the management of familial
colorectal cancer. The use of registries, genetic testing,
surveillance, and prophylactic surgery means that
familial adenomatous polyposis now accounts for less
than 0.5% of all new colorectal cancers, and patients’
life expectancy is much improved.2
Hereditary non-polyposis colorectal cancer syndrome accounts for the bulk of familial colorectal cancer.3 The name is misleading as these colorectal
cancers also arise from adenomas, but the degree of
Polyps in the colon
polyposis is less marked than in familial adenomatous
polyposis. Hereditary non-polyposis colorectal cancer
has a heterogeneous spectrum, and the phenotype is
more difficult to define than in familial adenomatous
polyposis.4 Some kindreds are predisposed to endometrial cancer, and other sites of cancer that may be associated include the stomach, ovaries, and urinary tract.
We now know that hereditary non-polyposis colorectal
cancer arises due to mutations in mismatch repair
genes.5 Mismatch repair proteins correct insertion and
deletion mutations that occur when DNA is copied
before cell division. Such errors accumulate markedly
in microsatellites, where the DNA sequence is
repetitive, and hence, these cancers are said to display
BMJ VOLUME 330
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Editorials
Revised Bethesda guidelines for identification
of patients who should be tested for
microsatellite instability9
Individuals with colorectal cancer before age 50 years
Individuals with synchronous or metachronous
colorectal cancer, or other cancers related to
hereditary non-polyposis colorectal cancer at any age
Individuals with colorectal cancer with MSI-H
histopathology diagnosed before age 60 years
Individuals with colorectal cancer and one or more
first-degree relatives with a hereditary non-polyposis
colorectal cancer related tumour, with one cancer
diagnosed before age 50 years
Colorectal cancer diagnosed in two or more first or
second degree relatives with tumours related to
hereditary non-polyposis colorectal cancer, at any age
microsatellite instability. There are several mismatch
repair genes and it appears that distinct gene mutation
patterns may underlie variability in the clinical phenotype of hereditary non-polyposis colorectal cancer
syndrome.
Stringent family history requirements, the Amsterdam criteria, were developed to identify families with
hereditary non-polyposis colorectal cancer for genetic
research.6 7 However, many families with hereditary
non-polyposis colorectal cancer do not fulfil these criteria despite carrying mismatch repair gene mutations.
Reliance solely on family history, which is often incomplete or limited by small family size, may hinder
diagnosis. Improved understanding of hereditary nonpolyposis colorectal cancer has led to the development
of the Bethesda guidelines, (box) that identify with high
sensitivity patients with colorectal cancer who may
harbour a genetic predisposition and should undergo
testing for microsatellite instability or mismatch repair
protein immunohistochemistry.8 9 If mismatch repair
defects are found the patient can then be appropriately
counselled and further tested for specific gene
mutations. Clearly, such services should be extended to
patients’ families. Ethical issues surrounding the implications of tests that discern hereditary syndromes are
complex, and the challenges posed by patients at high
risk who decline testing are difficult but merit careful
consideration.
Any young patient with colorectal cancer, or a
patient with synchronous or metachronous tumours
should best be assumed to have a genetic predisposition until proved otherwise. All patients under the age
of 50 years with cancers associated with hereditary
non-polyposis colorectal cancer should be appropriately counselled and offered further investigations.9
Clinicians dealing with these cancers should also be
alert to the common histological features of tumours
related to hereditary non-polyposis colorectal cancer—
they are characteristically right sided, poorly differentiated, mucinous, and densely infiltrated by lymphocytes.10 Histopathology reports may therefore raise
the suspicion of hereditary non-polyposis colorectal
cancer in a patient, even when criteria regarding
history criteria are not fulfilled.
The identification of such patients and their families
is important because of the implications for counselBMJ VOLUME 330
1 JANUARY 2005
bmj.com
ling, genetic testing, and surveillance. Screening for
colorectal cancer in families with hereditary nonpolyposis colorectal cancer has been shown to have
notable benefit,11 but the value of screening extracolonic sites needs further evaluation. Prophylactic
surgery may be an acceptable option for some patients
and should be discussed where appropriate. Hereditary
non-polyposis colorectal cancers may also have altered
prognostic outlook and selective chemosensitivity.12 13
Genetics and clinical practice need to be integrated
and additional resources assigned to the creation of
formal links between district general hospitals and tertiary referral centres capable of providing comprehensive genetic and clinicopathological analyses. The
potential benefits of surveillance and prophylactic surgery mean that the Bethesda guidelines (box) should
now be a part of routine clinical practice.
Research into the genetic mechanisms responsible
for familial colorectal cancer is pivotal to understanding this disease. An autosomal recessive form of
polyposis associated with a gene called MYH has
recently been characterised, and other genes or
molecular pathways predisposing to novel variants of
familial colorectal cancer may yet emerge. The genetic
spectrum of familial colorectal cancer should be
considered a “moving target” for the foreseeable
future.
Ayan Banerjea clinical research fellow
(a.banerjea@qmul.ac.uk)
Sue Clark consultant colorectal surgeon
Sina Dorudi professor of surgical oncology
Centre for Academic Surgery, Barts and the London Queen Mary
School of Medicine and Dentistry, Royal London Hospital, London
E1 1BB
Competing interests: None declared.
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M, et al. Environmental and heritable factors in the causation of cancer—
analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl
J Med 2000;343:78-85.
Bulow S. Results of national registration of familial adenomatous
polyposis. Gut 2003;52:742-6.
Vasen HF, Mecklin JP, Khan PM, Lynch HT. The international collaborative group on hereditary non-polyposis colorectal cancer (ICG-HNPCC).
Dis Colon Rectum 1991;34:424-5.
Lynch HT, Schuelke GS, Kimberling WJ, Albans WA, Lynch JF, Biscone
KA, et al. Hereditary nonpolyposis colorectal cancer (Lynch syndromes I
and II). Cancer 1985;56:939-51.
Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP,
et al. Clues to the pathogenesis of familial colorectal cancer. Science
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Vasen HF, Mecklin JP, Meera Khan P, Lynch HT. Hereditary
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Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for
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Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR,
Burt RW, et al. A National Cancer Institute workshop on microsatellite
instability for cancer detection and familial predisposition: development
of international criteria for the determination of microsatellite instability
in colorectal cancer. Cancer Res 1998;58:5248-57.
Umar A, Boland CR, Terdiman J, Syngal S, de la Chapelle A, Ruschhoff J,
et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal
cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst
2004;96:261-7.
Jass JR. Pathology of hereditary nonpolyposis colorectal cancer. Ann N Y
Acad Sci 2000;910:62-73.
Jarvinen H, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen L,
Peltomaki P, et al. Controlled 15-year trial on screening for colorectal
cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000;118:829-34.
Elsaleh H, Shannon B, Iacopetta B. Microsatellite instability as a molecular marker for very good survival in colorectal cancer patients receiving
adjuvant chemotherapy. Gastroenterology 2001;120:1309-10.
Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, et al.
Tumor microsatellite instability and clinical outcome in young patients
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