The Natural History and Genetics of Hyperplastic Polyposis
Protocol
WS Atkin MPH PhD
IPM Tomlinson PhD MRCPath
MJ Lockett BSc MBBS
Hyperplastic polyps are common and are generally thought to have no role in the development of
colorectal cancer. Hyperplastic polyposis, on the other hand, is recognised by the World Health
Organisation as a disease and is thought to be associated with a significant risk of colorectal cancer.
Seven cases of hyperplastic polyposis were described in 1980 by pathologists at St Marks Hospital 1.
Since then only a few other cases of hyperplastic polyposis have been described in the literature 2,
and little is known about its natural history. In addition to multiple polyps, patients with hyperplastic
polyposis may have a predisposition to develop colorectal cancer at an early age 3, 4 and cancer has
been found in 45% of cases at the time of diagnosis. However, in the absence of cancer the disease is
usually asymptomatic, so this high prevalence may be the result of selection bias. Follow up data are
scarce, but suggest that a further 20% without cancer will go on to develop cancer. A family history of
colon cancer is not a feature of this disease, although one familial case has been described 5].
However, in the majority of the hyperplastic polyposis cases described relatives have not been
investigated to exclude a family history. As an autosomal dominant inheritance pattern has not been
observed it is almost certain that if there is a genetic component, it will only be partially penetrant (a
susceptibility gene) and it is not expected that there will be any implications for the patients’ families.
Risk of the condition may therefore be associated environmental exposures such as cigarette
smoking, alcohol or diet. This is plausible since risk of sporadic hyperplastic polyps is associated with
smoking and meat consumption 6, 7. It is unlikely that these factors on their own would cause this
dramatic condition and some predisposition gene is likely to be the underlying cause, perhaps by
increasing susceptibility to environmental factor(s) 8-10.
Hyperplastic polyposis has usually appeared in the literature as individual case reports and only rarely
has there been any follow-up reported. Therefore, the natural history and ideal management strategies
for these patients are not known. Management currently ranges from regular colonoscopy to
colectomy.
We do not know the cause of hyperplastic polyposis. There has been some evidence to suggest that
the hyperplastic polyps in patients with hyperplastic polyposis have genetic mutations 11. We aim to
determine whether hyperplastic polyposis occurs because of mutations occurring in the polyps only or
whether mutations affect the entire large bowel lining or are found in all the patients cells. This may
have implications for their management or for screening of relatives. It may also provide evidence for a
new pathway by which a small proportion of colon cancers develop. By comparing the genetic
alterations in hyperplastic polyposis polyps with those in sporadic hyperplastic polyps, which appear
not to progress, we hope to identify the genes responsible for driving this pathway.
Outline of project
This is a descriptive case series of patients with hyperplastic polyposis to try to identify all cases seen
in the United Kingdom in recent years. As most hospitals do not have a diagnostic code for this
condition it is not possible to search hospital databases and we must rely on recall of cases. We are
doing this by sending mail-shots to members of the:
 Association of Coloproctology of Great Britain and Northern Ireland
 British Society of Gastroenterology
 Royal College of Pathologists
We will also contact the UK Cancer Registries to establish how we might identify cases from their
records.
The Consultant in charge of the patient’s care will be asked to send a letter to the patient on their
hospital headed notepaper asking the patient’s permission for their contact details to be forwarded to
us. We will then write to the patient giving them information about our research and a consent form to
sign. We will request access to their medical records and contact the patient by telephone at a time
convenient to them to build up a picture of the natural history. We will ask permission to borrow tissue
samples removed previously and stored locally and for the collection of a single 20-millilitre blood
sample. This will either be collected by us at St Marks hospital or arranged at a location convenient to
the patient and sent by courier to St Marks Hospital. These specimens will be used for genetic tests.
We propose to use a cytogenetic technique to screen the entire genome for chromosomal
amplifications or deletions to try to identify candidate causative genes. We shall look for mutations in
genes known to play a role in the adenoma-carcinoma sequence and microsatellite instability (a
marker of a defect in DNA mismatch repair) which is the mechanism responsible for the genetic
mutations that occur in about15% of sporadic colorectal cancers.
The genetic tests we are proposing to carry out are used routinely at the ICRF units at St Marks
Hospital and Lincoln’s Inn Fields and have previously been successful in identifying the causative
mutation in another rare polyposis syndrome 12.
Aims
 To identify as many patients as possible in the UK who have been diagnosed with the rare
condition hyperplastic polyposis.
 To describe the clinical features and lifestyle of patients with hyperplastic polyposis.
 To determine whether patients with hyperplastic polyposis have a family history of multiple
hyperplastic polyps suggesting that the condition may be inherited.
 To determine whether any genetic mutations are associated with hyperplastic polyposis. If so, do
these mutations occur only in the polyps, do they affect normal colonic mucosa, or are they found
in all the patients cells and can therefore be passed on to the next generation?
 To compare the genetic mutations that occur in hyperplastic polyps of patients with hyperplastic
polyposis with those that occur in sporadic hyperplastic polyps.
 To make recommendations for the management of patients with hyperplastic polyposis.
Patient Recruitment
A letter will be sent out to GI surgeons, Gastroenterologists and Histopathologists as a mail-shot from
the main UK association.
Doctors with any potentially eligible patients will write to Dr Wendy Atkin at St Marks Hospital to
confirm suitability for inclusion.
Patients with thirty or more colonic hyperplastic polyps or those with five or more hyperplastic polyps
proximal to the sigmoid colon with or without an associated adenocarcinoma who have agreed to
participate in the research.
Exclusion Criteria
Patients incapable of providing informed consent.
Patients who are too unwell to participate.
Patients who are unwilling to participate.
Initial Patient Contact
We will send a letter for the Consultant in charge of the patient’s care to send to the patient on their
Hospital Headed notepaper (Appendix 1). This requests the patient’s permission for us to contact
them. .If they agree their contact details will be forwarded to us.
Patients will be sent an information sheet (Appendix 2) and a consent form (Appendix 3). Non
responders will be sent a reminder letter (Appendix 2B) and a second information sheet after two to
four weeks Subjects returning the forms and wishing to participate will be entered into the case series.
The study
Copies of medical notes and tissue blocks relating to the diagnosis of hyperplastic polyposis will be
requested from the local hospital.
The patient will be telephoned at a time convenient to them to ask a few questions about the diagnosis
and their lifestyle and family history (Appendix 4).
A letter will be sent to the patient’s GP (Appendix 5) informing him of the research and if the patient
lives a distance from St Marks Hospital asking to help by taking a blood sample.
The patient will be asked to give a single blood sample. This will either be taken at St Marks Hospital,
or alternatively the bottles and instructions (Appendix 6) will be sent to the patient so that they can
arrange for the sample to be taken locally.
Specimen Handling
The tissue blocks will be sent to St Marks Hospital by post. Sections will be cut from each block for
DNA extraction and immunohistochemical tests. The blocks will be returned to the local Hospital when
all tests are completed.
The blood samples will be sent to St Marks Hospital by first class post on the day of collection and
frozen for subsequent DNA extraction.
References
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Jorgensen H, Mogensen A, Svendsen L. Hyperplastic polyposis of the large bowel. Three
cases and a review of the literature. Scand J Gastroenterol 1996;31:825-30.
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Keljo D, Weinberg A, Winick N, Tomlison G. Rectal cancer in an 11 year old girl with
hyperplastic polyposis. J Pediatr Gastroenterol Nutr 1999;28:327-32.
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Bengoechea O, Martinez-Penuela J, Larrinaga B, Valerdi J, Borda F. Hyperplastic polyposis of
the colorectum and adenocarcinoma in a 24-year-old man. Am J Surg Path 1987;11:323-7.
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Jass J, Iino H, Ruszkiewicz A, Painter D, Solomon M, Koorey D, Cohn D, Furlong K, Walsh M,
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