HEREDITARY COLORECTAL CANCER:
CANCER RISKS, SCREENING STRATEGIES AND THE ESTABLISHMENT OF
A HEREDITARY COLON CANCER REGISTRY
Assoc. Prof. Dr. Wendy Lim
Colorectal cancer is a major public health problem and a leading cause of cancer mortality in the western world. In Malaysia, it is now emerging as the third commonest cause of cancer in both males and females. The age standardized incidence is estimated at 10.4 per 100 000 population (Second Report of the National Cancer Registry, 2003). Ethnic variation is also observed with the disease being most common amongst the Chinese.
Environmental factors and genetics play varying roles in the aetiology of colorectal cancer. About 80% of colorectal cancers arise sporadically with no evidence of genetic susceptibility. In the remaining cases, genetic factors play a significant role. Hereditary forms of colorectal cancer are distinguished by the presence or absence of polyposis. The polyposis types are characterised by multiple colorectal polyps. These polyps can be adenomatous, hamartomatous, hyperplastic or polyposis with mixed pathology.
Examples are familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome and juvenile polyposis. Nonpolyposis colorectal cancer can be subdivided into hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome, hereditary colorectal-endometrial cancer syndrome) and families with clustering of colorectal cancer at an advanced age.
This review will focus on the colorectal cancer risks in these inherited colorectal cancer syndromes and the screening strategies in these high risk groups of patients. Also briefly discussed will be the rationale for establishing a hereditary colon cancer registry in Malaysia.
Hereditary nonpolyposis colorectal cancer (HNPCC)
HNPCC is transmitted as an autosomal dominant disease. It is associated with
germline mutations in five DNA mismatch repair (MMR) function, ie,
MSH2, MLH1, PMS1, PMS2 and MSH6. HNPCC accounts for about 3-5% of all
colorectal cases. A few studies have been performed on the cancer risk estimated
in proven mutation carriers and there may be possible differencs in risk between
carriers of the various mutations.
Individuals from HNPCC families are at high risk of developing colorectal cancer (70% to 85%), Colorectal cancer is often diagnosed at an early age (mean, 45 years), is multiple (synchronous or metachronous colorectal cancer present in 35% of patients), and, is located in the proximal part of the colon in two thirds of cases. The adenomas that occur in HNPCC tend to develop at an early age but florid polyposis is not a feature. Extracolonic cancers occur at sites such as the endometrium, renal pelvis/ureter, stomach, small bowel, ovary, brain, and hepatobiliary tract; sebaceous tumors.
In 1990, the International Collaborative Group (ICG) on HNPCC proposed a set of clinical diagnostic criteria (the Amsterdam criteria) to provide uniformity in the clinical diagnosis of HNPCC. Over the years, the initial Amsterdam criteria has undergone revisions and recently the ICG has recently proposed a definition of HNPCC that comprises all typical features of HNPCC. The higher the number of these features observed in a given family, the higher the suspicion of HNPCC. However, families initially suspected of HNPCC but not meeting the criteria should not be falsely reassured and excluded from genetic counseling and DNA testing if suspicion is still high enough for the diagnosis of HNPCC.
Familial clustering of late onset colorectal neoplasms
Cases of colorectal cancers that meet each of the Amsterdam criteria except
the age criterion have been described. All colorectal cancer cases were diagnosed
at ages greater than 50 years. There is a preponderance for distal tumors,
a low incidence of multiple primary colon cancers, and a high incidence of
adenomas associated with colorectal cancer. Extracolonic cancers frequently
encountered in HNPCC, such as endometrial cancer, are not seen in these families.
Mutation analysis in such families has not revealed any mutation in the DNA
mismatch repair (MMR) genes. Other investigators suggest the possible
roles of other genes, such as APC gene (I1309K) and transforming growth factor-beta
type II receptor gene, in the pathogenesis.
Familial adenomatous polyposis (FAP)
FAP is an autosomal dominant syndrome with a germline mutation of the APC
gene on chromosome 5q21. It occurs in 1 in 8300 to14025 live births with an
average age of diagnosis from 35 to 43 years. In addition to diffuse multiple
(>100) colonic adenomas, polyps in the small intestine and stomach can
be found. Extraintestinal manifestations such as cutaneous lesions (fibromas,
lipomas, sebaceous and epidermoid cysts), desmoids tumours, pigmented ocular
lesions (congenital hypertrophy of the retinal pigment epithelium), osteomas,
nasopharyngeal angiofibromas have been described. These individuals are also
at an increased risk of developing extracolonic malignancies such as upper
gastrointestinal tract malignancies (duodenum and periampullary area), hepatoblastoma,
biliary tree, pancreas, thyroid and brain.
Mutations in the 5' (5' to codon 158) and 3' (3' to codon 1596) ends of the APC gene are associated with a less severe form of FAP. This variant is known as attenuated familial adenomatous polyposis with less polyposis and a delayed onset of colorectal cancer (on average 12 years) than in classic FAP.
Peutz-Jeghers syndrome (PJS)
PJS is an autosomal dominantly inherited syndrome characterised by muccocutaenous
pigmentation and gastrointestinal polyposis. The most common cancers represented
are gastrointestinal in origin - gastrooesophageal, small bowel, colorectal,
and pancreatic - and the risk for these cancers at ages 30, 40, 50, and 60
years was 1%, 9%, 15% and 33% respectively. In addition to an elevated risk
of gastrointestinal cancers, an increased risk of cancers at other sites such
as breast, ovary, uterus, cervix, lung and testis has been described. In women
with PJS the risk of breast cancer was substantially increased, being 8% and
31% at age 40 and 60 years respectively.
Germline mutations in the serine/threonine kinase gene (STK11), a
tumour suppressor gene, on chromosome 19p13.3 have been shown to cause PJS.
A causative germline mutation in STK11 can be identified in between
30% - 80% of PJS patients. Failure to identify a STK11 mutation in
all PJS patients suggests that the disease may be genetically heterogeneous.
Juvenile polyposis (JP)
Juvenile polyposis (JP) is an uncommon autosomal dominant inherited condition
characterized by multiple (usually 50 to 200) juvenile polyps in the colorectum
and, in certain cases, in the stomach and small intestine. Two genes have
been identified to be involved in JP, ie, SMAD4 and PTEN.
Several studies have shown that affected patients have an increased risk
of developing colorectal cancer. Among 87 patients known at the St Mark's
Polyposis Registry were 18 male patients with colorectal cancer, diagnosed
at an average age of 34 years (range, 15 to 59 years). It was estimated that
the risk of developing colorectal cancer was 68% by age 60 years.
Other polyposis syndromes
There are case reports and series of patients with large numbers of hyperplastic
polyps (hyperplastic polyposis) and some with multiples polyps of mixed pathology
(mixed polyposis syndromes). These reports suggest that these patients have
a preponderance of colon cancer.
Colorectal cancer risks
The risks of colorectal cancer associated with these familial groups are outlined
in the table below:
| Family groups |
Lifetime risk of death from
colorectal cancer
|
| Familial Adenomatous Polyposis (FAP) |
1 in 2.5
|
| Hereditary Nonpolyposis Colorectal Cancer(HNPCC) |
1 in 2
|
| Juvenile polyposis (JP) |
1 in 3
|
| Peutz-Jeghers syndrome (PJS) |
1 in 3
|
| More than 2 first degree relative with colorectal cancer |
1 in 2
|
| 2 first degree relative with colorectal cancer |
1 in 6
|
| 1 first degree relative with colorectal cancer <45 y |
1 in 10
|
Recommendations for colorectal cancer screening and surveillance in patients
with hereditary colorectal cancer
With the increased risk of colorectal cancer in the groups described, various
screening strategies have been devised (see appendix 2). Early detection of
cancer and timely appropriate therapy is the cornerstone of cancer prevention
efforts. Only then will reduction in cancer mortality is achieved in these
high risk groups of patients.
Prevalence of hereditary colorectal cancer in Malaysia
Accurate data on the prevalence of hereditary colon cancer in Malaysia is
currently not available as no customized registry exists to collect such information.
| Family groups |
Age at initial screening
(years)
|
Screening procedure
|
Interval
|
| FAP |
10-12 30 |
Sigmoidoscopy Duodenoscopy |
2 yearly 1-5 yearly |
| Attenuated FAP |
15-20
|
Colonoscopy
|
2 yearly
|
| HNPCC |
20-25 30-35 |
Colonoscopy |
2 yearly 1-2 yearly |
| Juvenile polyposis (JP) |
25(?)
|
Colonoscopy
|
3-5 yearly
|
| Peutz-Jeghers syndrome (PJS) |
15-20 |
OGD, small bowel follow through |
2 yearly
2 yearly |
| 2 or more first degree relative with colorectal cancer |
At 1st consultation/ age 35-40y whichever is the later
|
Colonoscopy
|
5 yearly
|
| 1 first degree relative with colorectal cancer <45 y |
At 1st consultation/ age 35-40y whichever is the later
|
Colonoscopy
|
5 yearly
|
Future Directions - establishment of a hereditary colon cancer registry
There are currently at least 142 registries established in 31countries. At
present, no such registry exists in Malaysia. The key areas benefiting from
establishing a hereditary colon cancer registry are:
1. Patient care and education
- A computerized database makes risk assessment and person contact easier.
- Identification of high risk patients for colorectal cancer by virtue of their family history.
- Follow up of family history is important as self reported family history is not wholly accurate.
- Educating patients and families on the nature and implications of inherited colorectal genetics.
- Selection of appropriate screening tests to detect cancer early, thereby reducing mortality from colon cancer.
- Selection of appropriate therapy.
- Providing specialized counselling and appropriate genetic testing.
2. Education of healthcare professionals
- Educating physicians, surgeons, geneticists, pathologists and basic scientists about the basics of colorectal cancer genetics and their clinical implications.
- Fostering collaboration with other inherited colorectal cancer registries throughout the world.
- Ensure that the same screening protocol is offered to the various branches of large families that are followed-up by different specialists.
- Focus of audit in terms of service delivery and outcomes such as results of long term surveillance.
3. Research
- In line with Universiti Putra Malaysia's status as a centre of excellence for research, the registry will facilitate clinically important research on inherited colorectal cancer from data collected in the registry.
- Researchers (e.g. Doctorate and post doctoral researchers) that are likely
to benefit from the use of patients' data and tissue samples in the conduct
of studies include those from the departments of:
I. Medicine
II. Surgery
III. Pathology
IV. Immunology
V. Community Health
VI. Bioscience - Generate data for publication of original scientific papers.
- Provide a more accurate and refined prevalence estimates of hereditary colon cancer in Malaysia.
Conclusion
Hereditary colon cancer is a heterogenous disease with differing clinical
histopathological and molecular features. Diagnosis of some cases may be difficult
in atypical forms. Cancer surveillance of these high risk patients can result
in lower incidence, morbidity and mortality. A multidisciplinary approach
is required in the management of these individuals. Establishment of a national
registry will be valuable in identifying these at-risk patients and monitoring
surveillance.
References
|