| FAP |
— |
+ |
More frequent |
le>
|
|
| Disease |
Inheritance |
Gene penetration |
| HNPCC |
Autosomal dominant |
85-90% |
| FAP |
Autosomal dominant |
100% |
HNPCC is due to mutations in mismatch repair genes (MMR) such as hMLH1, hMSH2,
hPMS2, hMSH3, hMSH6. Also the mutation of TGFbIIR, seen in HNPCC, allows escape
from inhibitory controls through interference between TGFb and the receptor.
Therefore in HNPCC, carcinogenesis is accelerated due to defective DNA mismatch
repair.
FAP occurs because of inactivation of both the alleles of the adenomatous
polyposis colli gene (APC gene; chromosome 5q21) which is a tumour suppressor
gene. This inactivation results in the loss of control of cell growth and
proliferation.
Criteria For Referral for Genetic Testing/counseling
HNPCC [13,14]
The minimum criteria for diagnosing an HNPCC family (Amsterdam criteria) are:
1.At least three relatives with histologically proved colorectal cancer. One
of them should be a first degree relative.
2.At least two successive generations should be affected.
3.In one of the affected relatives, colorectal cancer should be diagnosed
under 50 years.
As the phenotype expression in HNPCC may not fit into the above classical
Amsterdam criteria, the International Collaborative Group on HNPCC (ICG-HNPCC)14
has also included some additional criteria in the definition of HNPCC.
1.Familial clustering of endometrial cancer along with colorectal cancer.
2.Development of multiple cancers in the colon.
3.Associated cancer of stomach, ovary, ureter, renal pelvis, brain, small
bowel, hepatobiliary tract and skin (sebaceous tumours).
FAP [15]
All offsprings of an affected individual are at 50% risk of inheriting this
condition and are candidates for genetic counseling.
Therefore it is clear from the above criteria that, individuals who are thought
to be at 50% or more genetic risk, based on their position in the pedigree,
are primary targets for genetic counseling and testing. All other family members
who are interested apart from the above can also be counseled.
Method of Genetic Testing [6,16,17]
Genetic testing begins with the testing of an affected person to first identify
the mutant gene. Family members are then tested for the presence or absence
of the mutant gene.
Predictive molecular testing for all at-risk children is done at the age of
10-12.
The genetic techniques used are:
1.cDNA micro-array analysis.
2.Protein Truncation Test (PTT).
3.Linkage analysis using restriction fragment length polymorphisms (RFLP).
Test Results (What do they mean?) [18]
In both HNPCC and FAP, only when the particular mutation causing the disease
is documented and found to segregate within a family, is the test result considered
reliable and helpful for predicting the lifetime cancer risk of individual
family members.
Interpretation of Genetic Testing Results in HNPCC [13,19]
Molecular diagnosis of HNPCC is based on the search for mutant MMR genes.
Individuals who have an increased frequency of microsatellite instability
(MSI) are candidates for more expensive germline mutation analysis.
Current recommendations specify that abnormalities in 2 out of a minimum of
4 micro-satellites should be regarded as diagnostic of HNPCC.
Interpretation of Genetic Testing Results in FAP [12,20]
Presence of a mutant FAP gene (APC gene) on chromosome 5q21 is solely enough
for diagnosing FAP and it has a 100% penetrance.
This means that mutation carriers almost always develop the disease and the
absence of mutation gene in asymptomatic individuals from mutation positive
families excludes the disease.
If the APC gene mutation status in the family is unknown, no conclusion can
be drawn about a negative genetic test result.
Management Guidelines
This is proposed and can be considered even before the phenotype (clinical)
expression of the disease occurs.
|
TABLE 6
Management of established disease21
|
| Disease |
For
patients who have developed the disease |
| HNPCC |
Subtotal colectomy
with ileorectal anastamosis
+ life long surveillance of the remaining recto-sigmoid by colonoscopy.
+ transvaginal USG of endometrium and ovary
+ endometrium biopsy |
| FAP |
Options available
• Total colectomy and ileorectal anastomosis (IRA)
+ life long surveillance of remaining rectum by endoscopy or
• Proctocolectomy and ileal pouch - anal anastomosis or
• Total proctocolectomy and Brooke’s ileostomy or
• Total proctocolectomy and continent ileostomy |
TABLE 7
Screening guidelines for mutation carriers (family members who have
at least 50% risk)[ 6,22]
|
| Disease |
Clinical screening |
Genetic screening |
| HNPCC |
Complete annual colonoscopy
starting from the age of 20-25 years for detection of polyps |
Germ line mutation
testing for mutant MMR genes hMLH1, hMSH2. |
| FAP |
Annual procto- sigmoidoscopy
starting from 10 years of age. Per oral X-ray of jaw for osteomas. Ophthalmic
checkup yearly for CHRPE. . |
Identification of germline FAP
mutation |
|
TABLE 8
Prophylactic treatment of Genotype positive mutation carriers
|
| Disease |
Prophylactic surgical
treatment options |
| HNPCC 23,24 |
Same as that for
established disease
+ Total abdominal hysterectomy and Bilateralsalpingo- oophorectomy |
| FAP 25 |
Same as that for
established disease |
DISCUSSION
The understanding, diagnosis and management of hereditary colorectal cancer
was previously based on clinical and pedigree criteria. Attenuated and atypical
phenotypes (both in HNPCC and FAP), that did not meet the classical definition
cri teria of these two diseases, used to go undetected. Due to this there was,
and still is, a serious lack of cancer control in both HNPCC and FAP. Even in
FAP, a disease with striking phenotype of hundreds and sometimes even thousands
of colonic adenomas, there is a high incidence of metastatic colorectal cancer.[10]
A case of late disease expression, in both HNPCC and FAP, is another nagging
problem.
Clinicians have now acted based on the genetic understanding of these two diseases
and translated that knowledge into clinical patient benefit.
Early diagnosis of both classical HNPCC and FAP and their atypical phenotypes
is now possible.[18,22] Both HNPCC and FAP
are found to have an autosomal dominant inheritance with a high penetration
rate (90% and 100% respectively).[12,13]
Subject with a negative genetic test result for mutation in a family with a
history of a specific mutation can now be more confidently dismissed from clinical
screening protocols, established specifically for HNPCC and FAP.[12,13]
Hereditary colorectal cancer can now be divided into two categories based upon
molecular genetic findings.[12,13]
Category 1 : Tumours (such as HNPCC) that show MSI (microsatellite instability)
occur more frequently in the proximal colon, have diploid DNA, harbour characteristic
mutations such as TGFbIIR, and behave indolently.
Cateogry 2 : Tumours (such as FAP with chromosomal instability (C/N), which
tend to be more in the left colon, show aneuploid DNA, harbour characteristic
mutations in APC, K-ras and p53 genes and behave more aggressively.
In HNPCC, clinical screening of family members at risk can now be combined with
genetic screening for germline mutations in DNA MMR genes MLH1 and MSH2 that
are the common culprits.
Prophylactic subtotal colectomy (with prophylactic total abdominal hysterectomy
and bilateral salpingo-oophorectomy in females) and ileorectal anastamosis[23,24]
has been proposed for HNPCC germline mutation carriers (i.e. genotype positive
subjects). This is based on the finding that lifetime risk of colon cancer is
80-85% in Lynch syndrome in genotype positive patients.[24]
This issue requires careful genetic counseling of mutation carriers to ensure
the acceptability of prophylactic surgery among them.
All patients of FAP require surgery.[12] The options available
are listed in Table 6.
Vasan et al studied 87 patients with known APC mutations following IRA and demonstrated
that requirement of a second operation was significantly higher in patients
with mutations distal to codon 1250 than in patients with mutations upstream
of this codon.[25] Church et al showed that majority of patients
who required removal of rectum after an IRA or after partial colectomy carried
a mutation at codons 1309 or 1328.[26]
Thus mutation locus is another factor which should be considered in deciding
whether IRA is appropriate for an FAP patient.[12,13,25,26]
As regards screening of at-risk individuals in FAP families, the drawbacks of
a purely clinical approach are now overcome by a combined genetic and clinical
approach.[6]
Since FAP is 100% penetrant, it is proposed that genotype positive carriers
undergo prophylactic surgery.[25] The various options are
given in Table 8.
However, screening for extra-colonic malignancies in these hereditary diseases
remains an unresolved issue.[27]
Late onset phenotypes can now be diagnosed early. Mutations located at the extreme
5’end of the gene (exon 3 and 4) and distal to codon 1578 at the 3’end of the
gene are known to cause this type of phenotype.[28] Genetic
testing will now forewarn the clinician to expect this. n FAP, APC mutations
upstream of exon 9 or distal to codon 1445 will not develop CHRPE.[29,30]
Ophthalmic examination for CHRPE can be excluded from clinical screening protocols
for these patients.
Mutations in APC gene between codon 1445 and 1578 were associated with severe
desmoids, osteomas, epidermoid cysts and upper gastrointestinal polyposis.[12,25]
Therefore in subjects with these mutations increased chances of extra-colonic
manifestations should be suspected and sought for by further clinical and radiological
investigations.[7,8,12,13,18]
A passing mention about Peutz-Jegher’s syndrome,[6,31]
Muir Torre Syndrome [6] and Juvenile polyposis[6,32]
is worthwhile. These three extremely rare diseases have an autosomal dominant
inheritance, variable penetration and can all lead to colorectal cancer. Currently
only mutations in STK11 (alternatively denoted LKB1), located on chromosome
19p13, have been identified as a cause for Peutz-Jeghers syndrome.[31]
Juvenile polyposis coli (JPC) is shown to have SMAD4 mutations in some cases.[32]
However the significance of these findings remain unclear to date.
CONCLUSION
There is a definite need to differentiate between sporadic and hereditary colorectal
cancers by taking help from genetic clues. Management strategies for HNPCC and
FAP are different from those for sporadic colorectal cancer and should include
genetic counseling and testing of family members who are at risk of developing
these diseases.
Site of the mutation has a role in determining the type of operation that should
be considered for the disease to reduce re-operation rates. Furthermore, it
is also helpful in predicting the chance of developing extra-colonic manifestations
of the disease.
A combined clinical and genetic screening of mutation carriers will not only
detect HNPCC and FAP early, but will also eliminate the problems of atypical,
attenuated, and late onset phenotypes. Early detection, and even prophylactic
surgery in selected patients, will go a long way to reduce the morbidity and
mortality associated with occurrence of hereditary colorectal cancer.
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