Genetic counseling should be an integral component of the management
of hereditary cancer. This paper will provide an overview of genetic
counseling in cancer using hereditary nonpolyposis colorectal
cancer (HNPCC) as a prototype. Our purpose will be to describe
an approach to genetic counseling that is in concert with the
genetics, natural history, surveillance, and management of HNPCC.
Hereditary colorectal cancers are exceedingly heterogeneous (Figure
1). Hereditary nonpolyposis colorectcal cancer, one subset of
these disorders, is subdivided into Lynch syndromes I and II.
Lynch syndrome I is characterized by early-onset (age, 40 years)
colorectal cancer that shows a predilection (70%) for the proximal
colon (ie, to the right of the splenic flexure) and has a high
rate of metachronous colorectal carcinoma. (In patients who undergo
less than a subtotal colectomy for the initial cancer, the rate
of metachronous cancer is approximately 45% by age 40.) The Lynch
syndrome II variant has all of the features of Lynch syndrome
I, but in addition, includes a litany of extracolonic cancers.
Foremost among these is endometrial carcinoma, followed by carcinoma
of the ovary, small bowel, stomach, and pancreas, and transitional-cell
carcinoma of the ureter and renal pelvis. The penetrance of the
HNPCC genes is about 90% [1,2].
Although HNPCC is not a polyposis disorder, affected individuals
do form colonic adenomas, and there is strong circumstantial evidence
that these adenomas are precursor lesions to malignancy.
The colorectal malignancies in HNPCC do not have unique histologic
features, but some differences have been observed when large series
of HNPCC and sporadic colon cancer cases have been compared. Most
comparison studies indicate that HNPCC is more likely to produce
poorly differentiated carcinoma, coupled with an excess of mucinous
and signet-cell histologies. A small, but significant percentage
(9%)  of colorec tal cancers in HNPCC form solid sheets of
cells with an expanding growth pattern and a marked host lymphocytic
response-a pattern that has been referred to as "medullary
carcinoma" by Jessurun and Manivel . This pattern is interesting
because it is the usual histology of sporadic colon cancers with
defective mismatch repair . In turn, this immunologic response
may be responsible for the improved prognosis noted in some HNPCC
Molecular genetic studies have identified germ-line mutations
in an increasingly large number of hereditary cancer syndromes
(Table 1). The genetic basis for HNPCC has been proved by genetic
linkage between cancer occurrences and chromosome 2p in some families
and chromosome 3p in other families [7,8].
Localization of a DNA mismatch repair gene in the critical region
of chromosome 2p was documented by Leach et al  and Fishel
et al  with the discovery of hMSH2 mutations in this gene
in several HNPCC families. Subsequently, a second mismatch repair
gene (hMLH1) was identified in the critical region of chromosome
3p, and mutations of that gene were found in the HNPCC families
previously linked to chromosome 3p [11,12]. Mutations in these
genes appear to account for 90% of all known HNPCC families .
Also, hPMS1 and hPMS2 have been demonstrated to be mismatch repair
genes in HNPCC .
Defective DNA mismatch repair results in a steady accumulation
of mutations. The mutation load can be detected as errors in long
tandem repeat sequences, which produce microsatellite instability.
A tumor with microsatellite instability is said to show replication
error phenotype (RER+).
Vasen et al  followed a cohort of 51 HNPCC families that included
394 first-degree relatives who participated in a nationwide colonoscopy
surveillance program. During mean follow-up of 5 years, these
researchers observed an unexpectedly high rate of advanced colorectal
cancers, which were diagnosed within 2 to 5 years after a negative
colon screening examination. The shortest interval between a negative
screening examination and the diagnosis of colorectal carcinoma
was 2 to 3 years (six patients).
Our experience with interval cancers has been comparable. For
example, a woman with Lynch syndrome II who had manifested endometrial
carcinoma at age 36 years underwent colonoscopies every 2 years.
Eighteen months after a normal colonoscopic evaluation, she was
diagnosed with a Duke's B1 cancer of the transverse colon and
underwent a segmental colonic resection. At that point, she insisted
on having colonoscopies every 6 months. Five months after her
most recent colonoscopy, she was found to have two primary colon
cancers-a Duke's B1 tumor in the cecum and a Duke's A lesion in
the lower rectum.
There are several possible explanations for these interval cancers:
First, lesions may have been missed at the time of colonoscopy.
Also, it is possible that the gene accelerates the progression
of adenomas, even those that are very small, to cancer. The latter
explanation is consonant with postulates of Jass et al  who
suggested that adenomas in HNPCC are more likely to show a villous
growth pattern with a high degree of dysplasia than are adenomas
in a necropsy series, and that these features cause the HNPCC
adenomas to undergo more rapid malignant transformation. The hypothesized
rapid progression of the adenoma-carcinoma sequence in HNPCC,
which may be as short as 2 to 3 years, is in striking contrast
to findings from the National Polyp Study, which found that the
adenoma-carcinoma sequence in the general population is about
8 to 10 years.
Another potential explanation for interval cancers in HNPCC is
that gene carriers develop "de novo" cancers [17,18].
Adenomas and Accelerated Carcinogenesis
As mentioned above, strong circumstantial evidence suggests that
adenomas are precursor lesions to malignancy in patients with
HNPCC [19-21]. Leach et al , however, found that the HNPCC
genes do not initiate adenoma development, but rather accelerate
adenoma evolution. In turn, Cannon-Albright et al  have shown
that genetic factors are responsible for proneness to develop
It is hypothesized that when adenomas do occur in patients with
HNPCC, they are more likely to progress to carcinoma than are
adenomas in the general population. In theory, the "mutator
phenotype" of HNPCC could drive the promotion of adenoma
to carcinoma, once the neoplastic process has been initiated.
The existence of "aggressive adenomas" in HNPCC is supported
by prospective surveillance studies showing a much lower adenoma-to-carcinoma
ratio than in the general population. Jarvinen et al , for
example, found 22 adenomas and 5 cancers in HNPCC families over
a 3-year period. In the Netherlands, 14 adenomas and 6 cancers
were discovered in a screening program of HNPCC kindreds ,
and Jass et al  in New Zealand found 25 adenomas and 2 cancers.
In contrast, data from the National Polyp Study suggest that 41
to 119 polypectomies are required to prevent 1 colorectal cancer
in the general population [17,18].
Knowledge of the natural history and molecular genetics of HNPCC
has been useful in developing the following guidelines for surveillance
(Table 2) and management of high-risk patients:
Genetic Counseling is initiated at age 20 years.
Full Colonoscopy--We recommend that these patients undergo
full colonoscopy beginning sometime between age 20 and 25 (flexible
sigmoidoscopy is not adequate). Colonoscopy is repeated
every 2 years to age 35 and annually thereafter. If colonoscopy
expertise is unavailable, double air-contrast barium enema can
be used instead.
Endometrial Curettage should be done yearly, beginning
at age 30 years.
Ovarian Screening--Transvaginal ultrasound, Doppler color
blood flow imaging, and CA 125 determinations are all initiated
at age 30 years and are repeated annually thereafter.
Patients Who Develop Colorectal Cancer--If colorectal cancer
occurs, surgical resection must be no less than a subtotal
colectomy because the entire colonic mucosa is at risk for
malignant transformation. Women who have completed their families
at the time they manifest colorectal cancer are given the option
of undergoing a prophylactic total abdominal hysterectomy and
bilateral salpingo-oophorectomy at the time of their subtotal
Prophylactic Surgery--Individuals who have germ-line mutations
(hMSH2, hMLH1, hPMS1, hPMS2) are given the option of prophylactic
subtotal colectomy or lifetime colonoscopy screening.
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