Laboratory screening for germline mutations that
predispose to cancer is an appealing idea but screen-
ing for a mutation is only of practical value when
four conditions are met: (1) the mutation must confer
an appreciable risk of cancer, (2) screened individu-
als must have a significant probability of harboring
the mutation, (3) the screening laboratory study must
have acceptable diagnostic performance, and (4)
there must be something that can done to substan-
tially reduce the risk of developing invasive cancer
in individuals who have the mutation (Ponder 1997).
Unless the risk of cancer is increased to an
unacceptable level by the presence of an oncogenic
mutation, individuals will not be willing to undergo
a test for the mutation, especially if the test is expen-
sive. If the baseline risk for a cancer is high, such
as with the most common cancers, a modest
mutation-related increase in the risk of the cancer
may yield an level of risk that is unacceptable to
most individuals. Thus, for these cancers, even
mutations with relatively minor oncogenic effects
may be desirable targets for screening. If the
baseline risk for a cancer is low, a mutation needs to
have a major oncogenic effect to be considered for
screening because only a dramatic mutation-related
increase in the risk of the cancer will result in a
unacceptable level of risk for the cancer.
The prevalence of oncogenic germline mutations
is very low. Screening random individuals for one
of these mutations would therefore be inefficient
and, if the screening test did not have perfect speci-
ficity, there would be a large number of false-
positive results. To minimize these problems,
screening studies are performed only on individuals
who have an increased likelihood of having the
mutation as indicated by a family history of the type
or types of cancer associated with the mutation.
Screening for oncogenic mutations relies primar-
ily on molecular diagnostic studies. These studies
normally have excellent specificity. They are, how-
ever, usually limited to the detection of well-
characterized mutations. Consequently, the diag-
nostic sensitivity of a study will be very high among
members of families with well-characterized
mutations but will be it will be very low among
individuals who come from families with novel
mutations. The overall sensitivity of a study will be
determined by the proportion of families who have a
predisposition to cancer due to well-characterized
mutations. For those cancers in which the sensitiv-
ity of the laboratory screening test is unsatisfactory,
the practical solution is to use the family history as
the screening tool.
Screening for a predisposition to cancer is
clearly justified when there is an intervention that
can be undertaken to lessen or eliminate the risk of
developing the cancer. This may mean something as
simple as a change in lifestyle designed to lessen the
exposure to a carcinogen implicated in the develop-
ment of the cancer but, more often, it means prophy-
lactic removal of the organ or organs likely to
develop the cancer. In the absence of intervention
options, screening can be useful for identifying those
individuals who should undergo intensified cancer
surveillance. This usually consists of early institu-
tion of cancer screening and shorter screening inter-
vals to account for the tendency for an early age of
appearance in mutation-related cancers and for their
rapid evolution into invasive and metastatic disease.
Colorectal cancer is an example of a cancer that
has hereditary forms. Two of these are familial
adenomatous polyposis and hereditary nonpolyposis
colorectal cancer (HNPCC). HNPCC is responsible
for approximately 5 percent of the cases of colorec-
tal cancer. It can be caused by loss-of-function
mutations in a number of DNA mismatch repair
genes; about half of the cases are caused by
mutations in hMLH1 and hMSH2 (Boland 2000,
Lynch and de la Chapelle 1999). Mutations in either
hMLH1 or hMSH2 result in an 80 percent probabil-
ity of developing colorectal cancer and, in females, a
40 to 60 percent probability of developing endome-
trial cancer (Vasen
et al.
1996). Carriers of
mutations in hMSH2 also have an increased risk of
cancer of a number of other organs. There are two
clinical approaches available to reduce the burden of
this very high probability of developing cancer. In
the first approach, the risk of developing invasive
cancer is lowered by beginning a program of annual
colonoscopic surveillance when an individual at risk
for HNPCC is in his or her twenties (Lynch and
Lynch 2000). This program addresses the earlier
age of onset of the hereditary form of the cancer.
The program also accounts for the preference for
proximal colon (colonoscopy) and the shorter
adenoma-to-carcinoma transition time (annual proce-
dures). In the second approach, prophylactic subto-
tal colectomy is performed, reducing the risk of
developing cancer by removing most of the tissue at
risk (Lynch and Lynch 2000).
Individuals at increased risk for a predisposition
to colorectal cancer are identified by a family history
Cancer
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