Hereditary nonpolyposis colorectal cancer (HNPCC) is a dominantly inherited
syndrome that is estimated to be responsible for between 0.5% to 5% of
all colorectal cancers. The syndrome is caused by germline mutations
in any of at least four mismatch repair genes.
In one study of HNPCC, mutations in the MSH2 gene were found in 44%
of the affected families, MLH1 gene mutations in 23% of families, and PMS1
and PMS2 gene mutations in 6% of families. In 27% of the affected families,
mutations could not be ascertained. [See Oncology News International, April
1997, for a review of HNPCC genetics.]
In carriers of the mutated genes, colo-rectal carcinoma develops typically
before the age of 50. The tumors appear in the proximal colon more often
than in patients with sporadic colon cancer. The lifetime risk of cancer
in carriers is close to 100%.
Since the 1970s, there have been reports of a possible survival advantage
for colorectal cancer in HNPCC patients.[4-6] In 1981, Henry T. Lynch and
colleagues hypothesized "that the genotype in hereditary cancer determines
both susceptibility and natural history, such that increased survival is
a manifestation of the natural history."
A recent study from Finland provides strong evidence in favor of this
hypothesis. The study included 175 patients with colorectal carcinoma
from 39 families fulfilling the Amsterdam criteria of HNPCC. Of these
patients, 120 came from 22 families with three different germline mutations
in the MLH1 gene.
The patients were those diagnosed before the age of 65. Older patients
were excluded because of the possibility that they could be sporadic cases
among family members not carrying the germline mutation.
The patients were diagnosed between 1953 and 1993. The cancer diagnoses
were ascertained from the files of the nationwide, population-based Finnish
Cancer Registry. All the rest of the 14,261 colorectal cancer patients
diagnosed in Finland in the same age group and calendar years were used
Utilizing Finland's Central Population Register, the patients were followed
until death, emigration, or the common closing date of the study, December
31, 1993, whichever came first. Since everyone in Finland has a unique
personal identification number, none of the patients were lost to follow-up.
Avoiding Potential Biases
To avoid confounding by competing causes of death, cumulative relative
survival rates were calculated by dividing observed rates by expected rates.
The expected rates were derived from sex, age, and calendar-period-specific
life tables of the general Finnish population.
All available prognostic factors, ie, disease stage, primary site, age
and sex of the patient, and calendar year, were simultaneously adjusted
for by calculating relative excess risk of death using a life table proportional
hazards model based on annual relative survival rates for the first five
Using these methods, most of the potential biases present in previous
studies could be avoided. The HNPCC patients were collected retrospectively
from the whole country as they had entered the health care system. In the
1950s through 1970s, HNPCC was not recognized in clinical practice, and
thus there was no detection bias. Even in the 1980s through 1993, the proportion
of HNPCC patients from all colorectal cancer patients did not increase.
Since the follow-up was complete, all deaths, as well as healthy person-years,
were taken into account for both HNPCC and sporadic colon cancer patients.
The expected survival rates were based on the same homogeneous Finnish
population from which the patients came. Finally, for the majority of patients,
the HNPCC diagnosis was made on a molecular basis at the family level so
that results were much more reliable than if diagnosis had been based on
the Amsterdam criteria alone.
The cumulative relative survival rates were uniformly better for the
HNPCC patients in all strata that were analyzed. The five-year relative
survival rate was 65% for all HNPCC patients, compared with 44% for all
control colorectal cancer patients.
For the 120 patients from families with germline MLH1 mutations, the
relative survival rate was better than for the 55 purported HNPCC patients
with no data on germline mutations who were identified using the Amsterdam
The relative survival rates among patients with localized tumors were
85% and 68%, respectively, for HNPCC and sporadic patients. The corresponding
figures among patients with nonlocalized tumors were 40% and 18%, respectively.
The relative survival rates were better among HNPCC patients than among
controls in age groups 0 to 44 years and 45 to 64 years, in men and women,
in patients with tumors of the colon and the rectum, and in all four calendar
Recent advances in molecular genetics have revealed many details of
the underlying mechanisms and pathways involved in HNPCC (for a review,
see references 1 and 2). However, the reasons for the evident survival
advantage remain obscure. Several interesting hypothesis have been put
Despite aggressive histologic tumor features in HNPCC patients, the
carcinomas are diploid predominant, indicating better survival.[10,11]
The numerous mutations occurring in the tumor cells might trigger the host
immune system defenses. Rhyu discusses the possibility that due to
the multitude of mutations, the loss of vital functions would drive the
tumor cells toward premature death rather than immortality.
Additional DNA repair mechanisms might also be involved. One such
alternative could be the p53-related apoptosis pathway.
Until further research provides more detailed understanding of the complex
mechanisms and pathways in the tumorigenesis and natural history of HNPCC
tumors, the original hypothesis by Lynch from 15 years ago is still valid.[5,14]
The same genetic defect that is responsible for tumor initiation and progression
may also reduce the viability of cancer cells.
At the moment, there are no reliable clinical indicators of good prognosis
in HNPCC-related colorectal carcinomas. Thus, clinical screening and treatment
protocols must be based on the strictest criterion: To improve the survival
rates of all patients.
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3. Lynch HT, Smyrk TC, Watson P, et al: Genetics, natural history, tumor
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