Incidence Of A Hereditary Colon Cancer Brings Call For Screening

Contact: Albert de la Chapelle, (614) 688-4781
Written by Darrell E. Ward, (614) 292-8456

INCIDENCE OF A HEREDITARY COLON CANCER BRINGS CALL FOR SCREENING

COLUMBUS, Ohio -- Gene mutations that predispose people to a form of hereditary colon cancer may be found in at least one person per thousand, making it a relatively common hereditary disorder, new research shows.

The study also recommended a cost-effective way of screening for the mutations, which are linked to hereditary nonpolyposis colorectal cancer (HNPCC).

People who carry one or more of the mutations for HNPCC have a greater than 85 percent chance of developing colorectal cancer by age 75. The mutations also increase the risk of endometrial and other cancers, with tumors usually developing before age 50.

If we compare the incidence of this condition with other hereditary disorders, it ranks among the most common ones," said Albert de la Chapelle, director of the Human Cancer Genetics Program at Ohio State University's Comprehensive Cancer Center. "Cystic fibrosis, for example, has an incidence of 1 in 2,500."

de la Chapelle was senior author of the study, which appeared in a May issue of the New England Journal of Medicine.

"We have the means to screen for HNPCC, and it should be done," said de la Chapelle.

Screening is all the more important because the incidence of HNPCC as determined by the researchers is clearly a minimum. "The true figure has to be higher because we couldn't study everyone affected by the mutations," said de la Chapelle. It did not include cases of endometrial cancer that might have been caused by mutations in HNPCC genes, for example.

Screening colorectal cancer patients for HNPCC mutations is important because patients who carry the mutations often have first-degree relatives who have inherited the mutations but in whom cancer hasn't yet occurred. Genetic testing can reveal which family members carry the mutations, enabling them to take steps to prevent the disease.

"These tumors are often preventable," said de la Chapelle. "Regular colonoscopy exams in people with genetic mutations for this condition significantly reduces mortality from HNPCC."

Mutations in two genes, known as MLH1 and MSH2, have been linked to HNPCC. Testing all colorectal cancer patients for mutations in these genes would cost millions of dollars, making it too expensive to be practical.

However, researchers have found a way to screen people who might have the mutations by testing tumor cells for the presence of oddities called "instability of microsatellite repeats."

Microsatellite repeats are minute regions of DNA that are repeated dozens of times. They are thought to result from errors introduced when cancer cells replicate their DNA during cell division. The errors often occur because of mutations in genes causing HNPCC. Thus, everyone at risk for HNPCC has unstable microsatellite repeats, but not everyone with unstable microsatellite repeats is at risk for HNPCC.

Furthermore, unstable microsatellite repeats can be detected easily using the polymerase chain reaction (PCR), a relatively inexpensive test. The use of microsatellite repeats as a marker for possible carriers of the HNPCC gene reduces the number of patients who should receive the much more expensive genetic testing and makes screening for HNPCC economically feasible.

Of the 509 colorectal cancer patients in Finland involved in de la Chapelle's study, 63 (12 percent) had unstable microsatellite repeats.

The researchers then did genetic testing for the HNPCC mutations on normal cells (white blood cells or normal intestinal cells adjacent to the tumor) from the individuals with unstable microsatellite repeats.

Ten of the 63 patients (2 percent of the original 509) had mutations in one of the HNPCC genes, and therefore represent newly detected families with HNPCC.

The presence of HNPCC mutations in normal cells indicated that the person was born with the mutations, and that he or she had been predisposed to develop the disease.

It also meant that first-degree relatives of that individual might also carry one of the mutations and be at high risk of developing colorectal or endometrial cancer.

Based on the results of this study, de la Chapelle recommends screening for unstable microsatellite repeats in all colorectal-cancer patients under 50 years of age who have a personal or family history of colorectal or endometrial cancer. Those who test positive for the repeats should be offered genetic testing for the HNPCC mutations.

The researchers are now verifying the incidence of HNPCC mutations through a study under way in Italy, and one they hope to begin in Ohio.

The research reported here was funded by grants from the National Cancer Institute and the Academy of Finland.

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The study also recommended a cost-effective way of screening for the mutations, which are linked to hereditary nonpolyposis colorectal cancer (HNPCC).

People who carry one or more of the mutations for HNPCC have a greater than 85 percent chance of developing colorectal cancer by age 75. The mutations also increase the risk of endometrial and other cancers, with tumors usually developing before age 50.

"If we compare the incidence of this condition with other hereditary disorders, it ranks among the most common ones," said Albert de la Chapelle, director of the Human Cancer Genetics Program at Ohio State University's Comprehensive Cancer Center. "Cystic fibrosis, for example, has an incidence of 1 in 2,500."

de la Chapelle was senior author of the study, which appeared in a May issue of the New England Journal of Medicine.

"We have the means to screen for HNPCC, and it should be done," said de la Chapelle.

Screening is all the more important because the incidence of HNPCC as determined by the researchers is clearly a minimum. "The true figure has to be higher because we couldn't study everyone affected by the mutations," said de la Chapelle. It did not include cases of endometrial cancer that might have been caused by mutations in HNPCC genes, for example.

Screening colorectal cancer patients for HNPCC mutations is important because patients who carry the mutations often have first-degree relatives who have inherited the mutations but in whom cancer hasn't yet occurred. Genetic testing can reveal which family members carry the mutations, enabling them to take steps to prevent the disease.

"These tumors are often preventable," said de la Chapelle. "Regular colonoscopy exams in people with genetic mutations for this condition significantly reduces mortality from HNPCC."

Mutations in two genes, known as MLH1 and MSH2, have been linked to HNPCC. Testing all colorectal cancer patients for mutations in these genes would cost millions of dollars, making it too expensive to be practical.

However, researchers have found a way to screen people who might have the mutations by testing tumor cells for the presence of oddities called "instability of microsatellite repeats."

Microsatellite repeats are minute regions of DNA that are repeated dozens of times. They are thought to result from errors introduced when cancer cells replicate their DNA during cell division. The errors often occur because of mutations in genes causing HNPCC. Thus, everyone at risk for HNPCC has unstable microsatellite repeats, but not everyone with unstable microsatellite repeats is at risk for HNPCC.

Furthermore, unstable microsatellite repeats can be detected easily using the polymerase chain reaction (PCR), a relatively inexpensive test. The use of microsatellite repeats as a marker for possible carriers of the HNPCC gene reduces the number of patients who should receive the much more expensive genetic testing and makes screening for HNPCC economically feasible.

Of the 509 colorectal cancer patients in Finland involved in de la Chapelle's study, 63 (12 percent) had unstable microsatellite repeats.

The researchers then did genetic testing for the HNPCC mutations on normal cells (white blood cells or normal intestinal cells adjacent to the tumor) from the individuals with unstable microsatellite repeats.

Ten of the 63 patients (2 percent of the original 509) had mutations in one of the HNPCC genes, and therefore represent newly detected families with HNPCC.

The presence of HNPCC mutations in normal cells indicated that the person was born with the mutations, and that he or she had been predisposed to develop the disease.

It also meant that first-degree relatives of that individual might also carry one of the mutations and be at high risk of developing colorectal or endometrial cancer.

Based on the results of this study, de la Chapelle recommends screening for unstable microsatellite repeats in all colorectal-cancer patients under 50 years of age who have a personal or family history of colorectal or endometrial cancer. Those who test positive for the repeats should be offered genetic testing for the HNPCC mutations.

The researchers are now verifying the incidence of HNPCC mutations through a study under way in Italy, and one they hope to begin in Ohio.

The research reported here was funded by grants from the National Cancer Institute and the Academy of Finland.

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