By David N. Leff

A person who skims the newspaper's obituary pages may notice how often death is due to colorectal cancer.

In fact, this malignancy is the second-highest cause of cancer death in the U.S. — runner-up to pulmonary carcinoma.

Another salient fact is that most of these colorectal cancers are first diagnosed in men and women in their late 70s. Incidence in a recent year, according to National Cancer Institute numbers, was 391 cases per 100,000 population.

A far smaller statistic attaches to a colorectal disease in children and teen-agers that often progresses to gastrointestinal malignancy. This is juvenile polyposis — the presence of numerous, possibly precancerous polyps studding the intestinal tract's inner walls.

Most of these young people will go to the doctor's office because of rectal bleeding, which is a prediagnostic tip-off to juvenile polyposis (JP).

"That diagnosis is confirmed by colonoscopy or endoscopy," said surgical oncologist James Howe, at the University of Iowa School of Medicine, in Iowa City.

When seeing-eye optics at the tip of this flexible exploratory probe perceive a polyp, it lassos the benign growth with a thin wire snare. This then cauterizes the polyp at its base, and brings it to the surface for microscopic verification.

Such polyps usually grow on the end of a stalk, Howe observed, and may reach lengths of three or four centimeters, or more.

"Oftentimes," he added, "they may be sloughed off in the stool; that's one way they can bleed. Its surface layer can be stripped off by trauma, presumably from undigested particles in the stool that can cause bleeding from the polyp's tip as well as its base."

JP patients come in two persuasions: familial, with a strong family history of the disease, and sporadic, with no apparent inheritance.

"Most people with familial JP," Howe went on, "whom we're basically talking about, have multiple polyps in their gut — anywhere from a few up to 40 or 50. They are born with mutations in their germ line. This denotes a different disease than the hundreds or thousands of polyps we see in familial adenomatous polyposis — which will ultimately develop into colorectal cancer."

Familial JP is the subset of patients on whom Howe and his Iowa colleagues trained their molecular genetic sights.

Tracking Down The JP Risk Gene

Howe is senior author of a paper in today's issue of Science, dated May 15, 1998, titled: "Mutations in the SMAD4/DPC4 gene in juvenile polyposis."

Until recent decades, Howe told BioWorld Today, "People didn't believe that juvenile polyps had a malignant potential. Then in 1975, Robert Summers, a coauthor of the present Science paper, reported on an extended JP family in Iowa with many cancerous members. 'Hey,' he said in effect, '11 people in this kindred got colon cancer, stomach cancer, duodenal cancer and pancreatic cancer. Maybe there is a malignant predisposition in polyps.'"

That family had been seen intermittently at the Iowa University Hospital. Howe proceeded to genotype polymorphic DNA markers from throughout their members' genomes. "I focussed on 10 specific sites that I thought might be in a high-yield region," he recounted, "and I found gene linkage to the long arm of chromosome 18.

"That allowed us to narrow this gene hunt down to a 12-centiMorgan region," Howe continued, "roughly equivalent to 12 million base pairs of DNA. That's a pretty big stretch, in which there may be hundreds of genes. In that region we knew that there were two tumor-suppressor genes. One was called DCC, the other DCP4 — now better known as SMAD4.

"So it made sense to me," Howe went on, "that we should look for mutations in these two genes, because our family mapped to that region of the genome. And those were good candidate genes to look at, because of their involvement in GI cancers."

He and his crew found germ line mutations in SMAD4, a class of gene that's involved in development of bodily tissues and regulation of cell growth. It resides on the long arm of chromosome 18 and expresses a 552-amino-acid protein.

The co-authors sequenced all 11 of the SMAD4 gene's exons (discrete DNA coding segments) and detected a four-base-pair deletion in exon 9. That mutation creates a stop codon at the end of the exon, which truncates the encoded protein.

"The patient's brother," Howe recalled, "had the same heterozygous deletion, while his unaffected mother had the wild-type allele for exon 9." In the autosomal dominant JP disease, the heterozygous mutation is inherited from one carrier parent only.

Tell-Tale Sequence Ties In To Cancer Patients

Howe and his team then proceeded to sequence exon 9 from all 46 members of the Iowa JP kindred — one of the largest extant. They found the altered allele in all 13 JP-affected individuals, in none of their spouses, and in four of 26 individuals at 50 percent risk of contracting the cancer.

Howe already had established collaborations with groups in England and Finland, to conjointly study their JP kindreds by linkage analysis. "In fact," he recalled, "our family in Iowa, another in Mississippi, plus one in Finland, all found the same SMAD4 mutation. This," he pointed out, "raises the interesting question of whether they all have some common ancestral founder, or whether it's a mutational hotspot."

Howe added, "This is the first report of a germ line mutation in SMAD4 that is transmitted through families." He foresees as a clinical payoff that "we'll be able to do presymptomatic diagnostic testing in JP families that have this mutation. We'll be able to determine which members will develop the disease [and] which will not."

He is now trying to put in place the prerequisites permitting genetic counseling of such at-risk families. "There are a lot of people," he pointed out, "who don't get screened by colonoscopy for incipient cancer every year, or three years, as they need to be. If they could be told that they don't carry the gene, they might be able to avoid that altogether. And if they do need frequent screening, we can target those individuals, and make sure they don't develop colorectal cancer." *

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