By David N. Leff

And it came to pass, circa 2,218 B.C., that Noah the ark-builder begat three sons, Shem, Ham and Japheth. When Japheth grew up, his son begat a grandson named Ashkenaz — Noah's great-grandchild.

Fast forward to modern times.

During the Crusades (1200s to 1400s A.D.), Jewish populations from the Middle East migrated westward to Germany. They became known as the people of Ashkenaz — the Hebrew word for "German." From there these Ashkenazi Jews made their way eastward to Poland, Lithuania and Russia. By the 1800s, their descendants had so multiplied that the Ashkenazim of Central and Eastern Europe become the largest single Jewish population in the world — 90 percent compared to 10 percent for the Sephardim, of Spanish origin.

At some point in Ashkenazi history, a genetic founding ancestor apparently picked up, and transmitted to his descendants, a mutant gene that bestowed susceptibility to colorectal cancer.

Over 95 percent of the 6 million Jews living in the U.S. today are of Ashkenazi descent. The medical community regards them as more prone to contracting carcinoma of the colon and rectum than the U.S. population at large. But all the genes responsible have until lately remained unknown.

Familial breast and ovarian cancers are now famously traced to two mutant genes, BRCA1 and BRCA2. (See BioWorld Today, Sept. 19, 1994, p. 1.) What's more, individuals, male or female, who carry one or both of these two genes are reportedly four times more likely than the general public to incur colorectal cancer (CRC).

About 130,000 cases of CRC are diagnosed in the U.S. in a typical year, 15 percent or more of them with a familial inheritance pattern of the disease. It sometimes starts by sowing 100 or more precancerous polyps in the walls of the colon; over several years these mature into malignant tumors. This familial adenomatous polyposis (FAP) affects one individual per 1,000 worldwide.

The mutant gene guilty of causing FAP is APC (adenomatous polyposis coli), which sits on the long arm of chromosome 5. Its normal gene product acts as a tumor suppressor. Molecular oncologists Bert Vogelstein and Kenneth Kinzler, at Johns Hopkins University, cloned APC in 1991. They tracked the APC mutation to a switch between thymidine and adenine bases on codon 1307, and designated this APC mutation I1307K. It involved a single amino-acid substitution, lysine for isoleucine.

This year, the Hopkins team reported in the September 1997 issue of Nature Genetics its finding that this APC mutation occurs exclusively in Ashkenazi Jews.

"Rather than altering the function of the encoded protein," the scientists observed, "this mutation creates a small hypermutable region of the gene, indirectly causing cancer predisposition."

Lifetime Risk Of CRC Higher In APC Carriers

Their gene mutation hunt started in the clinic while examining a man with eight polyps in his lower bowel and CRC running in his family. Eventually they screened 766 Ashkenazi subjects and detected the truncated gene in 47 of them — 6.1 percent. They also found I1307K in 28 percent of patients with a family history of CRC. In this cohort, they proposed, it increased the lifetime risk of colorectal cancer.

But in 243 non-Jewish Americans, mutant APC's presence was zero.

Then, to determine whether the mutation figured in actual clinical CRC among Ashkenazim, they examined 211 patients with the cancer and found the culprit gene in 22 of them — 10.4 percent.

These data, Vogelstein told BioWorld Today, "document a common APC alteration in Ashkenazi Jews. To our knowledge this mutation is the most common cancer-associated mutation known in a specific population.

"As the lifetime incidence of CRC in the general Ashkenazi populationhas been estimated to be 9 percent to 15 percent," he pointed out, "the lifetime risk for patients with the I1307K — and from CRC kindred — is likely to be in the range of 18 percent to 30 percent.

"Based on these results," Vogelstein concluded, "screening by a simple blood test is now being offered by many centers, including Hopkins, to Ashkenazi Jews with CRC in their families."

Case Closed? Not Necessarily So

A differently slanted finding as to the high risk of colorectal cancer in the genes of Ashkenazi Jews appears in the current bimonthly journal Cancer Research, dated Dec. 15, 1997. Its title: "The I1307K APC mutation does not predispose to colorectal cancer in Jewish Ashkenazi breast and breast-ovarian cancer kindreds." The article's senior author is molecular biologist and human geneticist Andrew Godwin, at the Fox Chase Cancer Center in Philadelphia.

His paper concludes: "Our analysis indicates that the I1307K mutation does not contribute greatly to the risk of colon cancer in Ashkenazi breast-ovarian cancer families, and that general screening in the absence of a personal and/or family history of colorectal cancer is likely to be excessive."

Godwin and his co-authors evaluated 264 Ashkenazi Jews from 158 families. Of the total number of individuals, 51 (19.3 percent) carried either a BRCA1 or BRCA2 gene mutation. In the same ballpark as the Hopkins' 6.1 percent, the Fox Chase co-authors detected the APC I1307K mutation in 7 percent — 11 of their 158 families.

Of that 158, 42 testified to at least one family member with CRC, yet none of those families tested positive for the APC mutation.

But of 12 who possessed the I1307K APC mutation, not one had CRC, or even a remote family history of the disease.

"It is very important for people to know their risk of developing cancer, when it is possible," commented Carlo Croce, editor of Cancer Research. "At the same time," he added, "people should know when not to worry. We are pleased to be able to publish information that may help Ashkenazi Jews and their physicians to make a more reasoned decision about genetic screening for the I1307K mutation." *