Syngal S, Schrag D, Falchuk M, Tung N, Farraye FA, Chung D, Wright M, Whetsell A, Miller G, Garber JE. Phenotypic Characteristics Associated With the APC Gene I1307K Mutation in Ashkenazi Jewish Patients With Colorectal Polyps. JAMA. 2000;284(7):857-860. doi:10.1001/jama.284.7.857
Author Affiliations: Division of Gastroenterology, Brigham and Women's Hospital (Drs Syngal and Farraye), Population Sciences, Dana-Farber Cancer Institute (Drs Syngal, Garber, and Schrag), Divisions of Gastroenterology (Dr Falchuk) and Oncology (Dr Tung), Beth Israel-Deaconess Medical Center, Gastrointestinal Unit, Massachusetts General Hospital (Dr Chung), Harvard Medical School, and Genzyme Corporation (Mss Wright and Whetsell and Dr Miller), Boston, Mass. Dr Schrag is now with Memorial Sloan-Kettering Cancer Center, New York, NY.
Context The I1307K mutation of the APC gene is found
in approximately 6% of the Ashkenazi Jewish population and is associated with
elevated risk of colorectal cancer. The incidence of the mutation in patients
with colorectal adenomas is unknown.
Objectives To determine the carrier rate of the I1307K mutation in Ashkenazi Jewish
patients with a history of colorectal polyps but without colorectal cancer
and to compare phenotypic characteristics and family history of carriers vs
Design, Setting, and Patients A total of 231 patients who had at least 1 large bowel polyp diagnosed
between January 1, 1992, and January 31, 1999, at 1 of 5 centers in Boston,
Mass, were included, of whom 183 were Ashkenazi Jewish. DNA was isolated from
cheek swab samples.
Main Outcome Measures Presence of the I1307K variant in the APC gene.
Results The I1307K variant was identified in 22 (14%) of 161 Ashkenazi Jewish
patients with a history of adenomatous polyps and in 1 (5%) of 20 Ashkenazi
Jewish patients with hyperplastic polyps. The phenotypic features of adenomas,
family history of polyps, colorectal cancer, and other cancers were indistinguishable
between I1307K carriers and noncarriers.
Conclusions The frequency of the APC I1307K mutation is
elevated in Ashkenazi Jewish patients with adenomatous polyps, but not hyperplastic
polyps.The I1307K mutation represents a novel paradigm for cancer-predisposing
genes, as it is associated with moderately increased risk of neoplasia without
other associated distinguishing phenotypic features.
Colorectal cancer (CRC) is the second leading cause of cancer death
in North America. Approximately 15% to 20% of CRC occurs in familial aggregations.1,2 In 1997, a particular mutation in the
adenomatous polyposis coli (APC) gene, an isoleucine-to-lysine
variant at codon 1307 of the APC gene (I1307K), was
reported to confer susceptibility to apparently sporadic CRC.3
The I1307K mutation was carried by 6.1% of unselected Ashkenazi Jewish individuals
and 28% (7 of 25) of Jewish patients with CRC and a family history of CRC.3 In aggregate, subsequent studies4- 14
have generally supported a role for I1307K in the pathogenesis of CRC in the
Ashkenazi Jewish population but not in other ethnic groups or in Ashkenazi
patients with other forms of cancer. Some reports have suggested that the
mutation may be associated preferentially with early-onset CRC3,14
and certain distinguishing features, such as multiple colorectal adenomas.14 The prevalence of the mutation, specifically in individuals
with sporadic colorectal polyps, has not yet been reported.
We sought to determine the I1307K carrier rate in Ashkenazi Jewish patients
with a history of colorectal polyps but no CRC and to compare clinical characteristics
and family history of carriers vs noncarriers.
The study involved 5 sites in Boston, Mass, including Brigham and Women's
Hospital, Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute,
Harvard Vanguard Medical Associates, and the Massachusetts General Hospital.
Human subjects committees at each center approved the study protocol. Study
staff reviewed colonoscopy, pathology, and clinic records at each site to
identify subjects with at least 1 large-bowel polyp diagnosed from January
1, 1992, through January 31, 1999. Patient ethnicity was obtained from hospital
or clinic registration data; patients with Jewish or undeclared religious
affiliation were eligible for the study. Individuals with a history of familial
polyposis or CRC were excluded.
With the permission of the patient's primary physician or gastroenterologist,
eligible patients were mailed a study packet that included a letter describing
the purpose of the study, a questionnaire, an informed consent form that included
permission for medical record documentation and genetic analysis of the I1307K
mutation, and a kit for collection of cheek cells. Interested patients returned
a signed informed consent form, the questionnaire, and the cheek brushes via
overnight mail in a prepaid envelope.
Ethnicity was confirmed by patient self-report. Specifically, individuals
were asked, "Do you have any Ashkenazi (European-American) Jewish heritage?"
Personal and family history of cancer and colorectal polyps were obtained
via self-administered questionnaire. Medical records were obtained to confirm
all colorectal polyp and cancer diagnoses in index patients; pathological
confirmation was obtained for 91% of participants with colorectal adenomas.
Pathology and endoscopy reports were reviewed for extraction of phenotypic
characteristics of polyps, including size, number, and location.
DNA was isolated from blood or buccal swab samples using a QIAamp DNA
Mini kit (Qiagen Inc, Valencia, Calif). Isolated DNA was amplified using primers
specific for exon 15 of the APC gene, including the
region that encompassed the published I1307K polymorphism. Amplified material
was dot blotted onto Biotrans nylon membrane (ICN, Irvine, Calif) using a
GIBCO/BRL 96-well dot blot apparatus (Life Technologies, Rockville, Md). Blotted
membranes were hybridized with probes specific for either the normal APC gene sequence or the I1307K polymorphism.15
Results were determined by comparing the hybridization signal of positive
controls to patient samples in relation to background.
Specimens and genetic analysis results were anonymized to preserve confidentiality
(genetic test results were not linked to patient identifiers); thus, there
was no disclosure of genetic test results to participants or their physicians.
Between May 1998 and May 1999, we mailed a total of 836 study packets
to potentially eligible patients. A total of 272 individuals enrolled in the
study, for a participation rate of 32%. Participation rates were similar across
sites (ranging from 28% to 35%) and did not vary by type of practice or referring
physician. Forty-one individuals were excluded from the study: 5 because of
insufficient data, 19 because of a history of CRC; and 17 because of polymerase
chain reaction amplification failure.
Of the remaining 231 participants, 27 were not Ashkenazi Jewish and
21 were of unknown ethnicity. There were 20 participants with hyperplastic
polyps and 2 with inflammatory polyps. The 161 Ashkenazi Jewish patients with
adenomatous polyps are the main focus of this report. A total of 153 (95%)
were Ashkenazi Jewish on both maternal and paternal sides of the family; 8
(5%) were Ashkenazi only on 1 side of the family. There were 99 men (61%)
and 62 women (39%). The mean age at first adenoma diagnosis was 63 years.
Fifty-two individuals (32%) reported a first-degree relative with CRC, and
22 individuals (14%) had a first-degree relative with colorectal polyps.
To compare the characteristics of participants and those individuals
who chose not to enroll, we randomly sampled 83 records (14%) of nonresponders.
Comparison of demographic characteristics and findings on colonoscopy revealed
no significant difference between the 2 groups except that the mean age of
participants was 4 years younger than nonresponders.
Carrier rates were determined for several risk groups (Table 1). Among Ashkenazi Jewish patients with adenomas, 22 (14%)
of 161 carried the I1307K mutation, whereas the alteration was found in only
1 (5%) of 20 Ashkenazi Jewish individuals with hyperplastic polyps. The 14%
mutation rate in adenomatous polyps was significantly higher than reported
mutation rates of 6.1% to 7.0% in 2 large series of Ashkenazi Jewish controls
without CRC3,9 (2-sided P by Pearson χ2 = .005). The results were
not significantly different when the analysis was performed with the inclusion
of data from the 19 patients who had been excluded because of a history of
Analysis of the characteristics of adenomatous polyps in Ashkenazi Jewish
patients with colorectal polyps is presented in Table 2. Comparison of the mean age at first diagnosis of adenomas,
the mean number of adenomas per colonoscopy, the mean size of adenomas, and
the location of adenomas revealed no significant differences between carriers
and noncarriers. Furthermore, there were no significant differences in the
frequency of CRC, non-CRCs, or colorectal polyps in first-degree relatives
between carriers and noncarriers (Table
Cancer-predisposition genes have classically been associated with striking
phenotypic features, such as early age at onset of neoplasia, multiple affected
family members, rare tumors, and the presence of multiple tumors in the same
individual. Therefore, we hypothesized that patients with adenomatous polyps
who carried the I1307K mutation would exhibit unusual clinical characteristics
and be more likely to have a positive family history of colorectal polyps
or cancer than noncarriers. The I1307K carrier rate in Ashkenazi Jewish patients
with adenomatous polyps (but not hyperplastic polyps) was increased compared
with the population prevalence of the mutation and similar to the rate found
in Ashkenazi Jewish patients with CRC,3,14
confirming its role early in the pathogenesis of colorectal neoplasia. However,
in contrast to previous reports and our expectations, we found no differences
in family history of colorectal neoplasia or any phenotypic features of adenomas
in terms of age of onset and location, size, and number of polyps in I1307K
mutation carriers vs noncarriers.
Multiple issues may affect patients' willingness to participate in genetics
studies, including fear of confidentiality of individual results and stigmatization
of the Jewish community,16 and these factors
may have led to the suboptimal participation rate observed in our study. We
attempted to address this issue with an analysis of nonresponders, which revealed
similar demographic and polyp characteristics (except for a small difference
in age) between eligible patients who chose and did not choose to participate.
Ascertainment bias may still have affected enrollment, with a bias toward
those who were undergoing endoscopic surveillance or had a family history
of the disease. However, such a bias should not affect comparisons between
carriers and noncarriers, since they would not be expected to differ between
the mutation carrier and noncarrier groups.
When first identified, I1307K was hailed as the cause of a significant
proportion of CRC in Jewish patients, and clinical recommendations were made
advocating genetic testing for the mutation and intensified surveillance for
carriers. Our detailed comparison of mutation carriers and noncarriers indicates
that the I1307K mutation is distinctly different than classic high-penetrance
cancer susceptibility genes, which are typically rare, segregate with disease,
and are sufficient on their own to substantially increase risk with only minimal
impact by environmental factors.17 With completion
of the elucidation of the human genetic code, scientists will continue to
identify other polymorphisms such as I1307K that are common and increase risk
of cancer and other common diseases but can be strongly influenced by association
with other genetic or environmental factors. Ultimately, the best estimation
of risk is likely to be made by assessment of the combination and interaction
of multiple low-penetrance mutations, behavioral factors, and personal medical
history. In the meantime, it is important that patients who elect to undergo
testing for I1307K appreciate that although the test is relatively cheap and
easy to obtain, the results need to be interpreted in the context of a variety
of other factors. A positive result does not mean the inevitability of cancer,
and risk may be significantly affected by screening practices and behavioral
factors, such as physical activity and diet. Equally important, however, is
that a negative result does not imply protection from CRC, since there are
surely other low-penetrance genes affecting CRC risk that have not yet been
identified. The study of these complex interactions and clinical implementation
of testing of low-penetrance genes clearly pose novel challenges for genetic
epidemiologists, physicians, and patients.