Dear Sir
In a recent study published in the International Journal of Cancer, Fleischmann et al. 1 described the results of screening for germline mutations in the human homolog of the E. coli mutY gene (MYH) in a series of 358 individuals affected with early-onset colorectal cancer (CRC), arbitrarily defined as a diagnosis before age 56, and 354 control individuals. In Caucasians, the 2 MYH mutations Y165C and G382D, identified in a subset of familial adenomatous polyposis (FAP) patients who lack mutations in the APC gene, are by far the most frequent known disease-causing mutations. 2,3 With respect to these mutations characterized previously, one CRC case carried biallelic MYH mutations (0.3%), and 5 CRC cases (1.4%) and one control (0.3%) carried monoallelic MYH mutations. Even though the frequency of carriers of monoallelic MYH mutations in CRC cases was not statistically different from the frequency in controls, the authors suggested that MYH heterozygotes might be at increased risk of developing CRC. In the present study, we have similarly assessed the frequencies of diseasecausing MYH mutations in 555 CRC cases and 918 controls.
A consecutive series of individuals affected with CRC was identified, consisting of 555 individuals who visited the oncology clinic at Memorial Hospital in New York City. 4 Blood specimens were obtained regardless of ethnic origin and religion from 2002 to present. Before permanent anonymization of these samples, primary CRC diagnosis was confirmed by inspection of the electronic pathology record, and gender, religion, ethnic origin, history of chemotherapy, date of birth, age at diagnosis and date of diagnosis were recorded. DNA samples were prepared from blood as described previously. 5 Collection of these samples was performed under the auspices of an IRB-approved protocol.
Controls (918) were obtained from a cohort study of over 17,000 volunteers of varying ethnic backgrounds, ages 30 -69, unaffected by cancer, and ascertained from 2000 -2002 at hospitals and blood donation centers that are geographically close to Memorial Hospital. 6 To ensure comparability, controls were chosen so that numbers of persons in each age, ethnic origin and religion group were approximately equal. Subjects provided informed consent for use of their de-identified DNAs for cancer genetics research.
The Y165C mutation was detected in sequences amplified by polymerase chain reaction by pyrosequencing and the G382D mutation by restriction enzyme digestion with BglII. Because the 466delE mutation was recently described as disease-causing in some Italian familial FAP and attenuated FAP families, 7 we also screened for this mutation by direct sequencing. All