Frequency of BRCA1 and BRCA2 Mutations in Unselected Ashkenazi Jewish Patients With Colorectal Cancer

Kirchhoff, Tomas; Satagopan, Jaya M.; Kauff, Noah D.; Huang, Helen J.; Kolachana, Prema; Palmer, Crystal; Rapaport, Hannah; Nafa, Khédoudja; Ellis, Nathan A.; Offit, Kenneth

doi:10.1093/jnci/djh006

Cited by 67 publications

(56 citation statements)

References 21 publications

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“…DNA from case samples was analyzed for the three common Ashkenazi founder mutations in BRCA1 and BRCA2 (185delAG and 5182insC in BRCA1 and 6174delT in BRCA2) as described previously (14). Briefly, DNA was purified using the QiaAmp Blood DNA midi kit (Qiagen, Valencia, CA).…”

Section: Methodsmentioning

confidence: 99%

BRCA Mutations and Risk of Prostate Cancer in Ashkenazi Jews

Kirchhoff¹,

Kauff²,

Mitra

et al. 2004

Clinical Cancer Research

148

106

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Purpose: The Breast Cancer Linkage Consortium and other family-based ascertainments have suggested that male carriers of BRCA mutations are at increased risk of prostate cancer. Several series looking at the frequency of BRCA mutations in unselected patients with prostate cancer have not confirmed this finding. To clarify this issue, we conducted a large case-control study.Experimental Design: Blood specimens from 251 unselected Ashkenazi men with prostate cancer were screened for the presence of one of the three common Ashkenazi founder mutations in BRCA1 and BRCA2. The incidence of founder mutations was compared with the incidence of founder mutations in 1472 male Ashkenazi volunteers without prostate cancer using logistic regression analysis after adjusting for age.Results: Thirteen (5.2%) cases had a deleterious mutation in BRCA1 or BRCA2 compared with 28 (1.9%) controls. After adjusting for age, the presence of a BRCA1 or BRCA2 mutation was associated with the development of prostate cancer (odds ratio, 3.41; 95% confidence interval, 1.64 -7.06; P ‫؍‬ 0.001). When results were stratified by gene, BRCA2 mutation carriers demonstrated an increased risk of prostate cancer (odds ratio, 4.78; 95% confidence interval, 1.87-12.25; P ‫؍‬ 0.001), whereas the risk in BRCA1 mutation carriers was not significantly increased.Conclusions: BRCA2 mutations are more likely to be found in unselected individuals with prostate cancer than age-matched controls. These results support the hypothesis that deleterious mutations in BRCA2 are associated with an increased risk of prostate cancer.

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Section: Methodsmentioning

confidence: 99%

BRCA Mutations and Risk of Prostate Cancer in Ashkenazi Jews

Kirchhoff¹,

Kauff²,

Mitra

et al. 2004

Clinical Cancer Research

148

106

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“…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.…”

Section: Dear Sirmentioning

confidence: 99%

Colorectal cancer risk in individuals with biallelic or monoallelic mutations of MYH

Peterlongo

Mitra

Chuai

et al. 2004

Intl Journal of Cancer

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Dear SirIn 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 mutation carriers were confirmed by direct sequencing. Odds ratios and exact confidence intervals were calculated using StatXact (Cytel software corporation, Cambridge, MA). Exact tests for Hardy-Weinberg equilibrium were performed for each mutation and for both mutations together using SAS version 9.0 (SAS Institute Inc., Cary, NC). Power calculations fo...

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“…12 -15). Furthermore, it has been shown that mice deficient for either BRCA1 or BRCA2 develop a wide range of carcinomas, most commonly breast and lung but also endometrial, gastric, and colon cancer (12).Several studies in the past reported an increased risk of colorectal cancer in patients with BRCA1 or BRCA2 germ-line mutations (16 -19) whereas two more recent investigations could not confirm such an elevated risk (20,21). Loss of heterozygosity at the BRCA1 gene locus was shown to be Imaging, Diagnosis, Prognosis…”

mentioning

confidence: 99%

“…Several studies in the past reported an increased risk of colorectal cancer in patients with BRCA1 or BRCA2 germ-line mutations (16 -19) whereas two more recent investigations could not confirm such an elevated risk (20,21). Loss of heterozygosity at the BRCA1 gene locus was shown to be Imaging, Diagnosis, Prognosis…”

mentioning

confidence: 99%

Expression of DNA Double-Strand Break Repair Proteins ATM and BRCA1 Predicts Survival in Colorectal Cancer

Grabsch

Dattani

Barker

et al. 2006

Clinical Cancer Research

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Purpose: The double-strand break (DSB) is the major DNA lesion leading to chromosomal aberrations and faithful repair is crucial for maintaining genomic instability. Very little is known about the expression of DNA DSB repair proteins in colorectal cancer. To address this issue, we examined the expression pattern of DSB repair key proteins ATM, BRCA1, BRCA2, Ku70, and Ku80 and their putative role in patients survival in a large series of colorectal cancer. Experimental Design: 342 sporadic colorectal cancer were subjected to immunohistochemistry by using specific antibodies for the various proteins investigated. Staining results were compared with clinicopathologic data, patient survival, as well as expression of mismatch repair proteins MLH1 and MSH2. Results: The expression pattern of both ATM and BRCA1 predicted survival in all colorectal cancer patients as well as in the small subgroup of patients that received adjuvant therapy. Low expression of ATM and BRCA1 was associated with loss of MLH1 or MSH2 expression. Conclusions: This is the first study to show a relationship between the expression of DNA DSB repair proteins ATM and BRCA1 and survival in colorectal cancer patients. Studies in tumors from large randomized trials are now necessary to validate our pilot data and establish the clinical usefulness of the immunohistochemical assay in predicting response to a particular adjuvant therapy regimen. Furthermore, our results indicate a possible link between expression of DNA mismatch repair and DNA DSB repair proteins in sporadic colorectal cancer, which warrants further investigation. Genetic instability has been proposed to be a driving force in colorectal carcinogenesis (1). Two major types of genetic instability have been described in colorectal cancer: chromosomal instability and microsatellite instability (2). Up to 15% of colorectal cancer show a high frequency of microsatellite instability which is caused by a defect of the DNA mismatch repair pathway (3). The vast majority of colorectal cancer, however, shows chromosomal instability, which is characterized by gains and losses of whole chromosomes or large chromosomal regions.Whereas a large number of genes that trigger chromosomal instability have been identified in yeast in the past (reviewed in ref. 4), the underlying mechanisms leading to chromosomal instability in colorectal cancer remain to be characterized. The DNA double-strand break (DSB) is regarded as the most critical of all DNA lesions (5, 6) and it has been shown that defects in the cellular response to DSBs can lead to genetic alteration, chromosomal instability, and ultimately malignant transformation (7).In mammalian cells, DSBs can be repaired by two distinct pathways: homologous recombination and nonhomologous end joining (8). DSB repair by nonhomologous end joining involves the formation of a Ku70/Ku80 protein heterodimer and recruitment of DNA-dependent protein kinase C to the site of DNA damage (9). DSB repair by homologous recombination is mediated by a large number of...

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Frequency of BRCA1 and BRCA2 Mutations in Unselected Ashkenazi Jewish Patients With Colorectal Cancer

Cited by 67 publications

References 21 publications

BRCA Mutations and Risk of Prostate Cancer in Ashkenazi Jews

BRCA Mutations and Risk of Prostate Cancer in Ashkenazi Jews

Colorectal cancer risk in individuals with biallelic or monoallelic mutations of MYH

Expression of DNA Double-Strand Break Repair Proteins ATM and BRCA1 Predicts Survival in Colorectal Cancer

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