The effect of the I1307K APC polymorphism on the clinicopathological features and natural history of breast cancer

Abstract

Three founder mutations in BRCA1 and BRCA2 account for about 10% of breast cancer occurring in Ashkenazi Jewish women diagnosed at 65 years of age or less (Karp et al, 1997). Other genes, such as ATM and RASH may play a role in breast cancer susceptibility, but their contribution to breast cancer incidence is presently unknown. The I1307K polymorphism in APC has recently been found to be associated with an increased risk of colorectal cancer: the odds ratio (OR) of colorectal cancer in association with this polymorphism was 1.78 for all cases and 2.86 for those diagnosed at under age 66 (Laken et al, 1997). Interestingly, in four of the eight pedigrees illustrated in that paper, possible I1307K-carrying women had been diagnosed with breast (three kindreds) or ovarian cancer (one kindred). We and others have shown that the I1307K polymorphism is over-represented in Ashkenazi Jewish women with breast cancer, compared with ethnically-matched controls (OR = 1.5, P = 0.003) . To further understand the way in which the I1307K allele might increase the risk of breast cancer, we used a historical cohort approach to compare the clinicopathological features of breast cancers occurring in those carrying the I1307K polymorphism in APC, with those seen in non-carriers. The effect of the I1307K allele on breast cancer survival was determined. MATERIALS AND METHODS CasesStudy subjects were identified in the medical records department of the Sir Mortimer B Davis Jewish-General Hospital (SMBD-JGH) and included women who self-reported as being Ashkenazi Jewish by birth and who were diagnosed with invasive breast cancer below 65 years of age between 1 January 1986 and 1 November 1995. Two hundred and nine breast cancer blocks from eligible women were identified. All but nine of these samples were used in the primary study . These samples were rendered anonymous after clinicopathological information was obtained from chart review, and therefore we have no family history available for any of these women. All pathological and molecular analyses of the samples were carried out blinded. The study was approved by the Research Ethics Committee of the SMBD-JGH. Specimens were reviewed by one pathologist (LB). Histological tumour type, grade (1-3) and axillary lymph node status (positive or negative for breast cancer metastases, with the number of positive lymph nodes recorded) was determined by specimen and chart review. The specimens were then coded and DNA was extracted from the paraffin wax-embedded blocks using standard techniques. We used tumour tissue as a source of DNA, and it is possible that I1307K polymorphisms detected could represent somatic mutations. However, loss of heterozygosity (LOH) is not common on 5q in breast cancer (Thompson et al, 1993;Devilee and Cornelisse, 1994;Medeiros et al, 1994) and no shortened forms of the APC protein were observed in cell lines Summary The I1307K polymorphism in APC has been found to predispose to colorectal cancer in Ashkenazi Jews, and has recently been associated with an increased risk...

Glomeruloid microvascular proliferation is associated with p53 expression, germline BRCA1 mutations and an adverse outcome following breast cancer

“…Following ethics committee approval, specimens were evaluated by one pathologist (LR Bégin) using conventional methods. Accumulation of p53 protein was detected by immunohistochemistry as previously described (Yuan et al, 1999). Pathology blocks from all women were tested for founder BRCA1 mutations (185delAG, n ¼ 18; 5382insC, n ¼ 10) and BRCA2 mutation (6174delT, n ¼ 8) that are common in this population, using established techniques (Foulkes et al, 1997).embedded archival material as previously published (Straume and Akslen, 2001).…”

Vascular proliferation is increased in basal-like breast cancer

“…In Series I, 5 lm TMA sections (192 cases) were stained for various markers (ER, PR, HER2, EGFR, p53, p63, cytokeratin 5/6, P-cadherin, c-kit) according to previous publications [16,19], and 185-187 cases could be evaluated [19][20][21]. In Series II (239 cases), information on expression of the markers was available from previous studies for comparison [17,18,22,23]. EGFR expression was evaluated according to the Dako criteria [18].…”

Germline BRCA1 Mutations and a Basal Epithelial Phenotype in Breast Cancer

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