Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.

We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 x 10(-12) for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.

Experimental design: Cerebrospinal fluid (CSF) samples from 78 patients who received a diagnosis of epithelial-cell solid tumors and had clinical data suggestive of leptomeningeal carcinomatosis (LC) were studied. A novel FCI protocol was used to identify cells expressing the epithelial cell antigen EpCAM and their DNA content. Accompanying inflammatory cells were also described. FCI results (positive or negative for malignancy) were compared with those from CSF cytology and with the diagnosis established by the clinicians: patients with LC (n ¼ 49), without LC (n ¼ 26), and undetermined (n ¼ 3).Results: FCI described a wide range of EpCAM-positive cells with a hyperdiploid DNA content in the CSF of patients with LC. Compared with cytology, FCI showed higher sensitivity (75.5 vs 65.3) and negative predictive value (67.6 vs 60.5), and similar specificity (96.1 vs 100) and positive predictive value (97.4 vs 100). Concordance between cytology and FCI was high (Kp ¼ 0.83), although misdiagnosis of LC did not show differences between evaluating the CSF with 1 or 2 techniques (P ¼ .06). Receiveroperator characteristic curve analyses showed that lymphocytes and monocytes had a different distribution between patients with and without LC.Conclusion: FCI seems to be a promising new tool for improving the diagnostic examination of patients with suspicion of LC. Detection of epithelial cells with a higher DNA content is highly specific of LC, but evaluation of the nonepithelial cell compartment of the CSF might also be useful for supporting this diagnosis.Keywords: flow cytometry, immunophenotype, leptomeningeal carcinomatosis. L eptomeningeal carcinomatosis (LC) is a devastating cancer complication developing in at least 5% -10% of patients with solid tumors. Its prognosis is poor, with a median survival of 3-6 months among patients receiving chemotherapy.1 -3 Early diagnosis of LC and treatment initiation could offer the best chance of controlling symptoms and prevent the establishment of irreversible neurologic deficits that impair the patient's quality of life.3 -5 However, LC diagnosis currently remains a challenge. Cytological identification of malignant cells in the cerebrospinal fluid (CSF) remains the gold standard for LC diagnosis, but up to 45% of patients have an initial negative result of cytological examination of the CSF. This sensitivity may increase up to 90% when a high number of lumbar punctures are performed. 6,7 The implementation of imaging techniques and biochemical analysis of the CSF offers useful information for diagnosis; however, both of them should be considered in the right clinical context, because they lack specificity and their sensitivity is low. 1,3 It is therefore imperative to improve diagnostic tools.Multiparametric flow cytometry immunophenotyping (FCI) is an established and necessary laboratory instrument for diagnosis and follow-up of a wide range of hematological malignancies. In turn, FCI is not routinely used for the study of nonhematological tumors. Today, the number of monoclona...