Albert Y. Lin

CDX2 is an amplified lineage-survival oncogene in colorectal cancer

The mutational activation of oncogenes drives cancer development and progression. Classic oncogenes, such as MYC and RAS, are active across many different cancer types. In contrast, “lineage-survival” oncogenes represent a distinct and emerging class typically comprising transcriptional regulators of a specific cell lineage that, when deregulated, support the proliferation and survival of cancers derived from that lineage. Here, in a large collection of colorectal cancer cell lines and tumors, we identify recurrent amplification of chromosome 13, an alteration highly restricted to colorectal-derived cancers. A minimal region of amplification on 13q12.2 pinpoints caudal type homeobox transcription factor 2 (CDX2), a regulator of normal intestinal lineage development and differentiation, as a target of the amplification. In contrast to its described role as a colorectal tumor suppressor, CDX2 when amplified is required for the proliferation and survival of colorectal cancer cells. Further, transcriptional profiling, binding-site analysis, and functional studies link CDX2 to Wnt/β-catenin signaling, itself a key oncogenic pathway in colorectal cancer. These data characterize CDX2 as a lineage-survival oncogene deregulated in colorectal cancer. Our findings challenge a prevailing view that CDX2 is a tumor suppressor in colorectal cancer and uncover an additional piece in the multistep model of colorectal tumorigenesis.

Impact of initial surgical margins and residual cancer upon re-excision on outcome of patients with localized breast cancer

BACKGROUNDnA significant proportion of patients undergoing breast conservation therapy require additional operations to obtain clear margins. The aim of this study was to assess the impact of initial margins and residual carcinoma found on second surgery on the outcomes of breast cancer patients.nnnMETHODSnIn this retrospective study, Cox proportional-hazard regression analysis was performed to evaluate data from 437 patients with stage I to IIIA breast cancer who underwent initial breast-conserving surgery between 1994 and 2004.nnnRESULTSnThe distant recurrence rate was higher among patients with initial positive margins than among those with initial negative margins (15.5% vs 4.9%; hazard ratio, 3.6; 95% confidence interval 1.5-8.7; P = .003). For patients who had underwent second surgery, the finding of a residual invasive carcinoma was associated with increased risk for distant recurrence (22.8% vs 6.6%; hazard ratio, 3.5; 95% confidence interval, 1.8-7.4; P = .0001).nnnCONCLUSIONnInvasive residual carcinoma found during subsequent surgery after initial compromised margins is an important prognostic marker for distant recurrence.

Familial eosinophilia: Clinical and laboratory results on a U.S. Kindred

We describe a five-generation kindred with familial eosinophilia (FE; MIM131400), characterized by the occurrence of sustained eosinophilia of unidentifiable cause in multiple relatives. The inheritance pattern is consistent with an autosomal dominant pattern. Among 52 related subjects studied, 19 were affected and 33 were unaffected. Ten unaffected spouses were also evaluated. Four subjects with sustained eosinophilia were diagnosed with cardiac abnormalities and two of them also had neurologic symptoms. In comparison with the unaffected or spouses, evaluation of complete blood counts showed that the affected relatives had, as expected, significantly higher white cell (P < 0.005) and absolute eosinophil counts (P < 0.001) and lower red cell counts (P < 0.05). Evaluation of serum cytokine levels (IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GMCSF) and serology for parasitic helminth infection demonstrated no differences between the affected and unaffected individuals; no individuals studied had serologic evidence for parasitic infection. There were also no differences in anti-nuclear antibody, serum cobalamin (vitamin B12) level, immunoglobulin level, leukocyte alkaline phosphatase, rheumatoid factor, HLA analysis, and stool findings for ova and parasites. Among eight affected persons who had peripheral blood or bone marrow karyotype analysis, two carried the same chromosome abnormality, a pericentric inversion of chromosome 10, inv (10) (p11.2q21.2). A gene mapping study is currently underway to study the underlying genetic mechanism(s) of this syndrome.

Stromal responses among common carcinomas correlated with clinicopathologic features.

Purpose: We have previously characterized a tumor stroma expression signature in a subset of breast tumors that correlates with better clinical outcome. The purpose of this study is to determine whether this stromal signature, termed the “DTF fibroblast” (desmoid-type fibromatosis) signature, is specific to breast cancer or is a common stromal response found in different types of cancer. Experimental Designs: The DTF fibroblast signature was applied to gene expression profiles from five ovarian, five lung, two colon, and three prostate cancer expression microarray datasets. In addition, two different tissue microarrays of 204 ovarian tumors and 140 colon tumors were examined for the expression of previously characterized protein markers of DTF fibroblast signature. The DTF fibroblast stromal response was then correlated with clinicopathologic features. Results: The DTF fibroblast signature is robustly present in ovarian, lung, and colon carcinomas. Both expression microarray data and immunohistochemistry show that the subset of ovarian tumors with strong DTF fibroblast signature expression has statistically significant, worse survival outcomes. No reproducible survival differences were found in either the lung or the colon cancers. The prostate cancers failed to show a DTF fibroblast signature. Multivariant analysis showed that DTF fibroblast signature was significantly more prognostic than the proliferation status in ovarian carcinomas. Conclusions: Our results suggest that the DTF fibroblast signature is a common tumor stroma signature in different types of cancer, including ovarian, lung, and colon carcinomas. Our findings provide further insight into the DTF fibroblast stromal responses across different types of carcinomas and their potential as prognostic and therapeutic targets. Clin Cancer Res; 19(18); 5127–35. ©2013 AACR.

Autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly) is linked to chromosome 22q12-13

Abstract. Macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly) is a rare autosomal dominant disorder characterized by thrombocytopenia, giant platelets, and Döhle body-like inclusions in leukocytes. To determine the genetic basis of this disorder, we performed a genome-wide screen for linkage in three families with May-Hegglin anomaly. For the pooled analysis of the three families, three markers on chromosome 22 had two-point logarithm-of-difference (lod) scores greater than 3, with a maximum lod score of 3.91 at a recombination fraction (θ) of 0.076 for marker D22S683. Within the largest family (MHA-1), the maximum lod score was 5.36 at θ=0 at marker D22S445. Fine mapping of recombination events using eight adjacent markers indicated that the minimal disease region of family MHA-1 alone is in the ~26xa0cM region from D22S683 to the telomere. The maximum lod score for the three families combined was 5.84 at θ=0 for marker IL2RB. With the assumption of locus homogeneity, haplotype analysis of family MHA-4 indicated the disease region is centromeric to marker D22S1045. These data best support a minimal disease region from D22S683 to D22S1045, a span of about 1xa0Mb of DNA that contains 17 known genes and 4 predicted genes. Further analysis of this region will identify the genetic basis of May-Hegglin anomaly, facilitating subsequent characterization of the biochemical role of the disease gene in platelet formation.