Genome-Wide Analysis of Survival in Early-Stage Non–Small-Cell Lung Cancer

Huang, Yue; Heist, Rebecca S.; Chirieac, Lucian R.; Lin, Xihong; Skaug, Vidar; Zienolddiny, Shanbeh; Haugen, Aage; Wu, Michael C.; Wang, Zhao‐Xi; Su, Li; Asomaning, Kofi; Christiani, David C.

doi:10.1200/jco.2008.18.7906

Cited by 112 publications

(83 citation statements)

References 26 publications

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“…While most studies aimed at identifying factors that affect cancer patient outcome/survival have focused on genetic alterations or transcriptional changes in the cancer tissue, a recent study suggests a role for germ line variations in the control of lung cancer patient survival (3). Those findings are supported by results in mouse models of lung tumorigenesis showing that specific genetic loci modulate tumor progression (4,5).…”

Section: Introductionsupporting

confidence: 69%

Multiple Genetic Loci Modulate Lung Adenocarcinoma Clinical Staging

Frullanti

Galvan

Falvella

et al. 2011

Clinical Cancer Research

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Purpose: The main prognostic factor of lung cancer patient outcome is clinical stage, a parameter of tumor aggressiveness. Our study was conducted to test whether germ line variations modulate individual differences in clinical stage.Experimental Design: We conducted a case-only genome-wide association study (GWAS) using a 620,901 single-nucleotide polymorphism (SNP) array in a first series of 600 lung adenocarcinoma (ADCA) patients and in a replication series of 317 lung ADCA patients.Results: GWAS identified 54 putatively associated SNPs, 3 of which were confirmed in the replication series. Joint analysis of the two series pointed to 22 statistically associated (P < 0.01) genetic variants that together explained about 20% of the phenotypic variation in clinical staging (P < 2 Â 10 À16 ) and showed a statistically significant difference in overall survival (P ¼ 8.0 Â 10 À8

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Section: Introductionsupporting

confidence: 69%

Multiple Genetic Loci Modulate Lung Adenocarcinoma Clinical Staging

Frullanti

Galvan

Falvella

et al. 2011

Clinical Cancer Research

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“…Independent data from two recent studies further supports the association to outcome; in the first study, loss of heterozygosity at the chr16p-loss locus was associated with short overall survival in a cohort of Japanese CRCs, 12 and in the second study, a SNP in the chr16p-loss locus was associated with poor prognosis of non small cell lung cancer. 36 Our finding that chr16p-losses may be markers of complex genomic rearrangements, imply that genomic regions outside the chr16p-locus itself may be commonly affected.…”

Section: Discussionmentioning

confidence: 86%

Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

Andersen

Lamy

Thorsen

et al. 2011

Intl Journal of Cancer

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Genomic alterations play important roles in colorectal cancer (CRC) carcinogenesis. Here, we aimed to identify and characterize recurrent copy-number alterations (CNAs) associated with clinical outcome of CRC by the use of single nucleotide polymorphism arrays, genomic quantitative PCR (qPCR) and fluorescence in situ hybridization (FISH). Colorectal neoplasia specimens and paired germline samples from 144 patients (40 adenomas and 104 carcinomas) as well as 40 CRC cell lines were investigated. This large dataset revealed frequent loss, including homozygous loss, at chr16p13.2 (from 5.9 to 7.42Mb). The loss was observed in 30% of adenomas and even more frequently in carcinomas, 56%, indicating that the loss define a subset of adenomas with a propensity for invasion. Consistent with this, the loss occurred twice as frequent in villous (40%) as in tubular adenomas (20%). The loss occurred independently of microsatellite stability and could be validated by qPCR in an independent sample cohort (n 5 71). In Stage II/III, microsatellite stable (MSS) CRC it was associated with poor recurrence free survival (hazard ratio 2.4; p 5 0.02; Multivariate Cox regression analysis). No transcriptional consequences of the losses were observed, and the only gene, A2BP1, located in the region showed no mutations. Correlation with other CNAs was established for chr3p22 in carcinomas and chr20p (inverse) in adenomas. FISH documented the chr16p13.2 region to be involved in complex structural rearrangements that included translocation to chr3p22 in some cases. The findings indicate that structural rearrangements involving chr16p13.2 are very frequent in colorectal neoplasia, often lead to homozygous deletion, and are associated with poor clinical outcome.Despite major efforts over the recent years toward improving the survival outcome of patients with colorectal cancer (CRC), the disease remains a major health burden with over one million cases worldwide and a disease-specific mortality of $33% in the developed world. 1 Currently, the gold standard for prognostication is clinicopathological staging, based on the Tumor, Node, Metastasis (TNM) classifcation. However. Although CRC is often diagnosed at a stage where complete resection of the primary cancer (Stages I-III) is possible, 40-50% of patients who undergo potentially curative surgery alone relapse and die of metastatic disease. 2 Although most patients with Stage III (lymph-node positive) cancer receive adjuvant treatment, it is offered to only a subset of Stage II (localized disease) patients presenting with specific high-risk clinical features, including tumor perforation or invasion of adjacent organs. 3 This approach is clearly suboptimal, resulting in undertreatment of $20% of Stage II patients who will recur. Similarly, current adjuvant treatment is clearly ineffective in many Stage III patients, with a recurrence rate of $40% 4,5 highlighting the need for treatment with more aggressive or newly emerging targeted therapies, e.g., inhibitors of epidermal growth factor recepto...

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“…Recent studies suggest A2BP1 may also contribute to several other human diseases, including cancer, autism and osteoarthritis (Cheung et al, 2008;Huang et al, 2009;Martin et al, 2007;Zhai et al, 2009). Previous molecular analysis of mammalian A2BP1 has focused on its role in alternative splicing (Auweter et al, 2006;Fukumura et al, 2009;Jin et al, 2003;Kuroyanagi et al, 2007;Lee et al, 2009;Minovitsky et al, 2005;Nakahata and Kawamoto, 2005;Underwood et al, 2005;Zhang et al, 2008;Zhou et al, 2007;Zhou and Lou, 2008).…”

Section: Research Articlementioning

confidence: 99%

DrosophilaAtaxin 2-binding protein 1 marks an intermediate step in the molecular differentiation of female germline cysts

Tastan

Maines

et al. 2010

Development

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SUMMARYIn the Drosophila ovary, extrinsic signaling from the niche and intrinsic translational control machinery regulate the balance between germline stem cell maintenance and the differentiation of their daughters. However, the molecules that promote the continued stepwise development of ovarian germ cells after their exit from the niche remain largely unknown. Here, we report that the early development of germline cysts depends on the Drosophila homolog of the human ataxin 2-binding protein 1 (A2BP1) gene. Drosophila A2BP1 protein expression is first observed in the cytoplasm of 4-, 8-and 16-cell cysts, bridging the expression of the early differentiation factor Bam with late markers such as Orb, Rbp9 and Bruno encoded by arrest. The expression of A2BP1 is lost in bam, sans-fille (snf) and mei-P26 mutants, but is still present in other mutants such as rbp9 and arrest. A2BP1 alleles of varying strength produce mutant phenotypes that include germline counting defects and cystic tumors. Phenotypic analysis reveals that strong A2BP1 alleles disrupt the transition from mitosis to meiosis. These mutant cells continue to express high levels of mitotic cyclins and fail to express markers of terminal differentiation. Biochemical analysis reveals that A2BP1 isoforms bind to each other and associate with Bruno, a known translational repressor protein. These data show that A2BP1 promotes the molecular differentiation of ovarian germline cysts.

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Genome-Wide Analysis of Survival in Early-Stage Non–Small-Cell Lung Cancer

Abstract: Five SNPs were identified that may be prognostic of overall survival in early-stage NSCLC.

Cited by 112 publications

References 26 publications

Multiple Genetic Loci Modulate Lung Adenocarcinoma Clinical Staging

Multiple Genetic Loci Modulate Lung Adenocarcinoma Clinical Staging

Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

DrosophilaAtaxin 2-binding protein 1 marks an intermediate step in the molecular differentiation of female germline cysts

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