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Dive into the research topics where Alison P. Klein is active.

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Featured researches published by Alison P. Klein.


Science Translational Medicine | 2012

Colocalization of Inflammatory Response with B7-H1 Expression in Human Melanocytic Lesions Supports an Adaptive Resistance Mechanism of Immune Escape

Janis M. Taube; Robert A. Anders; Geoffrey D. Young; Haiying Xu; Rajni Sharma; Tracee L. McMiller; Shuming Chen; Alison P. Klein; Drew M. Pardoll; Suzanne L. Topalian; Lieping Chen

Activated tumor-infiltrating lymphocytes may induce B7-H1 on melanocytes, which suggests adaptive resistance to antitumor immunity. The Great Escape In the movie The Great Escape, “problem” prisoners with multiple escape attempts are put in an “escape-proof” POW camp, where they use their cleverness and specialized skills to outwit their captors. However, when it comes to escaping, even Steve McQueen doesn’t have anything on cancer cells. Although human cancers express tumor antigens recognized by the immune system, host immune responses often fail to control tumor growth. Taube et al. now explain one way in which tumor cells may adapt to escape from immune surveillance. The researchers found a strong association between expression of the immune-inhibitory molecule B7-H1 (PD-L1) on melanocytes and immune cell infiltration into tumors in patients with different stages of melanoma. The B7-H1+ melanocytes were found directly adjacent to the immune cells, with interferon-γ detected at the melanocyte–immune cell interface. Interferon-γ, which is secreted by the immune cells, induces B7-H1 expression; thus, the tumor may adapt by causing immune cells to trigger their own inhibition. Indeed, patients with B7-H1+ metastatic melanoma had prolonged overall survival when compared with B7-H1− metastatic melanoma patients, perhaps suggesting that B7-H1 expression by the tumors is stimulated by a more successful immune response. It remains to be seen whether blocking B7-H1 in these patients will further improve survival. But it is clear that for both prisoners and tumors, adaptation is the key to escape. Although many human cancers such as melanoma express tumor antigens recognized by T cells, host immune responses often fail to control tumor growth for as yet unexplained reasons. Here, we found a strong association between melanocyte expression of B7-H1 (PD-L1), an immune-inhibitory molecule, and the presence of tumor-infiltrating lymphocytes (TILs) in human melanocytic lesions: 98% of B7-H1+ tumors were associated with TILs compared with only 28% of B7-H1− tumors. Indeed, B7-H1+ melanocytes were almost always localized immediately adjacent to TILs. B7-H1/TIL colocalization was identified not only in melanomas but also in inflamed benign nevi, indicating that B7-H1 expression may represent a host response to tissue inflammation. Interferon-γ, a primary inducer of B7-H1 expression, was detected at the interface of B7-H1+ tumors and TILs, whereas none was found in B7-H1− tumors. Therefore, TILs may actually trigger their own inhibition by secreting cytokines that drive tumor B7-H1 expression. Consistent with this hypothesis, overall survival of patients with B7-H1+ metastatic melanoma was significantly prolonged compared with that of patients with B7-H1− metastatic melanoma. Therefore, induction of the B7-H1/PD-1 pathway may represent an adaptive immune resistance mechanism exerted by tumor cells in response to endogenous antitumor activity and may explain how melanomas escape immune destruction despite endogenous antitumor immune responses. These observations suggest that therapies that block this pathway may benefit patients with B7-H1+ tumors.


Clinical Cancer Research | 2014

Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy

Janis M. Taube; Alison P. Klein; Julie R. Brahmer; Haiying Xu; Xiaoyu Pan; Jung H. Kim; Lieping Chen; Drew M. Pardoll; Suzanne L. Topalian; Robert A. Anders

Purpose: Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. Experimental Design: Patients (N = 41) with melanoma, non–small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of anti–PD-1 (nivolumab) at one institution and had evaluable pretreatment tumor specimens. Immunoarchitectural features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes. Results: Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti–PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response. Conclusions: Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti–PD-1 blockade. Clin Cancer Res; 20(19); 5064–74. ©2014 AACR.


Journal of Clinical Oncology | 2009

DPC4 Gene Status of the Primary Carcinoma Correlates With Patterns of Failure in Patients With Pancreatic Cancer

Christine A. Iacobuzio-Donahue; Baojin Fu; Shinichi Yachida; Mingde Luo; Hisashi Abe; Clark Henderson; Felip Vilardell; Zheng Wang; Jesse Keller; Priya Banerjee; Joseph M. Herman; John L. Cameron; Charles J. Yeo; Marc K. Halushka; James R. Eshleman; Marian Raben; Alison P. Klein; Ralph H. Hruban; Manuel Hidalgo; D. Laheru

PURPOSE Contrary to the extensive data accumulated regarding pancreatic carcinogenesis, the clinical and molecular features characteristic of advanced stage (stage III and IV) disease are unknown. A comprehensive study of pancreatic cancers from patients who have succumbed to their disease has the potential to greatly expand our understanding of the most lethal stage of this disease and identify novel areas for intervention. MATERIALS AND METHODS Rapid autopsies were performed on 76 patients with documented pancreatic cancer. The histologic features of end stage disease were determined and correlated to the stage at initial diagnosis, patterns of failure (locally destructive v metastatic disease) and the status of the KRAS2, TP53, and DPC4 genes. RESULTS At autopsy, 30% of patients died with locally destructive pancreatic cancer, and 70% died with widespread metastatic disease. These divergent patterns of failure found at autopsy (locally destructive v metastatic) were unrelated to clinical stage at initial presentation, treatment history, or histopathologic features. However, Dpc4 immunolabeling status of carcinoma tissues harvested at autopsy, a sensitive marker of DPC4 genetic status, was highly correlated with the presence of widespread metastasis but not with locally destructive tumors (P = .007). CONCLUSION Pancreatic cancers are represented by distinct genetic subtypes with significantly different patterns of failure. Determinations of DPC4 status at initial diagnosis may be of value in stratifying patients into treatment regimens related to local control versus systemic therapy.


Science | 2009

Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene

Siân Jones; Ralph H. Hruban; Mihoko Kamiyama; Michael Borges; Xiaosong Zhang; D. Williams Parsons; Jimmy Lin; Emily Palmisano; Kieran Brune; Elizabeth M. Jaffee; Christine A. Iacobuzio-Donahue; Anirban Maitra; Giovanni Parmigiani; Scott E. Kern; Victor E. Velculescu; Kenneth W. Kinzler; Bert Vogelstein; James R. Eshleman; Michael Goggins; Alison P. Klein

Through complete sequencing of the protein-coding genes in a patient with familial pancreatic cancer, we identified a germline, truncating mutation in PALB2 that appeared responsible for this patients predisposition to the disease. Analysis of 96 additional patients with familial pancreatic cancer revealed three distinct protein-truncating mutations, thereby validating the role of PALB2 as a susceptibility gene for pancreatic cancer. PALB2 mutations have been previously reported in patients with familial breast cancer, and the PALB2 protein is a binding partner for BRCA2. These results illustrate that complete, unbiased sequencing of protein-coding genes can lead to the identification of a gene responsible for a hereditary disease.


Science | 2011

Altered telomeres in tumors with ATRX and DAXX mutations.

Christopher M. Heaphy; Roeland F. De Wilde; Yuchen Jiao; Alison P. Klein; Barish H. Edil; Chanjuan Shi; Chetan Bettegowda; Fausto J. Rodriguez; Charles G. Eberhart; Sachidanand Hebbar; G. Johan A. Offerhaus; Roger E. McLendon; B. Ahmed Rasheed; Yiping He; Hai Yan; Darell D. Bigner; Sueli Mieko Oba-Shinjo; Suely Kazue Nagahashi Marie; Gregory J. Riggins; Kenneth W. Kinzler; Bert Vogelstein; Ralph H. Hruban; Anirban Maitra; Nickolas Papadopoulos; Alan K. Meeker

Chromosome tips seem to be maintained by an unusual mechanism in tumors that have mutations in chromatin remodeling genes. The proteins encoded by ATRX and DAXX participate in chromatin remodeling at telomeres and other genomic sites. Because inactivating mutations of these genes are common in human pancreatic neuroendocrine tumors (PanNETs), we examined the telomere status of these tumors. We found that 61% of PanNETs displayed abnormal telomeres that are characteristic of a telomerase-independent telomere maintenance mechanism termed ALT (alternative lengthening of telomeres). All of the PanNETs exhibiting these abnormal telomeres had ATRX or DAXX mutations or loss of nuclear ATRX or DAXX protein. ATRX mutations also correlate with abnormal telomeres in tumors of the central nervous system. These data suggest that an alternative telomere maintenance function may operate in human tumors with alterations in the ATRX or DAXX genes.


American Journal of Roentgenology | 2008

Prevalence of unsuspected pancreatic cysts on MDCT.

Thomas A. Laffan; Karen M. Horton; Alison P. Klein; Bruce Berlanstein; Stanley S. Siegelman; Satomi Kawamoto; Pamela T. Johnson; Elliot K. Fishman; Ralph H. Hruban

OBJECTIVE Current generation MDCT technology facilitates identification of small, nonenhancing lesions in the pancreas. The objective of this study was to determine the prevalence of findings of unsuspected pancreatic cysts on 16-MDCT in a population of adult outpatients imaged for disease unrelated to the pancreas. MATERIALS AND METHODS Contrast-enhanced MDCT scans of the abdomen were reviewed from 2,832 consecutive examinations to identify pancreatic cysts. Patients with a history of pancreatic lesions or predisposing factors for pancreatic disease or who were referred for pancreatic CT were excluded. RESULTS A total of 73 patients had pancreatic cysts, representing a prevalence of 2.6 per 100 patients (95% CI, 2.0-3.2). Cysts ranged in size from 2 to 38 mm (mean, 8.9 mm) and were solitary in 85% of cases. Analysis of demographic information showed a strong correlation between pancreatic cysts and age, with no cysts identified among patients under 40 years and a prevalence of 8.7 per 100 (95% CI, 4.6-12.9) in individuals from 80 to 89 years. After controlling for age, cysts were more common in individuals of the Asian race than all other race categories, with an odds ratio of 3.57 (95% CI, 1.05-12.13). There was no difference by sex in the prevalence of cysts (p = 0.527); however, cysts were on average 3.6 mm larger (p = 0.014) in men than women. CONCLUSION In this outpatient population, the prevalence of unsuspected pancreatic cysts identified on 16-MDCT was 2.6%. Cyst presence strongly correlated with increasing age and the Asian race.


Science Translational Medicine | 2011

Recurrent GNAS Mutations Define an Unexpected Pathway for Pancreatic Cyst Development

Jian Wu; Hanno Matthaei; Anirban Maitra; Marco Dal Molin; Laura D. Wood; James R. Eshleman; Michael Goggins; Marcia I. Canto; Richard D. Schulick; Barish H. Edil; Christopher L. Wolfgang; Alison P. Klein; Luis A. Diaz; Peter J. Allen; C. Max Schmidt; Kenneth W. Kinzler; Nickolas Papadopoulos; Ralph H. Hruban; Bert Vogelstein

A mutation in the gene GNAS serves as a marker for pancreatic cysts that can progress to become invasive adenocarcinomas, guiding therapy. Staying Out of the Operating Room Like bad traffic, surgery is something to be avoided if at all possible. This was the guiding principle of Wu et al. when conducting their research on pancreatic cysts, found in more than 2% of the population. Physician and patient face a dilemma: Some pancreatic cysts will progress to form dangerous invasive carcinoma and some persist harmlessly forever. So, to err on the side of safety, many harmless cysts are removed, exposing patients to unnecessary risk. By sequencing DNA from pancreatic cysts and invasive pancreatic cancers, the authors have now determined that the presence of mutations in two oncogenes can identify the cysts that are likely to progress to carcinoma and so are good candidates for surgical removal. (Without KRAS or GNAS mutations, the cyst may be better left in place.) The authors assessed DNA from the cyst fluid of 19 intraductal papillary mucinous neoplasms and the corresponding normal tissue by massively parallel sequencing for mutations in 169 cancer genes. Two results stood out—one expected and one unexpected. Fourteen of the 19 tumors showed mutations in the known pancreatic oncogene KRAS, and 6 of the 19 carried a mutation in GNAS, a well-known oncogene in other tumor types. Of a larger set of fluid samples from these cystic neoplasms (132), 96% carried a mutation in at least one of the two oncogenes. In contrast, 44 benign cysts exhibited no GNAS or KRAS mutations. Cystic fluid that contains DNA with both the GNAS and KRAS mutations indicates, with high sensitivity and specificity, that the lesion is likely to be an intraductal papillary mucinous neoplasm (at risk for developing into an invasive carcinoma) and not a benign serous cystadenomas. These genetic markers could distinguish between benign tumors and more problematic neoplasms, enabling some patients to avoid the undesirable experience of surgery. More than 2% of the adult U.S. population harbors a pancreatic cyst. These often pose a difficult management problem because conventional criteria cannot always distinguish cysts with malignant potential from those that are innocuous. One of the most common cystic neoplasms of the pancreas, and a bona fide precursor to invasive adenocarcinoma, is called intraductal papillary mucinous neoplasm (IPMN). To help reveal the pathogenesis of these lesions, we purified the DNA from IPMN cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. In addition to the expected KRAS mutations, we identified recurrent mutations at codon 201 of GNAS. A larger number (113) of additional IPMNs were then analyzed to determine the prevalence of KRAS and GNAS mutations. In total, we found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight cases, the GNAS mutations present in the IPMNs were also found in the invasive lesion. GNAS mutations were not found in other types of cystic neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. In addition to defining a new pathway for pancreatic neoplasia, these data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions.


Nature Genetics | 2009

Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer

Laufey Amundadottir; Peter Kraft; Rachael Z. Stolzenberg-Solomon; Charles S. Fuchs; Gloria M. Petersen; Alan A. Arslan; H. Bas Bueno-de-Mesquita; Myron D. Gross; Kathy J. Helzlsouer; Eric J. Jacobs; Andrea Z. LaCroix; Wei Zheng; Demetrius Albanes; William R. Bamlet; Christine D. Berg; Franco Berrino; Sheila Bingham; Julie E. Buring; Paige M. Bracci; Federico Canzian; Françoise Clavel-Chapelon; Sandra Clipp; Michelle Cotterchio; Mariza de Andrade; Eric J. Duell; John W. Fox; Steven Gallinger; J. Michael Gaziano; Edward Giovannucci; Michael Goggins

We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 × 10−8; multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12–1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.


Cancer Research | 2004

Prospective Risk of Pancreatic Cancer in Familial Pancreatic Cancer Kindreds

Alison P. Klein; Kieran Brune; Gloria M. Petersen; Michael Goggins; Anne C. Tersmette; G. Johan A. Offerhaus; Constance A. Griffin; John L. Cameron; Charles J. Yeo; Scott E. Kern; Ralph H. Hruban

Individuals with a family history of pancreatic cancer have an increased risk of developing pancreatic cancer. Quantification of this risk provides a rational basis for cancer risk counseling and for screening for early pancreatic cancer. In a prospective registry-based study, we estimated the risk of pancreatic cancer in individuals with a family history of pancreatic cancer. Standardized incidence ratios were calculated by comparing the number of incident pancreatic cancers observed with those expected using Surveillance, Epidemiology and End Results (SEER) rates. Familial pancreatic cancer (FPC) kindreds were defined as kindreds having at least one pair of first-degree relatives with pancreatic cancer, and sporadic pancreatic cancer (SPC) kindreds as families without such an affected pair. Nineteen incident pancreatic cancers developed among 5,179 individuals from 838 kindreds (at baseline, 370 FPC kindreds and 468 SPC kindreds). Of these 5,179 individuals, 3,957 had at least one first-degree relative with pancreatic cancer and contributed 10,538 person-years of follow-up. In this group, the observed-to-expected rate of pancreatic cancer was significantly elevated in members of FPC kindreds [9.0; 95% confidence interval (CI), 4.5–16.1], but not in the SPC kindreds (1.8; 95% CI., 0.22–6.4). This risk in FPC kindreds was elevated in individuals with three (32.0; 95% CI, 10.2–74.7), two (6.4; CI, 1.8–16.4), or one (4.6; CI, 0.5–16.4) first-degree relative(s) with pancreatic cancer. Risk was not increased among 369 spouses and other genetically unrelated relatives. Risk was higher in smokers than in nonsmokers. Individuals with a strong family history of pancreatic cancer have a significantly increased risk of developing pancreatic cancer.


Proceedings of the National Academy of Sciences of the United States of America | 2011

Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways

Jian Wu; Yuchen Jiao; Marco Dal Molin; Anirban Maitra; Roeland F. De Wilde; Laura D. Wood; James R. Eshleman; Michael Goggins; Christopher L. Wolfgang; Marcia I. Canto; Richard D. Schulick; Barish H. Edil; Michael A. Choti; Volkan Adsay; David S. Klimstra; G. Johan A. Offerhaus; Alison P. Klein; Levy Kopelovich; Hannah Carter; Rachel Karchin; Peter J. Allen; C. Max Schmidt; Yoshiki Naito; Luis A. Diaz; Kenneth W. Kinzler; Nickolas Papadopoulos; Ralph H. Hruban; Bert Vogelstein

More than 2% of adults harbor a pancreatic cyst, a subset of which progresses to invasive lesions with lethal consequences. To assess the genomic landscapes of neoplastic cysts of the pancreas, we determined the exomic sequences of DNA from the neoplastic epithelium of eight surgically resected cysts of each of the major neoplastic cyst types: serous cystadenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and solid pseudopapillary neoplasms (SPNs). SPNs are low-grade malignancies, and IPMNs and MCNs, but not SCAs, have the capacity to progress to cancer. We found that SCAs, IPMNs, MCNs, and SPNs contained 10 ± 4.6, 27 ± 12, 16 ± 7.6, and 2.9 ± 2.1 somatic mutations per tumor, respectively. Among the mutations identified, E3 ubiquitin ligase components were of particular note. Four of the eight SCAs contained mutations of the von Hippel–Lindau gene (VHL), a key component of the VHL ubiquitin ligase complex that has previously been associated with renal cell carcinomas, SCAs, and other neoplasms. Six of the eight IPMNs and three of the eight MCNs harbored mutations of RNF43, a gene coding for a protein with intrinsic E3 ubiquitin ligase activity that has not previously been found to be genetically altered in any human cancer. The preponderance of inactivating mutations in RNF43 unequivocally establish it as a suppressor of both IPMNs and MCNs. SPNs contained remarkably few genetic alterations but always contained mutations of CTNNB1, previously demonstrated to inhibit degradation of the encoded protein (β-catenin) by E3 ubiquitin ligases. These results highlight the essential role of ubiquitin ligases in these neoplasms and have important implications for the diagnosis and treatment of patients with cystic tumors.

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Ralph H. Hruban

Johns Hopkins University School of Medicine

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James R. Eshleman

Johns Hopkins University School of Medicine

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Richard D. Schulick

University of Colorado Denver

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Priya Duggal

Johns Hopkins University

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Joan E. Bailey-Wilson

National Institutes of Health

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Kieran Brune

Johns Hopkins University

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