Christopher P Crum

Harvard Medical School, Boston, Massachusetts, United States

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Publications (261)1691.24 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: High-grade serous cancer (HGSC) progresses to advanced stages without symptoms and the 5-year survival rate is a dismal 30%. Recent studies of ovaries and fallopian tubes in patients with BRCA1 or BRCA2 mutations have documented a pre-metastatic intramucosal neoplasm that is found almost exclusively in the fallopian tube, termed "serous tubal intraepithelial carcinoma" or STIC. Moreover, other proliferations, termed p53 signatures, secretory cell outgrowths (SCOUTs) and lower grade serous tubal intraepithelial neoplasms (STINs) fall short of STIC but share similar alterations in expression, in keeping with an underpinning of genomic disturbances involved in, or occurring in parallel with, serous carcinogenesis. To gain insight into the cellular origins of this unique tubal pathway to high-grade serous cancer, we cloned and both immortalized and transformed fallopian tube stem cells (FTSC). We demonstrated that pedigrees of FTSCs were capable of multi-potent differentiation and that the tumors derived from transformed FTSC shared the histological and molecular features of HGSC. We also demonstrated that altered expression of some biomarkers seen in transformed FTSCs and HGSCs (Stathmin, EZH2, CXCR4, CXCL12 and FOXM1) could be seen as well in immortalized cells and their in vivo counterparts SCOUTs and STINs. Thus, a whole-genome transcriptome analysis comparing FTSC, immortalized FTSC, and transformed FTSC showed a clear molecular progression sequence that is recapitulated by the spectrum of accumulated perturbations characterizing the range of proliferations seen in vivo. Biomarkers unique to STIC relative to normal tubal epithelium provide a basis for novel detection approaches to early HGSC, but must be viewed critically given their potential expression in lesser proliferations. Perturbations shared by both immortalized and transformed FTSCs may provide unique early targets for prevention strategies. Central to these efforts has been the ability to clone and perpetuate multi-potent FTSCs.
    The Journal of Pathology 09/2015; DOI:10.1002/path.4649 · 7.43 Impact Factor

  • Clinical Cancer Research 08/2015; 21(16 Supplement):POSTER-TECH-1121-POSTER-TECH-1121. DOI:10.1158/1557-3265.OVCASYMP14-POSTER-TECH-1121 · 8.72 Impact Factor

  • Clinical Cancer Research 08/2015; 21(16 Supplement):POSTER-CTRL-1204-POSTER-CTRL-1204. DOI:10.1158/1557-3265.OVCASYMP14-POSTER-CTRL-1204 · 8.72 Impact Factor

  • Clinical Cancer Research 08/2015; 21(16 Supplement):POSTER-CTRL-1208-POSTER-CTRL-1208. DOI:10.1158/1557-3265.OVCASYMP14-POSTER-CTRL-1208 · 8.72 Impact Factor
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    Dataset: Ning JOP

  • Cancer Research 08/2015; 75(15 Supplement):4223-4223. DOI:10.1158/1538-7445.AM2015-4223 · 9.33 Impact Factor
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    ABSTRACT: . To credential Stathmin 1 (STMN1) and p16(INK4A) (p16) as adjunct markers for the diagnosis of serous tubal intraepithelial carcinoma (STIC), and to compare STMN1 and p16 expression in p53-positive and p53-negative STIC and invasive high-grade serous carcinoma (HGSC). . Immunohistochemistry (IHC) was used to examine STMN1 and p16 expression in fallopian tube specimens (n=31) containing p53-positive and p53-negative STICs, invasive HGSCs, and morphologically normal FTE (fallopian tube epithelium). STMN1 and p16 expression was scored semiquantitatively by four individuals. The semiquantitative scores were dichotomized, and reported as positive or negative. Pooled siRNA was used to knockdown p53 in a panel of cell lines derived from immortalized FTE and HGSC. . STMN1 and p16 were expressed in the majority of p53-positive and p53-negative STICs and concomitant invasive HGSCs, but only scattered positive cells were positive in morphologically normal FTE. Both proteins were expressed consistently across multiple STICs from the same patient and in concomitant invasive HGSC. Knockdown of p53 in immortalized FTE cells and in four HGSC-derived cell lines expressing different missense p53 mutations did not affect STMN1 protein levels. This study demonstrates that STMN1 and p16 are sensitive and specific adjunct biomarkers that, when used with p53 and Ki-67, improve the diagnostic accuracy of STIC. The addition of STMN1 and p16 helps to compensate for practical limitations of p53 and Ki-67 that complicate the diagnosis in up to one third of STICs. Copyright © 2015. Published by Elsevier Inc.
    Gynecologic Oncology 07/2015; 139(1). DOI:10.1016/j.ygyno.2015.07.100 · 3.77 Impact Factor
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    ABSTRACT: Currently available human tumour cell line panels consist of a small number of lines in each lineage that generally fail to retain the phenotype of the original patient tumour. Here we develop a cell culture medium that enables us to routinely establish cell lines from diverse subtypes of human ovarian cancers with >95% efficiency. Importantly, the 25 new ovarian tumour cell lines described here retain the genomic landscape, histopathology and molecular features of the original tumours. Furthermore, the molecular profile and drug response of these cell lines correlate with distinct groups of primary tumours with different outcomes. Thus, tumour cell lines derived using this methodology represent a significantly improved platform to study human tumour pathophysiology and response to therapy.
    Nature Communications 06/2015; 6. DOI:10.1038/ncomms8419 · 11.47 Impact Factor
  • Michael Herfs · Christopher P Crum ·

    Nature Reviews Clinical Oncology 06/2015; 12(7). DOI:10.1038/nrclinonc.2015.104 · 14.18 Impact Factor
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    ABSTRACT: Human papilloma virus (HPV) infection causes cancers and their precursors (high-grade squamous intraepithelial lesions) near cervical and anal squamocolumnar junctions. Recently described cervical squamocolumnar junction cells are putative residual embryonic cells near the cervical transformation zone. These cells appear multipotential and share an identical immunophenotype (strongly CK7-positive) with over 90% of high-grade squamous intraepithelial lesions and cervical carcinomas. However, because the number of new cervical cancers discovered yearly world wide is 17-fold that of anal cancer, we posed the hypothesis that this difference in cancer risk reflects differences in the transition zones at the two sites. The microanatomy of the normal anal transformation zone (n=37) and topography and immunophenotype of anal squamous neoplasms (n=97) were studied. A discrete anal transition zone was composed of multilayered CK7-positive/p63-negative superficial columnar cells and an uninterrupted layer of CK7-negative/p63-positive basal cells. The CK7-negative/p63-positive basal cells were continuous with-and identical in appearance to-the basal cells of the mature squamous epithelium. This was in contrast to the cervical squamocolumnar junction, which harbored a single-layered CK7-positive/p63-negative squamocolumnar junction cell population. Of the 97 anal intraepithelial neoplasia/squamous cell carcinomas evaluated, only 27% (26/97) appeared to originate near the anal transition zone and only 23% (22/97) were CK7-positive. This study thus reveals two fundamental differences between the anus and the cervix: (1) the anal transition zone does not harbor a single monolayer of residual undifferentiated embryonic cells and (2) the dominant tumor immunophenotype is in keeping with an origin in metaplastic (CK7-negative) squamous rather than squamocolumnar junction (CK7-positive) epithelium. The implication is that, at birth, the embryonic cells in the anal transition zone have already begun to differentiate, presenting a metaplasia that-similar to vaginal and vulvar epithelium-is less prone to HPV-directed carcinogenesis. This in turn underscores the link between cancer risk and a very small and discrete population of vulnerable squamocolumnar junction cells in the cervix.Modern Pathology advance online publication, 15 May 2015; doi:10.1038/modpathol.2015.54.
    Modern Pathology 05/2015; 28(7). DOI:10.1038/modpathol.2015.54 · 6.19 Impact Factor
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    ABSTRACT: Stem cells of the gastrointestinal tract, pancreas, liver and other columnar epithelia collectively resist cloning in their elemental states. Here we demonstrate the cloning and propagation of highly clonogenic, 'ground state' stem cells of the human intestine and colon. We show that derived stem-cell pedigrees sustain limited copy number and sequence variation despite extensive serial passaging and display exquisitely precise, cell-autonomous commitment to epithelial differentiation consistent with their origins along the intestinal tract. This developmentally patterned and epigenetically maintained commitment of stem cells is likely to enforce the functional specificity of the adult intestinal tract. Using clonally derived colonic epithelia, we show that toxins A or B of the enteric pathogen Clostridium difficile recapitulate the salient features of pseudomembranous colitis. The stability of the epigenetic commitment programs of these stem cells, coupled with their unlimited replicative expansion and maintained clonogenicity, suggests certain advantages for their use in disease modelling and regenerative medicine.
    Gastroenterology 04/2015; 148(4):S-729. DOI:10.1016/S0016-5085(15)32490-2 · 16.72 Impact Factor
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    ABSTRACT: Recent studies have suggested the involvement of a unique population of cells at the cervical squamo-columnar junction (SCJ) in the pathogenesis of early (squamous intraepithelial lesion or SIL) and advanced (squamous cell and adeno-carcinomas) cervical neoplasia. However, there is little evidence to date showing that SCJ cells harbour carcinogenic HPV or are instrumental in the initial phases of neoplasia. This study was designed to 1) determine if normal-appearing SCJ cells contained evidence of carcinogenic HPV infection and 2) trace their transition to early SIL. Sections of cervix from high-risk reproductive age women were selected and SCJ cells were analyzed by using several techniques which increasingly implicated HPV infection: HPV DNA (genotyping and in situ hybridization)/RNA (PCR), immunostaining for HPV16 E2 (an early marker of HPV infection), p16ink4, Ki67 and HPV L1 protein. In 22 cases with a history of SIL and no evidence of preneoplastic lesion in the excision specimen, HPV DNA was isolated from 8 of 10 with visible SCJ cells, 6 of which were HPV16/18 DNA positive. In 5 of these latter cases, the SCJ cells were positive for p16ink4 and/or HPV E2. Transcriptionally active HPV infection (E6/E7 mRNAs) was also detected in micro-dissected SCJ cells. Early squamous atypia associated with the SCJ cells demonstrated in addition diffuse p16ink4 immunoreactivity, elevated proliferative index and rare L1 antigen positivity. We present for the first time direct evidence that normal-appearing SCJ cells can be infected by carcinogenic HPV. They initially express HPV E2 and their progression to SIL is heralded by an expanding metaplastic progeny with increased proliferation and p16ink4 expression. Whether certain SCJs are more vulnerable than others to carcinogenic HPV genotypes and what variables determine transition to high grade SIL remain unresolved, but the common event appears to be a vulnerable cell at the SCJ.
    The Journal of Pathology 03/2015; 236(3). DOI:10.1002/path.4533 · 7.43 Impact Factor
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    ABSTRACT: Recent studies suggest that a proportion of ovarian tumors may actually originate in the distal fallopian tube. The objective of this study was to examine the relationship between dominance (a surrogate for site of origin) and survival, following a diagnosis of epithelial ovarian cancer. We classified 1,386 tumors as dominant (putatively originating in the ovary) and non-dominant (putatively originating in the fallopian tube), using parameters obtained from pathology reports. Dominant tumors were restricted to one ovary or one involved ovary that exceeded the other in dimension by at least twofold, while non-dominant tumors were identified as having a greater likelihood of a tubal origin if the disease was equally distributed across the ovaries. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95 % confidence intervals (CIs) associated with dominance. Non-dominant tumors were more likely to be serous, stage III/IV, and be associated with a BRCA1/2 mutation, increasing parity and use of estrogen hormone replacement therapy (p ≤ 0.01). In contrast, 46 and 26 % of the dominant tumors were serous and endometrioid, respectively, with a more even distribution of stage (p < 0.0001). Women with a non-dominant tumor had an increased risk of death compared to women with a dominant tumor (multivariate HR 1.28; 95 % CI 1.02-1.60). Findings were similar in our analysis restricted to serous only subtypes (HR 1.28; 95 % CI 1.01-1.63). These preliminary findings suggest significantly worse survival among women diagnosed with a tumor putatively arising from fallopian tube.
    Cancer Causes and Control 03/2015; 26(4). DOI:10.1007/s10552-015-0547-y · 2.74 Impact Factor
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    ABSTRACT: Epithelioid trophoblastic tumor (ETT) is a rare form of gestational trophoblastic neoplasm which is distinct based on its development from intermediate trophoblast cells and nodular growth pattern. The aim of this study is to describe a case series from a single institution with review of the literature to better understand the clinical characteristics and outcomes for patients with ETT. A retrospective review was performed using the IRB approved New England Trophoblastic Disease Center (NETDC) database from 1998 to 2014. Eight patients were identified of which seven had complete records. Follow up data was obtained from the longitudinal medical records. Four (57.1%) patients presented with vaginal bleeding and two (28.6%) patients were asymptomatic at presentation. Three (42.9%) patients had extrauterine disease. All three patients with extrauterine disease who received chemotherapy had stable or progressive disease at follow up. Only two (29%) patients who presented with non-metastatic disease and underwent hysterectomy were alive with no evidence of disease. The mean interval following antecedent pregnancy was 104months. All patients with an interval >4years demonstrated stable or progressive disease despite intensive chemotherapy. Two patients with non-metastatic disease who declined hysterectomy developed stable or progressive disease despite chemotherapy. This series highlights several features of ETT including the potential for asymptomatic presentation of extrauterine disease. The series also demonstrates chemoresistance, even with multi-agent therapy and a poor prognosis with extrauterine disease and an interval greater than 4years following the antecedent pregnancy suggesting surgery remains critical in disease control. Copyright © 2015 Elsevier Inc. All rights reserved.
    Gynecologic Oncology 03/2015; 137(3). DOI:10.1016/j.ygyno.2015.03.006 · 3.77 Impact Factor
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    Elizabeth M Poole · Megan S Rice · Christopher P Crum · Shelley S Tworoger ·

    JNCI Journal of the National Cancer Institute 02/2015; 107(2). DOI:10.1093/jnci/dju490 · 12.58 Impact Factor
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    ABSTRACT: While rates of cervical squamous cell carcinoma have been declining, rates of cervical adenocarcinoma are increasing in some countries. Outcomes for advanced cervical adenocarcinoma remain poor. Precision mapping of genetic alterations in cervical adenocarcinoma may enable better selection of therapies and deliver improved outcomes when combined with new sequencing diagnostics. We present whole-exome sequencing results from 15 cervical adenocarcinomas and paired normal samples from Hong Kong Chinese women. These data revealed a heterogeneous mutation spectrum and identified several frequently altered genes including FAT1, ARID1A, ERBB2, and PIK3CA. Exome sequencing identified human papillomavirus (HPV) sequences in 13 tumors in which the HPV genome might have integrated into and hence disrupted the functions of certain exons, raising the possibility that HPV integration can alter pathways other than p53 and pRb. Together, these provisionary data suggest the potential for individualized therapies for cervical adenocarcinoma based on genomic information. This article is protected by copyright. All rights reserved. © 2015 UICC.
    International Journal of Cancer 01/2015; 137(4). DOI:10.1002/ijc.29456 · 5.09 Impact Factor
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    ABSTRACT: Most early adnexal carcinomas detected in asymptomatic women with germline BRCA mutations (BRCA) present as serous tubal intraepithelial carcinomas (STIC). However, STICs are found in only ∼40% of symptomatic high-grade serous carcinomas (HGSCs) and less frequently in pseudoendometrioid variants of HGSC. Consecutive cases of untreated HGSC from BRCA and BRCA women with detailed fallopian tube examination (SEE-FIM protocol) were compared. STIC status (+/-) was determined, and tumors were classified morphologically as SET ("SET", >50% solid, pseudoendometrioid, or transitional) or classic predominate ("Classic"). SET tumors trended toward a higher frequency in BRCA versus BRCA women (50% vs. 28%, P=0.11), had a significantly younger mean age than those with classic HGSC in BRCA women (mean 56.2 vs. 64.8 y, P=0.04), and displayed a better clinical outcome in both groups combined (P=0.024). STIC was significantly more frequent in tumors from the BRCA cohort (66% vs. 31%, P=0.017) and specifically the BRCA tumors with classic morphology (83%) versus those with SET morphology (22%, P=0.003). Overall, several covariables-histology, BRCA status, age, coexisting STIC, and response to therapy-define 2 categories of HGSC with differences in precursor (STIC) frequency, morphology, and outcome. We introduce a dualistic HGSC model that could shed light on the differences in frequency of STIC between symptomatic and asymptomatic women with HGSC. This model emphasizes the need for further study of HGSC precursors to determine their relevance to the prevention of this lethal malignancy.
    American Journal of Surgical Pathology 01/2015; 39(3). DOI:10.1097/PAS.0000000000000369 · 5.15 Impact Factor
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    Hanna G Kaspar · Christopher P Crum ·
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    ABSTRACT: Context: Immunohistochemistry has assumed an increasing role in the identification and characterization of gynecologic disorders including lesions with deceptively bland morphology, uncommon and underdiagnosed neoplasms, and neoplasms with specific genetic alterations associated with overexpression or loss of expression of specific proteins. The diagnostic accuracy has been significantly improved owing to the discovery and increasing experience with the tumor-associated biomarkers, and the increasing demand for precise tumor classification to assess suitability for the expanding therapeutic modalities including clinical trials. Objective: To differentiate lesions of the gynecologic tract through the use of effective immunohistochemical panels. Data sources: Literature review and authors' personal practice experience. Conclusions: The application of diagnostic and prognostic immunohistochemical panels has enabled pathologists to better guide therapeutic decisions and to better predict the clinical outcome. It is now well established that the use of ancillary testing, including immunohistochemistry, has a significant power in the identification, differentiation, and classification of reactive, premalignant, and malignant gynecologic disorders. This article discusses the utilities and pitfalls of the commonly used immunohistochemical markers in the context of overlapping morphologic features encountered in the uterus, ovaries, and fallopian tubes.
    Archives of pathology & laboratory medicine 01/2015; 139(1):39-54. DOI:10.5858/arpa.2014-0057-RA · 2.84 Impact Factor
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    ABSTRACT: The oviducts contain high grade serous cancer (HGSC) precursors (serous tubal intraepithelial neoplasia or STINs), which are γ-H2AXp- and TP53 mutation-positive. Although they express wild type p53, secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer; moreover both STINs and SCOUTs share a loss of PAX2 expression (PAX2n). We evaluated PAX2 expression in proliferating adult and embryonic oviductal cells, normal mucosa, SCOUTs, Walthard cell nests (WCNs), STINs and HGSCs, and the expression of genes chosen empirically or from SCOUT expression arrays. Clones generated in vitro from embryonic gynecologic tract and adult fallopian tube were Krt7p/ PAX2n/EZH2p and underwent ciliated (PAX2n/EZH2n/FOXJ1p) and basal (Krt7n/EZH2n/Krt5p) differentiation. Similarly non-ciliated cells in normal mucosa were PAX2p but became PAX2n in multilayered epithelium undergoing ciliated or basal (Walthard cell nests or WCN) cell differentiation. PAX2n SCOUTs fell into two groups; Type I were secretory or secretory/ciliated with a “tubal” phenotype and were ALDH1n and β-cateninmem (membraneous only). Type II displayed a columnar to pseudostratified (endometrioid) phenotype, with an EZH2p, ALDH1p, β-cateninnc (nuclear and cytoplasmic), stathminp, LEF1p, RCN1p and RUNX2p expression signature. STINs and HGSCs shared the Type I immunophenotype of PAX2n, ALDH1n, β-cateninmem, but highly expressed EZH2p, LEF1p, RCN1p, and stathminp. This study, for the first time, links PAX2n with proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumor suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2), calcium binding (RCN1) and oncogenesis (stathmin). This shared expression signature between benign and neoplastic entities links normal progenitor cell expansion to abnormal and neoplastic outgrowth in the oviduct and exposes a common pathway that could be a target for early prevention.
    The Journal of Pathology 12/2014; 234(4). DOI:10.1002/path.4417 · 7.43 Impact Factor

Publication Stats

10k Citations
1,691.24 Total Impact Points


  • 1995-2015
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Pathology
      • • Department of Cell Biology
      Boston, Massachusetts, United States
  • 1992-2015
    • Brigham and Women's Hospital
      • • Division of Women's and Perinatal Pathology
      • • Department of Pathology
      • • Division of General Obstetrics and Gynecology
      Boston, Massachusetts, United States
  • 1994-2014
    • Harvard University
      • Department of Molecular and Cell Biology
      Cambridge, Massachusetts, United States
  • 2006-2012
    • Dana-Farber Cancer Institute
      • Department of Cancer Biology
      Boston, Massachusetts, United States
  • 2009
    • Boston Children's Hospital
      • Department of Pathology
      Boston, MA, United States
  • 2008
    • Universitat de Lleida
      • Department of Vegetal Production and Forestry Science
      Lérida, Catalonia, Spain
  • 2007
    • Partners HealthCare
      Boston, Massachusetts, United States
  • 2004
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 2002
    • Massachusetts Institute of Technology
      • George R. Harrison Spectroscopy Laboratory
      Cambridge, Massachusetts, United States
  • 1999
    • University of Washington Seattle
      Seattle, Washington, United States
    • Universidade Federal do Paraná
      • Departamento de Patologia Básica
      Curitiba, Estado do Parana, Brazil
  • 1987
    • Zagazig University
      • Department of Obstetrics and Gynecology
      Ez Zaqāzīq, Eastern Province, Egypt
  • 1986-1987
    • Hiroshima University
      • Department of Obstetrics and Gynecology
      Hirosima, Hiroshima, Japan
  • 1981-1987
    • Columbia University
      • College of Physicians and Surgeons
      New York, New York, United States
  • 1983-1984
    • CUNY Graduate Center
      New York City, New York, United States
    • West Georgia Obstetrics and Gynecology
      Georgetown, Georgia, United States