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Bradley Joseph Quade, MD, PhD
Pathologist, Brigham and Women's Hospital
Associate Professor of Pathology, Harvard Medical School

Brigham and Women's Hospital
Department of Pathology
75 Francis Street
Boston, MA 02115

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Research Narrative:

     Dr. Quade has active programs investigating the pathobiology of uterine smooth muscle tumors and organogenesis of the female genital tract. Dr. Quade is the Clinical Director of Pathology for the BWH Center For Uterine Fibroids.  As a part of this multi-laboratory center, the goal of his laboratory is to discover the pathologic mechanism of benign and malignant uterine smooth muscle neoplasms.  Benign uterine leiomyomata (aka fibroids) are the most common human tumor.  They are found in nearly 80% of reproductive age women, each woman has an average of six tumors, and one fifth of women have significant symptoms.  Consequently, these benign tumors pose a major public health problem and are the leading indication for hysterectomy.  Nearly one half of leiomyomata have simple chromosomal abnormalities.  We began our studies by focusing on one of the most common cytogenetic abnormalities, a balanced translocation between chromosome 12 and 14.  Our studies showed that the t(12;14) causes aberrant expression of the chromatin factor HMGA2, a gene responsible for regulating adiposity and height during development.  Expression of the DNA binding domains of HMGA2 in mesenchymal cells of the female genital tract results in uterine leiomyomata (particularly those with particular histological pattern rich in extracellular matrix deposition), vulvar aggressive angiomyxomas, endometrial polyps , disseminated peritoneal and intravenous leiomyomatosis (DPL and IVL, respectively).  The explanation as to why HMGA2 expression can result in pathobiologically distinct phenotypes (i.e., local invasiveness in vulvar tumors, clonal intraperitoneal metastasis in DPL, and vascular invasiveness in IVL) remains a mystery and is of great interest to our laboratory.  In contrast to the simple cytogenetic aberrations in benign leiomyomata, leiomyosarcoma have complex numerical and structural abnormalities, precluding a straightforward positional cloning strategy.  Consequently, we have taken a different approach and have shown that loss of heterozygosity for chromosomes 10 and 13 is very frequent.  In conjunction with Tyler Jacks’ laboratory at the Whitehead Institute, we have shown that loss of p53 is a key contributor to tumorigenesis in a mouse leiomyosarcoma model.  We hypothesize that another tumor suppressor is located on chromosome 10.  To discover this novel suppressor, we cloned the breakpoint from a cytogenetic subgroup of leiomyomata with chromosome 10 rearrangements.  Interestingly, we found that a gene disrupted in leukemia, MYST4, at the breakpoint in hypercellular leiomyomata.  Similar to HMGA2, MYST4 histone acetyltransferase is a chromatin factor controlling gene expression, suggesting a common pathological mechanism in smooth muscle neoplasia.  In addition, our previous studies have identified critical differences in the gene expression of leiomyosarcoma relative to leiomyoma.  This expression signature also is found in atypical leiomyomata, particularly those with chromosome 1p rearrangements and IVL.  In fact, these studies and our clinical observations suggest that histologically atypical leiomyoma may be the precursor for malignant leiomyosarcoma, and studies are underway to test this hypothesis.

     In the second project, our aim is to find the genes needed for development of the uterus during embryogenesis.  This project is part of the Developmental Genome Anatomy Project (DGAP), a NIH PO1 project that was recently refunded.  DGAP seeks to find developmentally critical genes by studying individuals with balanced chromosomal rearrangements and congenital anomalies.  DGAP is a collaboration between the Morton (BWH Ob/Gyn), Maas (BWH Medicine), Gusella (MGH Neurology) and Quade laboratories.  The DGAP study was recently recognized in an article entitled “The Genetic Dimension Of Height And Health” in Science News (S. Barazesh, May 9th, 2009; vol 175 #10, p. 22).  In humans, the paired Müllerian ducts fuse to form the uterine corpus.  Abnormalities of Müllerian duct development have been poorly studied because they reduce fertility, which precludes typical genetic linkage studies.  Furthermore, mouse genetics cannot be applied to study Müllerian anomalies, as two uterine horns is the default anatomy in rodents.  Consequently, the positional gene discovery approach used by DGAP is highly suited to discover genes required for human female genital tract development.  Of note, the congenital abnormalities of two DGAP cases include bicornuate uteri.  In one, Dr. Cordero, a fellow in the Quade laboratory, mapped the breakpoints by FISH and Southern hybridization and cloned the breakpoint using PCR.  Interesting, the disrupted gene is epsin 2 (EPN2), a clathrin-associated adapter protein.  Dr. Cordero’s functional studies have shown that EPN2 plays a cell polarization and migration.  Interestingly, both the mouse brain in his gene suppression studies and our original DGAP subject have neuronal migration abnormalities, and this and other experiments suggests that EPN2 may play a larger role in controlling midline development.  Finally, work is in progress in a second DGAP case with abnormal uterine development and one of the candidate genes also plays a role in endocytosis.  If confirmed, our studies may lead to the elucidation of a new pathway required for human development.


Lab Members:

Dwight Cordero, MD, Women’s Reproductive Health Research Career Development Program Scholar

Publications (Pulled from Harvard Catalyst Profiles):

1. Amin-Mansour A, George S, Sioletic S, Carter SL, Rosenberg M, Taylor-Weiner A, Stewart C, Chevalier A, Seepo S, Tracy A, Getz G, Hornick JL, Nucci MR, Quade B, Demetri GD, Raut CP, Garraway LA, Van Allen EM, Wagner AJ. Genomic Evolutionary Patterns of Leiomyosarcoma and Liposarcoma. Clin Cancer Res. 2019 Jun 04.

2. Currall BB, Chen M, Sallari RC, Cotter M, Wong KE, Robertson NG, Penney KL, Lunardi A, Reschke M, Hickox AE, Yin Y, Wong GT, Fung J, Brown KK, Williamson RE, Sinnott-Armstrong NA, Kammin T, Ivanov A, Zepeda-Mendoza CJ, Shen J, Quade BJ, Signoretti S, Arnos KS, Banks AS, Patsopoulos N, Liberman MC, Kellis M, Pandolfi PP, Morton CC. Corrigendum: Loss of LDAH associated with prostate cancer and hearing loss. Hum Mol Genet. 2019 05 15; 28(10):1753-1754.

3. Ditzel HM, Strickland KC, Meserve EE, Stover E, Konstantinopoulos PA, Matulonis UA, Muto MG, Liu JF, Feltmate C, Horowitz N, Berkowitz RS, Gupta M, Hecht JL, Lin DI, Jochumsen KM, Welch WR, Hirsch MS, Quade BJ, Lee KR, Crum CP, Mutter GL, Nucci MR, Howitt BE. Assessment of a Chemotherapy Response Score (CRS) System for Tubo-Ovarian High-Grade Serous Carcinoma (HGSC). Int J Gynecol Pathol. 2019 May; 38(3):230-240.

4. Cho KR, Cooper K, Croce S, Djordevic B, Herrington S, Howitt B, Hui P, Ip P, Koebel M, Lax S, Quade BJ, Shaw P, Vidal A, Yemelyanova A, Clarke B, Hedrick Ellenson L, Longacre TA, Shih IM, McCluggage WG, Malpica A, Oliva E, Parkash V, Matias-Guiu X. International Society of Gynecological Pathologists (ISGyP) Endometrial Cancer Project: Guidelines From the Special Techniques and Ancillary Studies Group. Int J Gynecol Pathol. 2019 Jan; 38 Suppl 1:S114-S122.

5. Currall BB, Chen M, Sallari RC, Cotter M, Wong KE, Robertson NG, Penney KL, Lunardi A, Reschke M, Hickox AE, Yin Y, Wong GT, Fung J, Brown KK, Williamson RE, Sinnott-Armstrong NA, Kammin T, Ivanov A, Zepeda-Mendoza CJ, Shen J, Quade BJ, Signoretti S, Arnos KS, Banks AS, Patsopoulos N, Liberman MC, Kellis M, Pandolfi PP, Morton CC. Loss of LDAH associated with prostate cancer and hearing loss. Hum Mol Genet. 2018 12 15; 27(24):4194-4203.

6. Dong F, Quade BJ, Dal Cin P, Jo VY. Expanding the spectrum of translocations in sclerosing epitheloid fibrosarcoma: A new case with EWSR1-CREB3L3 fusion. Genes Chromosomes Cancer. 2018 12; 57(12):675-677.

7. Strickland KC, Yuan L, Quade BJ, Nucci MR, Howitt BE. Clinicopathological and immunohistochemical features of uterine adenomyomatous polyps. Hum Pathol. 2019 Feb; 84:239-245.

8. Craig JW, Quade BJ, Muto MG, MacConaill LE. Endometrial cancer with an EML4-ALK rearrangement. Cold Spring Harb Mol Case Stud. 2018 08; 4(4).

9. Gupta M, Laury AL, Nucci MR, Quade BJ. Predictors of adverse outcome in uterine smooth muscle tumours of uncertain malignant potential (STUMP): a clinicopathological analysis of 22 cases with a proposal for the inclusion of additional histological parameters. Histopathology. 2018 Aug; 73(2):284-298.

10. Hayden MA, Ordulu Z, Gallagher CS, Quade BJ, Anchan RM, Middleton NR, Srouji SS, Stewart EA, Morton CC. Clinical, pathologic, cytogenetic, and molecular profiling in self-identified black women with uterine leiomyomata. Cancer Genet. 2018 04; 222-223:1-8.