45 results on '"McAlpine, Jessica N."'
Search Results
2. Variability in endometrial carcinoma pathology practice: opportunities for improvement with molecular classification
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Thompson, Emily F., Huvila, Jutta, Jamieson, Amy, Leung, Samuel, Lum, Amy, Offman, Saul, Lytwyn, Alice, Sur, Mona Lisa, Hoang, Lynn, Irving, Julie, van der Westhuizen, Nicholas, Morin, Chantale, Bicamumpaka, Cyrille, Azordegan, Nazilla, Gougeon, François, Ennour-Idrissi, Kaoutar, Senz, Janine, McConechy, Melissa K., Aguirre-Hernandez, Rosalia, Lui, Victoria, Kuo, Carolyn, Bell, Cassidy, Salisbury, Taylor, Lawson, James, He, Ellen, Wang, Shanzhao, Chiu, Derek, Kean, Sarah, Samouëlian, Vanessa, Salvador, Shannon, Gotlieb, Walter, Helpman, Limor, Scott, Stephanie, Wohlmuth, Christoph, Vicus, Danielle, Plante, Marie, Talhouk, Aline, Huntsman, David, Parra-Herran, Carlos, Kinloch, Mary, Grondin, Katherine, Gilks, C. Blake, McAlpine, Jessica N., McAlpine, Jessica, Agrawal, Anita, Al-Nourhji, Omar, Altman, Alon, Bernardini, Marcus, Bicamumpaka, C., Carey, Mark, Clarke, Blaise, Azordegan, Nazila, Djordjevic, Bojana, Elit, Laurie, Ferenczy, Alex, Finlayson, Sarah, Fyles, Anthony, Garneau, Hugo, Gauthier, France, Ghatage, Prafull, Gilks, Blake, Gotlieb, Walter, Grondin, Katherine, Han, Kathy, Helpman, Limor, Hirte, Hal, Huang, Fleur, Irving, Julie, Kean, Sarah, Kieser, Katharina, Kinlloch, Mary, Kong, Iwa, Kumar, Aalok, Kwon, Janice, Lee, Sandra, Leung, Eric, Mackay, Helen, Marchand, Eve-Lyne, Mcginnis, Justin, Miller, Dianne, Morin, Chantale, Nelson, Gregg, Offman, Saul, Pelmus, Manuela, Pina, Annick, Plante, Marie, Plotkin, Anna, Provencher, Diane, Salvador, Shannon, Scott, Stephanie, Tinker, Anna, Tone, Alicia, Vicus, Danielle, Welch, Stephen, Westhuizen, Nicholas, Jerzak, Katarzyna, and Jamieson, Amy
- Abstract
We assessed the landscape of diagnostic pathology practice and how molecular classification could potentially impact management of patients with endometrial cancer by collecting patient samples, clinicopathologic data, and patient outcomes from EC patients diagnosed in 2016 at 10 Canadian tertiary cancer centers and 19 community hospitals. ProMisE molecular subtype (POLEmut, MMRd, p53abn, No Specific Molecular Profile (NSMP)) was assigned retrospectively. 1357 patients were fully evaluable including 85 POLEmut (6.3%), 380 MMRd (28.0%), 643 NSMP (47.4%), and 249 p53abn ECs (18.3%). Immunohistochemistry (IHC) for MMR proteins was undertaken at the time of primary diagnosis in 2016 in only 42% of the cohort (570/1357; range 3.5–95.4%/center). p53 IHC had only been performed in 21.1% of the cohort (286/1357; range 10.1–41.9%/center). Thus, based on the retrospective molecular subtype assignment, 54.7% (208/380) of MMRd EC had not been tested with MMR IHC (or MSI) and 48.2% (120/249) of p53abn ECs were not tested with p53 IHC in 2016. Molecular subtype diversity within histotypes was profound; most serous carcinomas were p53abn (91.4%), but only 129/249 (51.8%) p53abn EC were serous. Low-grade (Gr1-2) endometrioid carcinomas were mostly NSMP (589/954, 61.7%) but included all molecular subtypes, including p53abn (19/954, 2.0%). Molecular subtype was significantly associated with clinical outcomes (p< 0.001) even in patients with stage I disease (OS p= 0.006, DSS p< 0.001, PFS p< 0.001). Assessment of national pathologic practice in 2016 shows highly variable use of MMR and p53 IHC and demonstrates significant opportunities to improve and standardize biomarker reporting. Inconsistent, non-reflexive IHC resulted in missed opportunities for Hereditary Cancer Program referral and Lynch Syndrome diagnosis, and missed potential therapeutic implications (e.g., chemotherapy in p53abn EC, immune blockade for MMRd EC). Routine integration of molecular subtyping into practice can improve the consistency of EC pathology assessment and classification.
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- 2022
- Full Text
- View/download PDF
3. Single-cell genomic variation induced by mutational processes in cancer
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Funnell, Tyler, O’Flanagan, Ciara H., Williams, Marc J., McPherson, Andrew, McKinney, Steven, Kabeer, Farhia, Lee, Hakwoo, Salehi, Sohrab, Vázquez-García, Ignacio, Shi, Hongyu, Leventhal, Emily, Masud, Tehmina, Eirew, Peter, Yap, Damian, Zhang, Allen W., Lim, Jamie L. P., Wang, Beixi, Brimhall, Jazmine, Biele, Justina, Ting, Jerome, Au, Vinci, Van Vliet, Michael, Liu, Yi Fei, Beatty, Sean, Lai, Daniel, Pham, Jenifer, Grewal, Diljot, Abrams, Douglas, Havasov, Eliyahu, Leung, Samantha, Bojilova, Viktoria, Moore, Richard A., Rusk, Nicole, Uhlitz, Florian, Ceglia, Nicholas, Weiner, Adam C., Zaikova, Elena, Douglas, J. Maxwell, Zamarin, Dmitriy, Weigelt, Britta, Kim, Sarah H., Da Cruz Paula, Arnaud, Reis-Filho, Jorge S., Martin, Spencer D., Li, Yangguang, Xu, Hong, de Algara, Teresa Ruiz, Lee, So Ra, Llanos, Viviana Cerda, Huntsman, David G., McAlpine, Jessica N., Shah, Sohrab P., and Aparicio, Samuel
- Abstract
How cell-to-cell copy number alterations that underpin genomic instability1in human cancers drive genomic and phenotypic variation, and consequently the evolution of cancer2, remains understudied. Here, by applying scaled single-cell whole-genome sequencing3to wild-type, TP53-deficient and TP53-deficient;BRCA1-deficient or TP53-deficient;BRCA2-deficient mammary epithelial cells (13,818 genomes), and to primary triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSC) cells (22,057 genomes), we identify three distinct ‘foreground’ mutational patterns that are defined by cell-to-cell structural variation. Cell- and clone-specific high-level amplifications, parallel haplotype-specific copy number alterations and copy number segment length variation (serrate structural variations) had measurable phenotypic and evolutionary consequences. In TNBC and HGSC, clone-specific high-level amplifications in known oncogenes were highly prevalent in tumours bearing fold-back inversions, relative to tumours with homologous recombination deficiency, and were associated with increased clone-to-clone phenotypic variation. Parallel haplotype-specific alterations were also commonly observed, leading to phylogenetic evolutionary diversity and clone-specific mono-allelic expression. Serrate variants were increased in tumours with fold-back inversions and were highly correlated with increased genomic diversity of cellular populations. Together, our findings show that cell-to-cell structural variation contributes to the origins of phenotypic and evolutionary diversity in TNBC and HGSC, and provide insight into the genomic and mutational states of individual cancer cells.
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- 2022
- Full Text
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4. Data Set for the Reporting of Carcinomas of the Vulva: Recommendations From the International Collaboration on Cancer Reporting (ICCR)
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Hoang, Lynn, Webster, Fleur, Bosse, Tjalling, Focchi, Gustavo, Gilks, C. Blake, Howitt, Brooke E., McAlpine, Jessica N., Ordi, Jaume, Singh, Naveena, Wong, Richard Wing-Cheuk, Lax, Sigurd F., and McCluggage, W. Glenn
- Abstract
A cogent and comprehensive pathologic report is essential for optimal patient management, cancer staging, and prognostication. This article details the International Collaboration on Cancer Reporting (ICCR) process and the development of the vulval carcinoma reporting data set. It describes the “core” and “noncore” elements to be included in pathology reports for vulval carcinoma, inclusive of clinical, macroscopic, microscopic, and ancillary testing considerations. It provides definitions and commentary for the evidence and/or consensus-based deliberations for each element included in the data set. The commentary also discusses controversial issues, such as p16/human papillomavirus testing, tumor grading and measurements, as well as elements that show promise and warrant further evidence-based study. A summary and discussion of the updated vulval cancer staging system by the International Federation of Obstetricians and Gynaecologists (FIGO) in 2021 is also provided. We hope the widespread implementation of this data set will facilitate consistent and accurate reporting, data collection, comparison of epidemiological and pathologic parameters between different populations, facilitate research, and serve as a platform to improve patient outcomes.
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- 2022
- Full Text
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5. Differentiated Exophytic Vulvar Intraepithelial Lesions: Case Reports and Review of Literature
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Mendlowitz, Ariel R., Hoang, Lien N., McAlpine, Jessica N., and Sadownik, Leslie Ann
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- 2022
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6. Endometrial cancer
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Crosbie, Emma J, Kitson, Sarah J, McAlpine, Jessica N, Mukhopadhyay, Asima, Powell, Melanie E, and Singh, Naveena
- Abstract
Endometrial cancer is the most common gynaecological cancer in high income countries and its incidence is rising globally. Although an ageing population and fewer benign hysterectomies have contributed to this trend, the growing prevalence of obesity is the major underlying cause. Obesity poses challenges for diagnosis and treatment and more research is needed to offer primary prevention to high-risk women and to optimise endometrial cancer survivorship. Early presentation with postmenopausal bleeding ensures most endometrial cancers are cured by hysterectomy but those with advanced disease have a poor prognosis. Minimally invasive surgical staging and sentinel-lymph-node biopsy provides a low morbidity alternative to historical surgical management without compromising oncological outcomes. Adjuvant radiotherapy reduces loco-regional recurrence in intermediate-risk and high-risk cases. Advances in our understanding of the molecular biology of endometrial cancer have paved the way for targeted chemotherapeutic strategies, and clinical trials will establish their benefit in adjuvant, advanced, and recurrent disease settings in the coming years.
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- 2022
- Full Text
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7. Opportunistic Salpingectomy Between 2017 and 2020: A Descriptive Analysis
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Kaur, Paramdeep, Rufin, Khaye, Finlayson, Sarah J., Huntsman, David G., Kwon, Janice S., McAlpine, Jessica N., Miller, Dianne M., and Hanley, Gillian E.
- Abstract
Opportunistic salpingectomy (OS) is the removal of fallopian tubes during another pelvic surgery for the purpose of ovarian cancer prevention. Herein, we describe the rates of OS at the time of hysterectomy and tubal sterilization between 2017 and 2020.
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- 2024
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8. Variability in endometrial carcinoma pathology practice: opportunities for improvement with molecular classification
- Author
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Thompson, Emily F., Huvila, Jutta, Jamieson, Amy, Leung, Samuel, Lum, Amy, Offman, Saul, Lytwyn, Alice, Sur, Mona Lisa, Hoang, Lynn, Irving, Julie, van der Westhuizen, Nicholas, Morin, Chantale, Bicamumpaka, Cyrille, Azordegan, Nazilla, Gougeon, François, Ennour-Idrissi, Kaoutar, Senz, Janine, McConechy, Melissa K., Aguirre-Hernandez, Rosalia, Lui, Victoria, Kuo, Carolyn, Bell, Cassidy, Salisbury, Taylor, Lawson, James, He, Ellen, Wang, Shanzhao, Chiu, Derek, Kean, Sarah, Samouëlian, Vanessa, Salvador, Shannon, Gotlieb, Walter, Helpman, Limor, Scott, Stephanie, Wohlmuth, Christoph, Vicus, Danielle, Plante, Marie, Talhouk, Aline, Huntsman, David, Parra-Herran, Carlos, Kinloch, Mary, Grondin, Katherine, Gilks, C. Blake, and McAlpine, Jessica N.
- Abstract
We assessed the landscape of diagnostic pathology practice and how molecular classification could potentially impact management of patients with endometrial cancer by collecting patient samples, clinicopathologic data, and patient outcomes from EC patients diagnosed in 2016 at 10 Canadian tertiary cancer centers and 19 community hospitals. ProMisE molecular subtype (POLEmut, MMRd, p53abn, No Specific Molecular Profile (NSMP)) was assigned retrospectively. 1357 patients were fully evaluable including 85 POLEmut (6.3%), 380 MMRd (28.0%), 643 NSMP (47.4%), and 249 p53abn ECs (18.3%). Immunohistochemistry (IHC) for MMR proteins was undertaken at the time of primary diagnosis in 2016 in only 42% of the cohort (570/1357; range 3.5–95.4%/center). p53 IHC had only been performed in 21.1% of the cohort (286/1357; range 10.1–41.9%/center). Thus, based on the retrospective molecular subtype assignment, 54.7% (208/380) of MMRd EC had not been tested with MMR IHC (or MSI) and 48.2% (120/249) of p53abn ECs were not tested with p53 IHC in 2016. Molecular subtype diversity within histotypes was profound; most serous carcinomas were p53abn (91.4%), but only 129/249 (51.8%) p53abn EC were serous. Low-grade (Gr1-2) endometrioid carcinomas were mostly NSMP (589/954, 61.7%) but included all molecular subtypes, including p53abn (19/954, 2.0%). Molecular subtype was significantly associated with clinical outcomes (p< 0.001) even in patients with stage I disease (OS p= 0.006, DSS p< 0.001, PFS p< 0.001). Assessment of national pathologic practice in 2016 shows highly variable use of MMR and p53 IHC and demonstrates significant opportunities to improve and standardize biomarker reporting. Inconsistent, non-reflexive IHC resulted in missed opportunities for Hereditary Cancer Program referral and Lynch Syndrome diagnosis, and missed potential therapeutic implications (e.g., chemotherapy in p53abn EC, immune blockade for MMRd EC). Routine integration of molecular subtyping into practice can improve the consistency of EC pathology assessment and classification.
- Published
- 2022
- Full Text
- View/download PDF
9. p53 Immunohistochemical Staining and TP53 Gene Mutations in Endometrial Cancer: Does Null Pattern Correlate With Prognosis?
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Kommoss, Felix K.F., Jamieson, Amy, McAlpine, Jessica N., and Gilks, C. Blake
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- 2024
- Full Text
- View/download PDF
10. Molecular characterization of invasive and in situ squamous neoplasia of the vulva and implications for morphologic diagnosis and outcome
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Tessier-Cloutier, Basile, Pors, Jennifer, Thompson, Emily, Ho, Julie, Prentice, Leah, McConechy, Melissa, Aguirre-Hernandez, Rosalia, Miller, Ruth, Leung, Samuel, Proctor, Lily, McAlpine, Jessica N., Huntsman, David G., Gilks, C. Blake, and Hoang, Lynn N.
- Abstract
Human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (VSCC) is an aggressive clinical entity. Current diagnostic guidelines for premalignant lesions are ambiguous, and their molecular profile and progression events are still unclear. We selected 75 samples, from 40 patients, including 33 VSCC, 8 verrucous carcinomas (VC), 13 differentiated-type vulvar intraepithelial neoplasia (dVIN), 11 suspicious for dVIN (?dVIN), 6 differentiated exophytic vulvar intraepithelial lesions (DE-VIL), 2 vulvar acanthosis with altered differentiation (VAAD), and 2 usual-type vulvar intraepithelial neoplasia (uVIN/HSIL). Invasive and precursor lesions were matched in 29 cases. Clinical information, p16 immunohistochemistry, and mutation analysis were performed on all lesions. All dVIN, ?dVIN, DE-VIL, and VAAD were p16 negative, all uVIN/HSIL were p16 positive. In the HPV-independent group, mutations were identified in 6 genes: TP53(n?=?40), PIK3CA(n?=?20), HRAS(n?=?12), MET(n?=?5), PTEN(n?=?4), and BRAF(n?=?1). TP53mutations occurred in 73% (22/30) VSCC, 85% (11/13) dVIN, 70% (7/10) ?dVIN and no VC (0/8), DE-VIL (0/6) nor VAAD (0/2). Basal atypia was the only reliable feature of TP53mutations. ?dVIN lesions that were non-acanthotic and atypical but obscured by inflammation, all harbored TP53mutations. In lesions without TP53mutations, PIK3CA(50% VC, 33% DE-VIL, 100% VAAD, 40% VSCC) and HRAS(63% VC, 33% DE-VIL, 0% VAAD, 20% VSCC) mutations were found. Mutational progression from in situ to invasive was seen (7/26, 27%) and usually involved TP53(4/26, 15%). Cases with TP53and PIK3CAco-mutations had the worse clinical outcomes (p?0.001). We recommend testing for p53 in all HPV-independent lesions suspicious for dVIN, even in the presence of marked inflammation or non-acanthotic skin, particularly when close to a margin. VC, VAAD, and DE-VIL, were almost never mutated for TP53, but instead often harbored PIK3CAand HRASmutations. In VSCC, combined TP53and PIK3CAmutations may inform prognosis.
- Published
- 2021
- Full Text
- View/download PDF
11. Molecular characterization of invasive and in situ squamous neoplasia of the vulva and implications for morphologic diagnosis and outcome
- Author
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Tessier-Cloutier, Basile, Pors, Jennifer, Thompson, Emily, Ho, Julie, Prentice, Leah, McConechy, Melissa, Aguirre-Hernandez, Rosalia, Miller, Ruth, Leung, Samuel, Proctor, Lily, McAlpine, Jessica N., Huntsman, David G., Gilks, C. Blake, and Hoang, Lynn N.
- Abstract
Human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (VSCC) is an aggressive clinical entity. Current diagnostic guidelines for premalignant lesions are ambiguous, and their molecular profile and progression events are still unclear. We selected 75 samples, from 40 patients, including 33 VSCC, 8 verrucous carcinomas (VC), 13 differentiated-type vulvar intraepithelial neoplasia (dVIN), 11 suspicious for dVIN (?dVIN), 6 differentiated exophytic vulvar intraepithelial lesions (DE-VIL), 2 vulvar acanthosis with altered differentiation (VAAD), and 2 usual-type vulvar intraepithelial neoplasia (uVIN/HSIL). Invasive and precursor lesions were matched in 29 cases. Clinical information, p16 immunohistochemistry, and mutation analysis were performed on all lesions. All dVIN, ?dVIN, DE-VIL, and VAAD were p16 negative, all uVIN/HSIL were p16 positive. In the HPV-independent group, mutations were identified in 6 genes: TP53(n= 40), PIK3CA(n= 20), HRAS(n= 12), MET(n= 5), PTEN(n= 4), and BRAF(n= 1). TP53mutations occurred in 73% (22/30) VSCC, 85% (11/13) dVIN, 70% (7/10) ?dVIN and no VC (0/8), DE-VIL (0/6) nor VAAD (0/2). Basal atypia was the only reliable feature of TP53mutations. ?dVIN lesions that were non-acanthotic and atypical but obscured by inflammation, all harbored TP53mutations. In lesions without TP53mutations, PIK3CA(50% VC, 33% DE-VIL, 100% VAAD, 40% VSCC) and HRAS(63% VC, 33% DE-VIL, 0% VAAD, 20% VSCC) mutations were found. Mutational progression from in situ to invasive was seen (7/26, 27%) and usually involved TP53(4/26, 15%). Cases with TP53and PIK3CAco-mutations had the worse clinical outcomes (p< 0.001). We recommend testing for p53 in all HPV-independent lesions suspicious for dVIN, even in the presence of marked inflammation or non-acanthotic skin, particularly when close to a margin. VC, VAAD, and DE-VIL, were almost never mutated for TP53, but instead often harbored PIK3CAand HRASmutations. In VSCC, combined TP53and PIK3CAmutations may inform prognosis.
- Published
- 2021
- Full Text
- View/download PDF
12. Refined cut-off for TP53 immunohistochemistry improves prediction of TP53mutation status in ovarian mucinous tumors: implications for outcome analyses
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Kang, Eun Young, Cheasley, Dane, LePage, Cecile, Wakefield, Matthew J., da Cunha Torres, Michelle, Rowley, Simone, Salazar, Carolina, Xing, Zhongyue, Allan, Prue, Bowtell, David D.L., Mes-Masson, Anne-Marie, Provencher, Diane M., Rahimi, Kurosh, Kelemen, Linda E., Fasching, Peter A., Doherty, Jennifer A., Goodman, Marc T., Goode, Ellen L., Deen, Suha, Pharoah, Paul D.P., Brenton, James D., Sieh, Weiva, Mateoiu, Constantina, Sundfeldt, Karin, Cook, Linda S., Le, Nhu D., Anglesio, Michael S., Gilks, C. Blake, Huntsman, David G., Kennedy, Catherine J., Traficante, Nadia, Bowtell, D., Chenevix-Trench, G., Green, A., Webb, P., DeFazio, A., Gertig, D., Traficante, N., Fereday, S., Moore, S., Hung, J., Harrap, K., Sadkowsky, T., Pandeya, N., Malt, M., Mellon, A., Robertson, R., Bergh, T. Vanden, Jones, M., Mackenzie, P., Maidens, J., Nattress, K., Chiew, Y.E., Stenlake, A., Sullivan, H., Alexander, B., Ashover, P., Brown, S., Corrish, T., Green, L., Jackman, L., Ferguson, K., Martin, K., Martyn, A., Ranieri, B., White, J., Jayde, V., Mamers, P., Bowes, L., Galletta, L., Giles, D., Hendley, J., Alsop, K., Schmidt, T., Shirley, H., Ball, C., Young, C., Viduka, S., Tran, Hoa, Bilic, Sanela, Glavinas, Lydia, Brooks, Julia, Stuart-Harris, R., Kirsten, F., Rutovitz, J., Clingan, P., Glasgow, A., Proietto, A., Braye, S., Otton, G., Shannon, J., Bonaventura, T., Stewart, J., Begbie, S., Friedlander, M., Bell, D., Baron-Hay, S., Ferrier, A., Gard, G., Nevell, D., Pavlakis, N., Valmadre, S., Young, B., Camaris, C., Crouch, R., Edwards, L., Hacker, N., Marsden, D., Robertson, G., Beale, P., Beith, J., Carter, J., Dalrymple, C., Houghton, R., Russell, P., Links, M., Grygiel, J., Hill, J., Brand, A., Byth, K., Jaworski, R., Harnett, P., Sharma, R., Wain, G., Ward, B., Papadimos, D., Crandon, A., Cummings, M., Horwood, K., Obermair, A., Perrin, L., Wyld, D., Nicklin, J., Davy, M., Oehler, M.K., Hall, C., Dodd, T., Healy, T., Pittman, K., Henderson, D., Miller, J., Pierdes, J., Blomfield, P., Challis, D., McIntosh, R., Parker, A., Brown, B., Rome, R., Allen, D., Grant, P., Hyde, S., Laurie, R., Robbie, M., Healy, D., Jobling, T., Manolitsas, T., McNealage, J., Rogers, P., Susil, B., Sumithran, E., Simpson, I., Phillips, K., Rischin, D., Fox, S., Johnson, D., Lade, S., Loughrey, M., O'Callaghan, N., Murray, W., Waring, P., Billson, V., Pyman, J., Neesham, D., Quinn, M., Underhill, C., Bell, R., Ng, L.F., Blum, R., Ganju, V., Hammond, I., Leung, Y., McCartney, A., Buck, M., Haviv, I., Purdie, D., Whiteman, D., Zeps, N., DeFazio, Anna, Kaufmann, Scott, Churchman, Michael, Gourley, Charlie, Stephens, Andrew N., Meagher, Nicola S., Ramus, Susan J., Antill, Yoland C., Campbell, Ian, Scott, Clare L., Köbel, Martin, Gorringe, Kylie L., Cheasley, Dane, Wakefield, Matthew J., Ryland, Georgina L., Allan, Prue E., Alsop, Kathryn, Ananda, Sumitra, Anglesio, Michael S., Au-Yeung, George, Böhm, Maret, Bowtell, David D.L., Brand, Alison, Chenevix-Trench, Georgia, Christie, Michael, Chiew, Yoke-Eng, Churchman, Michael, DeFazio, Anna, Dudley, Rhiannon, Fairweather, Nicole, Fereday, Sian, Fox, Stephen B., Gilks, C. Blake, Gourley, Charlie, Hacker, Neville F., Hadley, Alison M., Hendley, Joy, Ho, Gwo-Yaw, Huntsman, David G., Hunter, Sally M., Jobling, Tom W., Kalli, Kimberly R., Kaufmann, Scott H., Kennedy, Catherine J., Köbel, Martin, Le Page, Cecile, McNally, Orla M., McAlpine, Jessica N., Mes-Masson, Anne-Marie, Mileshkin, Linda, Provencher, Diane M., Pyman, Jan, Rahimi, Kurosh, Samimi, Goli, Sharma, Ragwha, Stephens, Andrew N., Traficante, Nadia, Antill, Yoland C., Scott, Clare L., Campbell, Ian G., and Gorringe, Kylie L.
- Abstract
TP53mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53mutation status in ovarian mucinous tumors and to evaluate the association of TP53mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5–14.3, p= 0.0087). Within MOC, 61.1% (259/424) harbored a TP53mutation, but this was not associated with survival (overall survival, p= 0.77). TP53 IHC is an accurate proxy for TP53mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53mutation status is an important biomarker to identify MBOT with a higher risk of mortality.
- Published
- 2021
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13. Interlaboratory Concordance of ProMisE Molecular Classification of Endometrial Carcinoma Based on Endometrial Biopsy Specimens
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Plotkin, Anna, Kuzeljevic, Boris, De Villa, Vanessa, Thompson, Emily F., Gilks, C. Blake, Clarke, Blaise A., Köbel, Martin, and McAlpine, Jessica N.
- Abstract
Supplemental Digital Content is available in the text.Molecular classifiers improve the consistency of categorization of endometrial carcinoma and provide valuable prognostic information. We aimed to evaluate the interlaboratory agreement in ProMisE assignment across 3 dedicated Canadian gynecologic oncology centers. Fifty cases of endometrial carcinoma diagnosed on biopsy were collected from 3 centers and 3 unstained sections were provided to each participating site so that immunohistochemistry for MSH6, PMS2, and p53 could be performed and interpreted at each center, blinded to the original diagnoses and the results from other centers. A core was taken for DNA extraction and POLEmutation testing. Overall accuracy and κ statistic were assessed. MSH6, PMS2, and p53 could be assessed for all 50 cases, with agreement for 140/150 results. There was a high level of agreement in molecular classification (κ=0.82), overall. Cases with a discordant result for one of the features used in classification (n=10) were reviewed independently and the most common reason for disagreement was attributable to the weak p53 staining in 1 laboratory (n=4). Interpretive error in PMS2 (n=1) and MSH6 (n=2) assessment accounted for 3 of the remaining disagreements. Interpretive error in the assessment of p53 was identified in 2 cases, with very faint p53 nuclear reactivity being misinterpreted as wild-type staining. These results show strong interlaboratory agreement and the potential for greater agreement if technical and interpretive factors are addressed. Several solutions could improve concordance: central quality control to ensure technical consistency in immunohistochemical staining, education to decrease interpretation errors, and the use of secondary molecular testing.
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- 2020
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14. p53 Immunohistochemical patterns in HPV-related neoplasms of the female lower genital tract can be mistaken for TP53null or missense mutational patterns
- Author
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Thompson, Emily F., Chen, Julia, Huvila, Jutta, Pors, Jennifer, Ren, Hezhen, Ho, Julie, Chow, Christine, Ta, Monica, Proctor, Lily, McAlpine, Jessica N., Huntsman, David, Gilks, C. Blake, and Hoang, Lynn
- Abstract
We have recently encountered p53 immunohistochemical (IHC) patterns in human papillomavirus (HPV)-associated carcinomas of the gynecologic tract, which were confused with absent (null) or overexpression TP53mutational staining. We therefore evaluated p53 and p16 IHC in 25 squamous cell carcinomas (SCC) (16 vulva, 4 Bartholin’s gland, and 5 cervix), 20 endocervical adenocarcinomas (EDAC), 14 high-grade squamous intraepithelial lesions (HSIL), 2 adenocarcinoma in situ (AIS), all of which exhibited morphologic features of HPV. Only cases showing diffuse/strong block-like p16 staining were included for further study. All EDACs underwent TP53sequencing and HPV in situ hybridization (ISH) was performed in selected cases. p53 IHC staining fell into two main patterns. The most common was designated as “markedly reduced (null-like)” (absence or significantly attenuated staining in >70% of cells), which could be confused with true null mutational pattern. This was present in 14/25 (56%) SCCs, 7/14 (50%) HSILs, and 18/20 (90%) EDACs. The second notable pattern was “mid-epithelial (basal sparing)” (distinct absence of staining in basal cells juxtaposed with strong staining in parabasal cells), seen in 10/25 (40%) SCC, 7/14 (50%) HSIL, and none of the EDACs. There was scattered weak to moderate p53 staining (conventional wild type) in 1/25 (4%) SCC and 2/20 (10%) EDAC. No cases showed strong/diffuse overexpression. One EDAC had a TP53missense mutation and exhibited “markedly reduced (null-like)” staining. HPV ISH revealed an inverse relationship with p53, cells positive for HPV mRNA were negative for p53. Knowledge of these patterns can help pathologists avoid misinterpreting p53 status in the setting of HPVA cancers.
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- 2020
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15. p53 Immunohistochemical patterns in HPV-related neoplasms of the female lower genital tract can be mistaken for TP53null or missense mutational patterns
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Thompson, Emily F., Chen, Julia, Huvila, Jutta, Pors, Jennifer, Ren, Hezhen, Ho, Julie, Chow, Christine, Ta, Monica, Proctor, Lily, McAlpine, Jessica N., Huntsman, David, Gilks, C. Blake, and Hoang, Lynn
- Abstract
We have recently encountered p53 immunohistochemical (IHC) patterns in human papillomavirus (HPV)-associated carcinomas of the gynecologic tract, which were confused with absent (null) or overexpression TP53mutational staining. We therefore evaluated p53 and p16 IHC in 25 squamous cell carcinomas (SCC) (16 vulva, 4 Bartholin's gland, and 5 cervix), 20 endocervical adenocarcinomas (EDAC), 14 high-grade squamous intraepithelial lesions (HSIL), 2 adenocarcinoma in situ (AIS), all of which exhibited morphologic features of HPV. Only cases showing diffuse/strong block-like p16 staining were included for further study. All EDACs underwent TP53sequencing and HPV in situ hybridization (ISH) was performed in selected cases. p53 IHC staining fell into two main patterns. The most common was designated as “markedly reduced (null-like)” (absence or significantly attenuated staining in >70% of cells), which could be confused with true null mutational pattern. This was present in 14/25 (56%) SCCs, 7/14 (50%) HSILs, and 18/20 (90%) EDACs. The second notable pattern was “mid-epithelial (basal sparing)” (distinct absence of staining in basal cells juxtaposed with strong staining in parabasal cells), seen in 10/25 (40%) SCC, 7/14 (50%) HSIL, and none of the EDACs. There was scattered weak to moderate p53 staining (conventional wild type) in 1/25 (4%) SCC and 2/20 (10%) EDAC. No cases showed strong/diffuse overexpression. One EDAC had a TP53missense mutation and exhibited “markedly reduced (null-like)” staining. HPV ISH revealed an inverse relationship with p53, cells positive for HPV mRNA were negative for p53. Knowledge of these patterns can help pathologists avoid misinterpreting p53 status in the setting of HPVA cancers.
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- 2020
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16. Major p53 immunohistochemical patterns in in situ and invasive squamous cell carcinomas of the vulva and correlation with TP53mutation status
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Tessier-Cloutier, Basile, Kortekaas, Kim E., Thompson, Emily, Pors, Jennifer, Chen, Julia, Ho, Julie, Prentice, Leah M., McConechy, Melissa K., Chow, Christine, Proctor, Lily, McAlpine, Jessica N., Huntsman, David G., Gilks, C. Blake, Bosse, Tjalling, and Hoang, Lynn N.
- Abstract
The recent literature has shown that vulvar squamous cell carcinoma (VSCC) can be stratified into two prognostically relevant groups based on human papillomavirus (HPV) status. The prognostic value of p53 for further sub-stratification, particularly in the HPV-independent group, has not been agreed upon. This disagreement is likely due to tremendous variations in p53 immunohistochemical (IHC) interpretation. To address this problem, we sought to compare p53 IHC patterns with TP53mutation status. We studied 61 VSCC (48 conventional VSCC, 2 VSCC with sarcomatoid features, and 11 verrucous carcinomas) and 42 in situ lesions (30 differentiated vulvar intraepithelial neoplasia [dVIN], 9 differentiated exophytic vulvar intraepithelial lesions [deVIL], and 3 high-grade squamous intraepithelial lesions or usual vulvar intraepithelial neoplasia [HSIL/uVIN]). IHC for p16 and p53, and sequencing of TP53exons 4–9 were performed. HPV in situ hybridization (ISH) was performed in selected cases. We identified six major p53 IHC patterns, two wild-type patterns: (1) scattered, (2) mid-epithelial expression (with basal sparing), and four mutant patterns: (3) basal overexpression, (4) parabasal/diffuse overexpression, (5) absent, and (6) cytoplasmic expression. These IHC patterns were consistent with TP53mutation status in 58/61 (95%) VSCC and 39/42 (93%) in situ lesions. Cases that exhibited strong scattered staining and those with a weak basal overexpression pattern could be easily confused. The mid-epithelial pattern was exclusively observed in p16-positive lesions; the basal and parabasal layers that had absent p53 staining, appeared to correlate with the cells that were positive for HPV-ISH. This study describes a pattern-based p53 IHC interpretation framework, which can be utilized as a surrogate marker for TP53mutational status in both VSCC and vulvar in situ lesions.
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- 2020
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17. Major p53 immunohistochemical patterns in in situ and invasive squamous cell carcinomas of the vulva and correlation with TP53mutation status
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Tessier-Cloutier, Basile, Kortekaas, Kim E., Thompson, Emily, Pors, Jennifer, Chen, Julia, Ho, Julie, Prentice, Leah M., McConechy, Melissa K., Chow, Christine, Proctor, Lily, McAlpine, Jessica N., Huntsman, David G., Gilks, C.Blake, Bosse, Tjalling, and Hoang, Lynn N.
- Abstract
The recent literature has shown that vulvar squamous cell carcinoma (VSCC) can be stratified into two prognostically relevant groups based on human papillomavirus (HPV) status. The prognostic value of p53 for further sub-stratification, particularly in the HPV-independent group, has not been agreed upon. This disagreement is likely due to tremendous variations in p53 immunohistochemical (IHC) interpretation. To address this problem, we sought to compare p53 IHC patterns with TP53mutation status. We studied 61 VSCC (48 conventional VSCC, 2 VSCC with sarcomatoid features, and 11 verrucous carcinomas) and 42 in situ lesions (30 differentiated vulvar intraepithelial neoplasia [dVIN], 9 differentiated exophytic vulvar intraepithelial lesions [deVIL], and 3 high-grade squamous intraepithelial lesions or usual vulvar intraepithelial neoplasia [HSIL/uVIN]). IHC for p16 and p53, and sequencing of TP53exons 4–9 were performed. HPV in situ hybridization (ISH) was performed in selected cases. We identified six major p53 IHC patterns, two wild-type patterns: (1) scattered, (2) mid-epithelial expression (with basal sparing), and four mutant patterns: (3) basal overexpression, (4) parabasal/diffuse overexpression, (5) absent, and (6) cytoplasmic expression. These IHC patterns were consistent with TP53mutation status in 58/61 (95%) VSCC and 39/42 (93%) in situ lesions. Cases that exhibited strong scattered staining and those with a weak basal overexpression pattern could be easily confused. The mid-epithelial pattern was exclusively observed in p16-positive lesions; the basal and parabasal layers that had absent p53 staining, appeared to correlate with the cells that were positive for HPV-ISH. This study describes a pattern-based p53 IHC interpretation framework, which can be utilized as a surrogate marker for TP53mutational status in both VSCC and vulvar in situ lesions.
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- 2020
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18. Probabilistic cell-type assignment of single-cell RNA-seq for tumor microenvironment profiling
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Zhang, Allen W., O’Flanagan, Ciara, Chavez, Elizabeth A., Lim, Jamie L. P., Ceglia, Nicholas, McPherson, Andrew, Wiens, Matt, Walters, Pascale, Chan, Tim, Hewitson, Brittany, Lai, Daniel, Mottok, Anja, Sarkozy, Clementine, Chong, Lauren, Aoki, Tomohiro, Wang, Xuehai, Weng, Andrew P, McAlpine, Jessica N., Aparicio, Samuel, Steidl, Christian, Campbell, Kieran R., and Shah, Sohrab P.
- Abstract
Single-cell RNA sequencing has enabled the decomposition of complex tissues into functionally distinct cell types. Often, investigators wish to assign cells to cell types through unsupervised clustering followed by manual annotation or via ‘mapping’ to existing data. However, manual interpretation scales poorly to large datasets, mapping approaches require purified or pre-annotated data and both are prone to batch effects. To overcome these issues, we present CellAssign, a probabilistic model that leverages prior knowledge of cell-type marker genes to annotate single-cell RNA sequencing data into predefined or de novo cell types. CellAssign automates the process of assigning cells in a highly scalable manner across large datasets while controlling for batch and sample effects. We demonstrate the advantages of CellAssign through extensive simulations and analysis of tumor microenvironment composition in high-grade serous ovarian cancer and follicular lymphoma.
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- 2019
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19. Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups
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Bosse, Tjalling, Nout, Remi A., McAlpine, Jessica N., McConechy, Melissa K., Britton, Heidi, Hussein, Yaser R., Gonzalez, Carlene, Ganesan, Raji, Steele, Jane C., Harrison, Beth T., Oliva, Esther, Vidal, August, Matias-Guiu, Xavier, Abu-Rustum, Nadeem R., Levine, Douglas A., Gilks, C. Blake, and Soslow, Robert A.
- Abstract
Supplemental Digital Content is available in the text.Our aim was to investigate whether molecular classification can be used to refine prognosis in grade 3 endometrial endometrioid carcinomas (EECs). Grade 3 EECs were classified into 4 subgroups: p53 abnormal, based on mutant-like immunostaining (p53abn); MMR deficient, based on loss of mismatch repair protein expression (MMRd); presence of POLEexonuclease domain hotspot mutation (POLE); no specific molecular profile (NSMP), in which none of these aberrations were present. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method (Log-rank test) and univariable and multivariable Cox proportional hazard models. In total, 381 patients were included. The median age was 66 years (range, 33 to 96 y). Federation Internationale de Gynecologie et d'Obstetrique stages (2009) were as follows: IA, 171 (44.9%); IB, 120 (31.5%); II, 24 (6.3%); III, 50 (13.1%); IV, 11 (2.9%). There were 49 (12.9%) POLE, 79 (20.7%) p53abn, 115 (30.2%) NSMP, and 138 (36.2%) MMRd tumors. Median follow-up of patients was 6.1 years (range, 0.2 to 17.0 y). Compared to patients with NSMP, patients with POLEmutant grade 3 EEC (OS: hazard ratio [HR], 0.36 [95% confidence interval, 0.18-0.70]; P=0.003; RFS: HR, 0.17 [0.05-0.54]; P=0.003) had a significantly better prognosis; patients with p53abn tumors had a significantly worse RFS (HR, 1.73 [1.09-2.74]; P=0.021); patients with MMRd tumors showed a trend toward better RFS. Estimated 5-year OS rates were as follows: POLE89%, MMRd 75%, NSMP 69%, p53abn 55% (Log rank P=0.001). Five-year RFS rates were as follows: POLE96%, MMRd 77%, NSMP 64%, p53abn 47% (P=0.000001), respectively. In a multivariable Cox model that included age and Federation Internationale de Gynecologie et d'Obstetrique stage, POLEand MMRd status remained independent prognostic factors for better RFS; p53 status was an independent prognostic factor for worse RFS. Molecular classification of grade 3 EECs reveals that these tumors are a mixture of molecular subtypes of endometrial carcinoma, rather than a homogeneous group. The addition of molecular markers identifies prognostic subgroups, with potential therapeutic implications.
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- 2018
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20. HPV-independent Differentiated Vulvar Intraepithelial Neoplasia (dVIN) is Associated With an Aggressive Clinical Course
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McAlpine, Jessica N., Kim, So Youn, Akbari, Ardalan, Eshragh, Sima, Reuschenbach, Miriam, von Knebel Doeberitz, Magnus, Prigge, Elena S., Jordan, Suzanne, Singh, Naveena, Miller, Dianne M., and Gilks, C. Blake
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Differentiated vulvar intrapeithelial neoplasia (dVIN) is an human papillomavirus (HPV)–independent precursor of squamous cell carcinoma (SCC), and the aim of this study was to better characterize its natural history. Cases of dVIN were identified from the pathology archives. Outcomes of patients with dVIN only, without associated invasive SCC, were compared with a cohort of patients with high-grade squamous intraepithelial lesion [HSIL(VIN3)]. Eighteen patients diagnosed with dVIN with adjacent invasive SCC (SCC/dVIN) and 7 patients with dVIN only, without invasive carcinoma, were identified. Mean age in both cohorts was 75 yr. All lesions but 1 were unifocal. In 35% of SCC/dVIN cases the surgical resection margins were positive for SCC, with 75% and 60% having margins positive for dVIN in the SCC/dVIN and dVIN-only cohorts, respectively. In total, 23/25 women with dVIN only or dVIN/SCC, for whom there was follow-up information, experienced either progression to or recurrence of invasive SCC, respectively, at a median of 1.1 yr, including all but 1 case of dVIN only, where the median time of progression to invasive SCC was 1.9 yr. A total of 22/25 women died of disease with a median overall survival of 3.4 yr. The outcome (i.e. progression to invasive carcinoma) of patients with dVIN only was significantly worse than that of a comparison group of 18 patients with HSIL(VIN3) (progression-free survival log-rank, P<0.001; disease-specific survival, P=0.04; overall survival, P=0.01). Six of 7 patients with dVIN only developed invasive carcinoma on follow-up, compared with 0 of 18 patients with HSIL(VIN3). The diagnosis of dVIN indicates the presence of a high-risk human papillomavirus–negative precursor of invasive SCC. These patients are likely to progress to invasive carcinoma over a relatively short period, at which point their prognosis is guarded.
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- 2017
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21. Corrigendum to “Grade and Estrogen Receptor Expression Identify a Subset of No Specific Molecular Profile Endometrial Carcinomas at a Very Low Risk of Disease-Specific Death”: [Modern Pathology 36 (2023) 100085]
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Jamieson, Amy, Huvila, Jutta, Chiu, Derek, Thompson, Emily F., Scott, Stephanie, Salvador, Shannon, Vicus, Danielle, Helpman, Limor, Gotlieb, Walter, Kean, Sarah, Samouelian, Vanessa, Köbel, Martin, Kinloch, Mary, Parra-Herran, Carlos, Offman, Saul, Grondin, Katherine, Irving, Julie, Lum, Amy, Senz, Janine, Leung, Samuel, McConechy, Melissa K., Plante, Marie, Kommoss, Stefan, Huntsman, David G., Talhouk, Aline, Gilks, C. Blake, and McAlpine, Jessica N.
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- 2023
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22. Grade and Estrogen Receptor Expression Identify a Subset of No Specific Molecular Profile Endometrial Carcinomas at a Very Low Risk of Disease-Specific Death
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Jamieson, Amy, Huvila, Jutta, Chiu, Derek, Thompson, Emily F., Scott, Stephanie, Salvador, Shannon, Vicus, Danielle, Helpman, Limor, Gotlieb, Walter, Kean, Sarah, Samouelian, Vanessa, Köbel, Martin, Kinloch, Mary, Parra-Harran, Carlos, Offman, Saul, Grondin, Katherine, Irving, Julie, Lum, Amy, Senz, Janine, Leung, Samuel, McConechy, Melissa K., Plante, Marie, Kommoss, Stefan, Huntsman, David G., Talhouk, Aline, Gilks, C. Blake, and McAlpine, Jessica N.
- Abstract
Endometrial carcinoma (EC) can be divided into 4 prognostic molecular subtypes, and no specific molecular profile (NSMP) type is the most commonly occurring type (∼50%). Although described as having an intermediate to favorable prognosis, this subtype encompasses pathologically and molecularly diverse tumors. We aimed to identify factors associated with outcomes within the NSMP ECs that might be used to stratify prognosis and direct treatment. Clinicopathologic, immunohistochemical, and genetic features of a large series of NSMP EC were used to identify parameters that could identify the subset associated with a very favorable outcome (disease-specific death rate <5% at 5 years, termed low-risk NSMP). A total of 1110 NSMP ECs were profiled. In a univariate analysis, stage, grade, lymphovascular invasion, estrogen receptor (ER) and progesterone receptor (PR) expression, L1CAM overexpression, and mutations in PIK3CAwere associated with disease-specific survival. Two critical features, grade and ER expression, identified a low-risk NSMP subset (grade 1-2, ER-positive [>1%], 84% of cases), which showed a 5-year disease-specific death rate of 1.6% across all stages and 1.4% within stage I. The remaining cases (high-risk NSMPs, grade 3, and/or ER-negative status) were responsible for most of the disease-specific deaths (disease-specific death rate at 5 years, 22.9%; hazard ratio compared with that of low-risk NSMPs: 16.3; 95% CI, 8.4-31.7). Within NSMP EC, the low-risk and high-risk categories were of prognostic significance independent of the stage on a multivariate analysis. Low-grade and ER-positive NSMP ECs are a homogeneous low-risk group associated with an exceptionally favorable prognosis in which de-escalation and/or endocrine therapy strategies can be applied. Grade 3 and/or ER-negative status identifies a high-risk NSMP subset, including rare high-grade histotypes (eg, clear cell, dedifferentiated, and mesonephric-like), responsible for most NSMP-related deaths. Subclassification of NSMPs allows for the category of low-risk EC molecular subtypes to be dramatically expanded because it now includes both POLEmut and the much more common low-risk NSMP EC.
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- 2023
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23. Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes
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Wang, Yi Kan, Bashashati, Ali, Anglesio, Michael S, Cochrane, Dawn R, Grewal, Diljot S, Ha, Gavin, McPherson, Andrew, Horlings, Hugo M, Senz, Janine, Prentice, Leah M, Karnezis, Anthony N, Lai, Daniel, Aniba, Mohamed R, Zhang, Allen W, Shumansky, Karey, Siu, Celia, Wan, Adrian, McConechy, Melissa K, Li-Chang, Hector, Tone, Alicia, Provencher, Diane, de Ladurantaye, Manon, Fleury, Hubert, Okamoto, Aikou, Yanagida, Satoshi, Yanaihara, Nozomu, Saito, Misato, Mungall, Andrew J, Moore, Richard, Marra, Marco A, Gilks, C Blake, Mes-Masson, Anne-Marie, McAlpine, Jessica N, Aparicio, Samuel, Huntsman, David G, and Shah, Sohrab P
- Abstract
We studied the whole-genome point mutation and structural variation patterns of 133 tumors (59 high-grade serous (HGSC), 35 clear cell (CCOC), 29 endometrioid (ENOC), and 10 adult granulosa cell (GCT)) as a substrate for class discovery in ovarian cancer. Ab initio clustering of integrated point mutation and structural variation signatures identified seven subgroups both between and within histotypes. Prevalence of foldback inversions identified a prognostically significant HGSC group associated with inferior survival. This finding was recapitulated in two independent cohorts (n = 576 cases), transcending BRCA1 and BRCA2 mutation and gene expression features of HGSC. CCOC cancers grouped according to APOBEC deamination (26%) and age-related mutational signatures (40%). ENOCs were divided by cases with microsatellite instability (28%), with a distinct mismatch-repair mutation signature. Taken together, our work establishes the potency of the somatic genome, reflective of diverse DNA repair deficiencies, to stratify ovarian cancers into distinct biological strata within the major histotypes.
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- 2017
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24. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer
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Phelan, Catherine M, Kuchenbaecker, Karoline B, Tyrer, Jonathan P, Kar, Siddhartha P, Lawrenson, Kate, Winham, Stacey J, Dennis, Joe, Pirie, Ailith, Riggan, Marjorie J, Chornokur, Ganna, Earp, Madalene A, Lyra, Paulo C, Lee, Janet M, Coetzee, Simon, Beesley, Jonathan, McGuffog, Lesley, Soucy, Penny, Dicks, Ed, Lee, Andrew, Barrowdale, Daniel, Lecarpentier, Julie, Leslie, Goska, Aalfs, Cora M, Aben, Katja K H, Adams, Marcia, Adlard, Julian, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia, Aravantinos, Gerasimos, Arnold, Norbert, Arun, Banu K, Arver, Brita, Azzollini, Jacopo, Balmaña, Judith, Banerjee, Susana N, Barjhoux, Laure, Barkardottir, Rosa B, Bean, Yukie, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Birrer, Michael J, Bjorge, Line, Black, Amanda, Blankstein, Kenneth, Blok, Marinus J, Bodelon, Clara, Bogdanova, Natalia, Bojesen, Anders, Bonanni, Bernardo, Borg, Åke, Bradbury, Angela R, Brenton, James D, Brewer, Carole, Brinton, Louise, Broberg, Per, Brooks-Wilson, Angela, Bruinsma, Fiona, Brunet, Joan, Buecher, Bruno, Butzow, Ralf, Buys, Saundra S, Caldes, Trinidad, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Carney, Michael E, Cescon, Terence, Chan, Salina B, Chang-Claude, Jenny, Chanock, Stephen, Chen, Xiao Qing, Chiew, Yoke-Eng, Chiquette, Jocelyne, Chung, Wendy K, Claes, Kathleen B M, Conner, Thomas, Cook, Linda S, Cook, Jackie, Cramer, Daniel W, Cunningham, Julie M, D'Aloisio, Aimee A, Daly, Mary B, Damiola, Francesca, Damirovna, Sakaeva Dina, Dansonka-Mieszkowska, Agnieszka, Dao, Fanny, Davidson, Rosemarie, DeFazio, Anna, Delnatte, Capucine, Doheny, Kimberly F, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer Anne, Domchek, Susan M, Dorfling, Cecilia M, Dörk, Thilo, Dossus, Laure, Duran, Mercedes, Dürst, Matthias, Dworniczak, Bernd, Eccles, Diana, Edwards, Todd, Eeles, Ros, Eilber, Ursula, Ejlertsen, Bent, Ekici, Arif B, Ellis, Steve, Elvira, Mingajeva, Eng, Kevin H, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Ferguson, Sarah, Ferrer, Sandra Fert, Flanagan, James M, Fogarty, Zachary C, Fortner, Renée T, Fostira, Florentia, Foulkes, William D, Fountzilas, George, Fridley, Brooke L, Friebel, Tara M, Friedman, Eitan, Frost, Debra, Ganz, Patricia A, Garber, Judy, García, María J, Garcia-Barberan, Vanesa, Gehrig, Andrea, Gentry-Maharaj, Aleksandra, Gerdes, Anne-Marie, Giles, Graham G, Glasspool, Rosalind, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, Goranova, Teodora, Gore, Martin, Greene, Mark H, Gronwald, Jacek, Gruber, Stephen, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas V O, Harrington, Patricia A, Harris, Holly R, Hauke, Jan, Hein, Alexander, Henderson, Alex, Hildebrandt, Michelle A T, Hillemanns, Peter, Hodgson, Shirley, Høgdall, Claus K, Høgdall, Estrid, Hogervorst, Frans B L, Holland, Helene, Hooning, Maartje J, Hosking, Karen, Huang, Ruea-Yea, Hulick, Peter J, Hung, Jillian, Hunter, David J, Huntsman, David G, Huzarski, Tomasz, Imyanitov, Evgeny N, Isaacs, Claudine, Iversen, Edwin S, Izatt, Louise, Izquierdo, Angel, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Jernetz, Mats, Jensen, Allan, Jensen, Uffe Birk, John, Esther M, Johnatty, Sharon, Jones, Michael E, Kannisto, Päivi, Karlan, Beth Y, Karnezis, Anthony, Kast, Karin, Kennedy, Catherine J, Khusnutdinova, Elza, Kiemeney, Lambertus A, Kiiski, Johanna I, Kim, Sung-Won, Kjaer, Susanne K, Köbel, Martin, Kopperud, Reidun K, Kruse, Torben A, Kupryjanczyk, Jolanta, Kwong, Ava, Laitman, Yael, Lambrechts, Diether, Larrañaga, Nerea, Larson, Melissa C, Lazaro, Conxi, Le, Nhu D, Le Marchand, Loic, Lee, Jong Won, Lele, Shashikant B, Leminen, Arto, Leroux, Dominique, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A, Liang, Dong, Liebrich, Clemens, Lilyquist, Jenna, Lipworth, Loren, Lissowska, Jolanta, Lu, Karen H, Lubinński, Jan, Luccarini, Craig, Lundvall, Lene, Mai, Phuong L, Mendoza-Fandiño, Gustavo, Manoukian, Siranoush, Massuger, Leon F A G, May, Taymaa, Mazoyer, Sylvie, McAlpine, Jessica N, McGuire, Valerie, McLaughlin, John R, McNeish, Iain, Meijers-Heijboer, Hanne, Meindl, Alfons, Menon, Usha, Mensenkamp, Arjen R, Merritt, Melissa A, Milne, Roger L, Mitchell, Gillian, Modugno, Francesmary, Moes-Sosnowska, Joanna, Moffitt, Melissa, Montagna, Marco, Moysich, Kirsten B, Mulligan, Anna Marie, Musinsky, Jacob, Nathanson, Katherine L, Nedergaard, Lotte, Ness, Roberta B, Neuhausen, Susan L, Nevanlinna, Heli, Niederacher, Dieter, Nussbaum, Robert L, Odunsi, Kunle, Olah, Edith, Olopade, Olufunmilayo I, Olsson, Håkan, Olswold, Curtis, O'Malley, David M, Ong, Kai-ren, Onland-Moret, N Charlotte, Orr, Nicholas, Orsulic, Sandra, Osorio, Ana, Palli, Domenico, Papi, Laura, Park-Simon, Tjoung-Won, Paul, James, Pearce, Celeste L, Pedersen, Inge Søkilde, Peeters, Petra H M, Peissel, Bernard, Peixoto, Ana, Pejovic, Tanja, Pelttari, Liisa M, Permuth, Jennifer B, Peterlongo, Paolo, Pezzani, Lidia, Pfeiler, Georg, Phillips, Kelly-Anne, Piedmonte, Marion, Pike, Malcolm C, Piskorz, Anna M, Poblete, Samantha R, Pocza, Timea, Poole, Elizabeth M, Poppe, Bruce, Porteous, Mary E, Prieur, Fabienne, Prokofyeva, Darya, Pugh, Elizabeth, Pujana, Miquel Angel, Pujol, Pascal, Radice, Paolo, Rantala, Johanna, Rappaport-Fuerhauser, Christine, Rennert, Gad, Rhiem, Kerstin, Rice, Patricia, Richardson, Andrea, Robson, Mark, Rodriguez, Gustavo C, Rodríguez-Antona, Cristina, Romm, Jane, Rookus, Matti A, Rossing, Mary Anne, Rothstein, Joseph H, Rudolph, Anja, Runnebaum, Ingo B, Salvesen, Helga B, Sandler, Dale P, Schoemaker, Minouk J, Senter, Leigha, Setiawan, V Wendy, Severi, Gianluca, Sharma, Priyanka, Shelford, Tameka, Siddiqui, Nadeem, Side, Lucy E, Sieh, Weiva, Singer, Christian F, Sobol, Hagay, Song, Honglin, Southey, Melissa C, Spurdle, Amanda B, Stadler, Zsofia, Steinemann, Doris, Stoppa-Lyonnet, Dominique, Sucheston-Campbell, Lara E, Sukiennicki, Grzegorz, Sutphen, Rebecca, Sutter, Christian, Swerdlow, Anthony J, Szabo, Csilla I, Szafron, Lukasz, Tan, Yen Y, Taylor, Jack A, Tea, Muy-Kheng, Teixeira, Manuel R, Teo, Soo-Hwang, Terry, Kathryn L, Thompson, Pamela J, Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L, Tihomirova, Laima, Tinker, Anna V, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda Ewart, Tone, Alicia, Trabert, Britton, Travis, Ruth C, Trichopoulou, Antonia, Tung, Nadine, Tworoger, Shelley S, van Altena, Anne M, Van Den Berg, David, van der Hout, Annemarie H, van der Luijt, Rob B, Van Heetvelde, Mattias, Van Nieuwenhuysen, Els, van Rensburg, Elizabeth J, Vanderstichele, Adriaan, Varon-Mateeva, Raymonda, Vega, Ana, Edwards, Digna Velez, Vergote, Ignace, Vierkant, Robert A, Vijai, Joseph, Vratimos, Athanassios, Walker, Lisa, Walsh, Christine, Wand, Dorothea, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Webb, Penelope M, Weinberg, Clarice R, Weitzel, Jeffrey N, Wentzensen, Nicolas, Whittemore, Alice S, Wijnen, Juul T, Wilkens, Lynne R, Wolk, Alicja, Woo, Michelle, Wu, Xifeng, Wu, Anna H, Yang, Hannah, Yannoukakos, Drakoulis, Ziogas, Argyrios, Zorn, Kristin K, Narod, Steven A, Easton, Douglas F, Amos, Christopher I, Schildkraut, Joellen M, Ramus, Susan J, Ottini, Laura, Goodman, Marc T, Park, Sue K, Kelemen, Linda E, Risch, Harvey A, Thomassen, Mads, Offit, Kenneth, Simard, Jacques, Schmutzler, Rita Katharina, Hazelett, Dennis, Monteiro, Alvaro N, Couch, Fergus J, Berchuck, Andrew, Chenevix-Trench, Georgia, Goode, Ellen L, Sellers, Thomas A, Gayther, Simon A, Antoniou, Antonis C, and Pharoah, Paul D P
- Abstract
To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
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- 2017
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25. Interobserver Agreement in Endometrial Carcinoma Histotype Diagnosis Varies Depending on The Cancer Genome Atlas (TCGA)-based Molecular Subgroup
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Hoang, Lien N., Kinloch, Mary A., Leo, Joyce M., Grondin, Katherine, Lee, Cheng-Han, Ewanowich, Carol, Köbel, Martin, Cheng, Angela, Talhouk, Aline, McConechy, Melissa, Huntsman, David G., McAlpine, Jessica N., Soslow, Robert A., and Gilks, C. Blake
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The Cancer Genome Atlas recently identified a genomic-based molecular classification of endometrial carcinomas, with 4 molecular categories: (1) ultramutated (polymerase epsilon [POLE] mutated), (2) hypermutated (microsatellite instability), (3) copy number abnormalities-low, and (4) copy number abnormalities-high. Two studies have since proposed models to classify endometrial carcinomas into 4 molecular subgroups, modeled after The Cancer Genome Atlas, using simplified and more clinically applicable surrogate methodologies. In our study, 151 endometrial carcinomas were molecularly categorized using sequencing for the exonuclease domain mutations (EDM) of POLE, and immunohistochemistry for p53 and mismatch repair (MMR) proteins. This separated cases into 1 of 4 groups: (1) POLEEDM, (2) MMR-D, (3) p53 wildtype (p53 wt), or (4) p53 abnormal (p53 abn). Seven gynecologic pathologists were asked to assign each case to one of the following categories: grade 1 to 2 endometrioid carcinoma (EC), grade 3 EC, mucinous, serous carcinoma (SC), clear cell, dedifferentiated, carcinosarcoma, mixed, and other. Consensus diagnosis among all 7 pathologists was highest in the p53 wt group (37/41, 90%), lowest in the p53 abn group (14/36, 39%), and intermediate in the POLEEDM (22/34, 65%) and MMR-D groups (23/40, 58%). Although the majority of p53 wt endometrial carcinomas are grade 1 to 2 EC (sensitivity: 90%), fewer than half of grade 1 to 2 EC fell into the p53 wt category (positive predictive value: 42%). Pure SC almost always resided in the p53 abn group (positive predictive value: 96%), but it was insensitive as a marker of p53 abn (sensitivity 64%) and the reproducibility of diagnosing SC was suboptimal. The limitations in the precise histologic classification of endometrial carcinomas highlights the importance of an ancillary molecular-based classification scheme.
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- 2017
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26. FOXL2402C>G Mutation Can Be Identified in the Circulating Tumor DNA of Patients with Adult-Type Granulosa Cell Tumor
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Färkkilä, Anniina, McConechy, Melissa K., Yang, Winnie, Talhouk, Aline, Ng, Ying, Lum, Amy, Morin, Ryan D., Bushell, Kevin, Riska, Annika, McAlpine, Jessica N., Gilks, C. Blake, Unkila-Kallio, Leila, Anttonen, Mikko, and Huntsman, David G.
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Adult granulosa cell tumors (AGCTs) of the ovary are molecularly characterized by the pathognomonic FOXL2402C>G (C134W) mutation. To improve diagnostics and follow-up, we developed a specific digital droplet PCR (ddPCR) assay to detect the FOXL2mutation in the circulating tumor DNA (ctDNA) of AGCT patients. Optimization of the ddPCR assay was performed using a TaqMan primer/probe with the RainDance RainDrop digital PCR system. The ddPCR assay was performed on circulating cell-free DNA extracted from 120 serial plasma samples collected prospectively from 35 AGCT patients. The ddPCR assay included a preamplification step that is sensitive and specific for detecting the FOXL2-mutated ctDNA at levels as low as 0.05%. FOXL2ctDNA mutations were detected in the plasma of 12 of 33 AGCT patients (36%), with both primary (6 of 17, 35%) and recurrent (6 of 31, 19%) tumors. The median tumor size was significantly larger in ctDNA mutation–positive compared with mutation-negative samples (13.5 cm versus 7.5 cm; P = 0.003). The ctDNA FOXL2mutation was detected in four patients without clinical disease, of which one relapsed during follow-up. As proof of concept, we established that specific molecular diagnosis of AGCT and detection of AGCT recurrence can be achieved noninvasively using ctDNA FOXL2mutation testing. Further studies are needed to determine the clinical value of ctDNA mutation testing.
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- 2017
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27. p53-Abnormal “Fields of Dysplasia” in Human Papillomavirus–Independent Vulvar Squamous Cell Carcinoma Impacts Margins and Recurrence Risk
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Thompson, Emily F., Wong, Richard W.C., Trevisan, Giorgia, Tessier-Cloutier, Basile, Almadani, Noorah, Chen, Julia, Cheng, Angela, Karnezis, Anthony, McConechy, Melissa K., Lum, Amy, Senz, Janine, McAlpine, Jessica N., Huntsman, David G., Gilks, Blake, Jamieson, Amy, and Hoang, Lynn N.
- Abstract
Abnormal p53 (p53abn) immunohistochemical (IHC) staining patterns can be found in vulvar squamous cell carcinoma (VSCC) and differentiated vulvar intraepithelial neoplasia (dVIN). They can also be found in the adjacent skin that shows morphology that falls short of the traditional diagnostic threshold for dVIN. Vulvectomy specimens containing human papillomavirus–independent p53abn VSCC with margins originally reported as negative for invasive and in situ disease were identified. Sections showing the closest approach by invasive or in situ neoplasia to margins were stained with p53 IHC stains. We evaluated the following: (1) detection of morphologically occult p53abn in situ neoplasia, (2) rates of margin status change after p53 IHC staining, and (3) effect of p53abn IHC staining at margins on the 2-year local recurrence rates. Seventy-three human papillomavirus–independent p53abn VSCCs were included. Half (35/73, 48%) had documented an in situ lesion in the original report. The use of p53 IHC staining identified 21 additional cases (29%) with the p53abn in situ lesions that were originally unrecognized. The histology of in situ lesions in the p53abn “field” varied and became more subtle (morphologically occult) farther away from the VSCC. Fifteen (21%) cases had a morphologically occult and previously unrecognized p53abn in situ lesion present at a resection margin, which conferred an increased risk of local recurrence (5/7 [71.4%] vs 6/22 [27.3%], P = .036). The p53abn in situ lesions at a margin were confirmed to have TP53mutations by sequencing. p53 IHC staining identified morphologically occult p53abn in situ lesions surrounding human papillomavirus–independent VSCC. p53abn IHC staining at a margin was associated with a 3-fold increased risk of local recurrence.
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- 2023
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28. Classification of Vulvar Squamous Cell Carcinoma and Precursor Lesions by p16 and p53 Immunohistochemistry: Considerations, Caveats and an Algorithmic Approach
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Yang, Hang, Almadani, Noorah, Thompson, Emily F, Tessier-Cloutier, Basile, Chen, Julia, Ho, Julie, Senz, Janine, McConechy, Melissa K, Chow, Christine, Ta, Monica, Cheng, Angela, Karnezis, Anthony, Huvila, Jutta, McAlpine, Jessica N, Gilks, Blake, Jamieson, Amy, and Hoang, Lynn N
- Abstract
There is emerging evidence that vulvar squamous cell carcinoma (VSCC) can be prognostically subclassified into 3 groups based on human papillomavirus (HPV) and p53 status: HPV-associated (HPV+), HPV-independent/p53 wild-type (HPV-/p53wt), or HPV-independent/p53 abnormal (HPV-/p53abn). Our goal was to assess the feasibility of separating VSCC and its precursors into these 3 groups using p16 and p53 immunohistochemistry (IHC). A tissue microarray (TMA) containing 225 VSCC, 43 usual vulvar intraepithelial neoplasia (uVIN/HSIL), 10 verruciform acanthotic vulvar intraepithelial neoplasia (vaVIN), and 34 differentiated VIN (dVIN), was stained for p16 and p53. Non-complementary p16 and p53 patterns were resolved by repeating p53 IHC and HPV RNA in-situ hybridization (ISH) on whole sections, and sequencing for TP53. Of 82 p16-positive VSCC, 73 (89%) had complementary p16 and p53 patterns and were classified into the HPV+ group, 4 (4.9%) had wild-type p53 staining, positive HPV ISH, and were classified into the HPV+ group, while 5 (6.1%) had p53 abnormal IHC patterns (1 null, 4 overexpression), negativity for HPV ISH and harboured TP53mutations (1 splice-site, 4 missense); they were classified as HPV-/p53abn. Of 143 p16-negative VSCC, 142 (99.3%) had complementary p53 and p16 patterns; 115 (80.4%) HPV-/p53abn and 27 (18.9%) HPV-/p53wt. One had a basal-sparing p53 pattern, positivity for HPV ISH, and was negative for TP53mutations; it was classified into the HPV+ category. The use of IHC also led to the following revised diagnoses: HSIL to dVIN (3/43), dVIN to vaVIN (8/34), and dVIN to HSIL (3/34). Overall, 215/225 VSCC (95.6%) could be easily classifiable into 3 groups with p16 and p53 IHC. We identified several caveats, with the major caveat being that ‘double positive’ p16/p53 should be classified as HPV-/p53abn, and propose an algorithm which will facilitate the application of p16 and p53 IHC to classify VSCC in pathology practice.
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- 2023
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29. Clonal genotype and population structure inference from single-cell tumor sequencing
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Roth, Andrew, McPherson, Andrew, Laks, Emma, Biele, Justina, Yap, Damian, Wan, Adrian, Smith, Maia A, Nielsen, Cydney B, McAlpine, Jessica N, Aparicio, Samuel, Bouchard-Côté, Alexandre, and Shah, Sohrab P
- Abstract
Single-cell DNA sequencing has great potential to reveal the clonal genotypes and population structure of human cancers. However, single-cell data suffer from missing values and biased allelic counts as well as false genotype measurements owing to the sequencing of multiple cells. We describe the Single Cell Genotyper (https://bitbucket.org/aroth85/scg), an open-source software based on a statistical model coupled with a mean-field variational inference method, which can be used to address these problems and robustly infer clonal genotypes.
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- 2016
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30. p16 Immunostaining Allows for Accurate Subclassification of Vulvar Squamous Cell Carcinoma Into HPV-Associated and HPV-Independent Cases
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Cheng, Angela S., Karnezis, Anthony N., Jordan, Suzanne, Singh, Naveena, McAlpine, Jessica N., and Gilks, C. Blake
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The aim of this study was to compare morphologic assessment and p16 immunohistochemistry (IHC) in the determination of human papilloma virus (HPV) status in vulvar squamous cell carcinoma (VSCC). A total of 201 invasive VSCC cases were classified as “HPV-associated” when warty/basaloid VSCC or high-grade squamous intraepithelial lesion (vulvar intraepithelial neoplasia 2/3) was observed, or “HPV-independent” in the presence of well-differentiated keratinizing invasive SCC or differentiated vulvar intraepithelial neoplasia. For p16 IHC, strong nuclear and cytoplasmic staining of all cells in at least the lowermost third of the epithelium was scored as positive. All cases with discrepant HPV predictions by hematoxylin and eosin morphology versus p16 IHC were further analyzed by polymerase chain reaction for HPV DNA. On the basis of hematoxylin and eosin morphologic assessment, 50/201 tumors showed features suggestive of HPV-associated, and 47 of those showed p16 immunoreactivity (94% concordance). Of the 146 cases considered HPV-independent based on hematoxylin and eosin, 115 (79%) showed negative p16 immunostaining. Thus 83% (162/196) concordance between morphologic assessment and p16 IHC was observed, overall. In 34 cases, where morphologic assessment and p16 IHC did not agree, HPV polymerase chain reaction agreed with p16 IHC in 32/34 (94%). The sensitivity and specificity of p16 IHC in classification of VSCC as HPV-independent or HPV-associated was 100% and 98.4%, respectively. Morphologic assessment and p16 IHC are concordant in classifying VSCC as HPV-independent or HPV-associated in a majority of cases (83%). Most of the discrepant cases are p16-positive well-differentiated keratinizing VSCC, and HPV polymerase chain reaction supports classification of a large majority of these (94%) as HPV-associated. p16 IHC is validated as an accurate surrogate marker for determination of HPV status in VSCC.
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- 2016
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31. Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer
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McPherson, Andrew, Roth, Andrew, Laks, Emma, Masud, Tehmina, Bashashati, Ali, Zhang, Allen W, Ha, Gavin, Biele, Justina, Yap, Damian, Wan, Adrian, Prentice, Leah M, Khattra, Jaswinder, Smith, Maia A, Nielsen, Cydney B, Mullaly, Sarah C, Kalloger, Steve, Karnezis, Anthony, Shumansky, Karey, Siu, Celia, Rosner, Jamie, Chan, Hector Li, Ho, Julie, Melnyk, Nataliya, Senz, Janine, Yang, Winnie, Moore, Richard, Mungall, Andrew J, Marra, Marco A, Bouchard-Côté, Alexandre, Gilks, C Blake, Huntsman, David G, McAlpine, Jessica N, Aparicio, Samuel, and Shah, Sohrab P
- Abstract
We performed phylogenetic analysis of high-grade serous ovarian cancers (68 samples from seven patients), identifying constituent clones and quantifying their relative abundances at multiple intraperitoneal sites. Through whole-genome and single-nucleus sequencing, we identified evolutionary features including mutation loss, convergence of the structural genome and temporal activation of mutational processes that patterned clonal progression. We then determined the precise clonal mixtures comprising each tumor sample. The majority of sites were clonally pure or composed of clones from a single phylogenetic clade. However, each patient contained at least one site composed of polyphyletic clones. Five patients exhibited monoclonal and unidirectional seeding from the ovary to intraperitoneal sites, and two patients demonstrated polyclonal spread and reseeding. Our findings indicate that at least two distinct modes of intraperitoneal spread operate in clonal dissemination and highlight the distribution of migratory potential over clonal populations comprising high-grade serous ovarian cancers.
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- 2016
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32. La salpingectomie opportuniste : Nous choisissons d'agir, pas d'attendre
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McAlpine, Jessica N., Tone, Alicia A., and Hanley, Gillian E.
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- 2016
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33. Expanding the Morphologic Spectrum of Differentiated VIN (dVIN) Through Detailed Mapping of Cases With p53 Loss
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Singh, Naveena, Leen, Sarah L., Han, Guangming, Faruqi, Asma, Kokka, Fani, Rosenthal, Adam, Jiang, Xin Rong, Kim, Rachel, McAlpine, Jessica N., and Gilks, C. Blake
- Abstract
The pathogenesis of vulvar squamous cell carcinoma follows 1 of 2 distinct pathways. A precursor lesion in the human papilloma virus–independent pathway, differentiated vulvar intraepithelial neoplasia (dVIN), was only recently characterized in detail and is infrequently diagnosed without an associated component of invasive carcinoma. Aberrant p53 immunostaining is frequently seen in dVIN, and in approximately 25% to 30% of cases it manifests as a complete loss or a p53-null pattern. The abrupt transition between p53 loss and basal p53 expression in lesional versus nonlesional epithelium allows clear demarcation between neoplastic and non-neoplastic epithelium. For this study, 14 specimens from 10 patients were identified from the pathology archives of 2 teaching hospitals on the basis of: (1) a diagnosis of dVIN, with or without invasive carcinoma; and (2) p53-null immunostaining pattern in lesional cells. Ten specimens had associated invasive carcinoma. All sections from each specimen that showed the specimen resection margin were stained for p53 and reviewed together with all hematoxylin and eosin sections. Detailed morphologic assessment of the p53-null epithelium was made and compared with the adjacent benign squamous epithelium. The status of the resection margins based on the original pathologic assessment was compared with that assessed with p53 immunohistochemistry. One specimen showed p53 loss in the invasive carcinoma but patchy basal positivity in the region originally diagnosed as dVIN, supporting interpretation as a benign hyperplastic focus, rather than dVIN. In the remaining 13 specimens the areas originally diagnosed as dVIN, as well as the associated invasive carcinoma (if present), were p53-null. In 8 of these specimens, on the basis of the presence of p53-null immunostaining and subtle morphologic abnormalities, dVIN was more extensive than originally recognized. The spectrum of morphologic changes in p53-null regions that were in continuity with areas originally recognized as dVIN were subtle and typically consisted of an abrupt change in maturation of the squamous epithelium (loss of keratohyaline granules and parakeratosis), tinctorial alterations in the keratinocytes, with cells containing more abundant eosinophilic cytoplasm, and minimal basal nuclear atypia. Margin status changed from negative to positive in 4 of 13 specimens and from focally to more extensively positive in an additional 3 specimens. In summary, the clonal in situ component of non–human papilloma virus vulvar squamous cell carcinoma can be characterized by very subtle morphologic abnormalities that may be misinterpreted as benign change. This results in underestimation of the extent of dVIN, and, as a result, resection margin involvement may be significantly underestimated. dVIN can also be overdiagnosed in areas of reactive change. Better tools for diagnosis of dVIN are needed; until such tools are developed the limitations in the current diagnosis of dVIN should be recognized.
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- 2015
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34. Determinants of Quality of Life in Ovarian Cancer Survivors: A Pilot Study
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Teng, Flora F., Kalloger, Steve E., Brotto, Lori, and McAlpine, Jessica N.
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Ovarian cancer treatments and outcomes vary substantially, yielding a diverse group of survivors. Few data exist on quality of life (QoL) concerns and the foremost needs of these patients. Our goal was to conduct a pilot study to determine the QoL needs of ovarian cancer survivors to establish priorities for future interventions.
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- 2014
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35. The Fallopian Tube as the Origin of High Grade Serous Ovarian Cancer: Review of a Paradigm Shift
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Reade, Clare J., McVey, Ruaidhrí M., Tone, Alicia A., Finlayson, Sarah J., McAlpine, Jessica N, Fung-Kee-Fung, Michael, and Ferguson, Sarah E.
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Research published over the past 10 years has suggested that most “ovarian cancer,” and specifically the high-grade serous carcinoma (HGSC) subtype of ovarian cancer, actually originates in the fallopian tube. In this review, we examine the evidence supporting the tubal origin hypothesis for HGSC, and discuss the clinical implications of our improved understanding of the pathogenesis of ovarian cancer. We searched Medline R and Medline in-process and non-indexed citations from inception to December 15, 2012, to identify all English or French language articles discussing the origins of HGSC. Articles and findings were summarized descriptively. A step-wise transformation from normal epithelium to a lesion with the ability to invade and metastasize has been demonstrated within the fallopian tube. Intraepithelial or early invasive carcinoma of the fallopian tube is frequently identified in BRCA mutation carriers who undergo prophylactic risk-reducing salpingo-oophorectomy. In both BRCA mutation carriers and women from the general population, pre-invasive changes within the fimbriated end of the fallopian tube appear in association with early HGSC. Molecular and genetic studies, as well as in vitro and animal models, have also supported a tubal origin for HGSC. Whether the removal of fallopian tubes (salpingectomy) at the time of pelvic surgery for other reasons will lead to reductions in mortality from ovarian cancer is currently unknown, but it is an important area for future clinical research.
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- 2014
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36. Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN mutation profiles
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McConechy, Melissa K, Ding, Jiarui, Senz, Janine, Yang, Winnie, Melnyk, Nataliya, Tone, Alicia A, Prentice, Leah M, Wiegand, Kimberly C, McAlpine, Jessica N, Shah, Sohrab P, Lee, Cheng-Han, Goodfellow, Paul J, Gilks, C Blake, and Huntsman, David G
- Abstract
Ovarian endometrioid carcinomas and endometrial endometrioid carcinomas share many histological and molecular alterations. These similarities are likely due to a common endometrial epithelial precursor cell of origin, with most ovarian endometrioid carcinomas arising from endometriosis. To directly compare the mutation profiles of two morphologically similar tumor types, endometrial endometrioid carcinomas (n=307) and ovarian endometrioid carcinomas (n=33), we performed select exon capture sequencing on a panel of genes: ARID1A, PTEN, PIK3CA, KRAS, CTNNB1, PPP2R1A, TP53. We found that PTEN mutations are more frequent in low-grade endometrial endometrioid carcinomas (67%) compared with low-grade ovarian endometrioid carcinomas (17%) (P<0.0001). By contrast, CTNNB1 mutations are significantly different in low-grade ovarian endometrioid carcinomas (53%) compared with low-grade endometrial endometrioid carcinomas (28%) (P<0.0057). This difference in CTNNB1 mutation frequency may be reflective of the distinct microenvironments; the epithelial cells lining an endometriotic cyst within the ovary are exposed to a highly oxidative environment that promotes tumorigenesis. Understanding the distinct mutation patterns found in the PI3K and Wnt pathways of ovarian and endometrial endometrioid carcinomas may provide future opportunities for stratifying patients for targeted therapeutics.
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- 2014
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37. Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1and PTENmutation profiles
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McConechy, Melissa K, Ding, Jiarui, Senz, Janine, Yang, Winnie, Melnyk, Nataliya, Tone, Alicia A, Prentice, Leah M, Wiegand, Kimberly C, McAlpine, Jessica N, Shah, Sohrab P, Lee, Cheng-Han, Goodfellow, Paul J, Gilks, C Blake, and Huntsman, David G
- Abstract
Ovarian endometrioid carcinomas and endometrial endometrioid carcinomas share many histological and molecular alterations. These similarities are likely due to a common endometrial epithelial precursor cell of origin, with most ovarian endometrioid carcinomas arising from endometriosis. To directly compare the mutation profiles of two morphologically similar tumor types, endometrial endometrioid carcinomas (n=307) and ovarian endometrioid carcinomas (n=33), we performed select exon capture sequencing on a panel of genes: ARID1A, PTEN, PIK3CA, KRAS, CTNNB1, PPP2R1A, TP53.We found that PTENmutations are more frequent in low-grade endometrial endometrioid carcinomas (67%) compared with low-grade ovarian endometrioid carcinomas (17%) (P<0.0001). By contrast, CTNNB1mutations are significantly different in low-grade ovarian endometrioid carcinomas (53%) compared with low-grade endometrial endometrioid carcinomas (28%) (P<0.0057). This difference in CTNNB1mutation frequency may be reflective of the distinct microenvironments; the epithelial cells lining an endometriotic cyst within the ovary are exposed to a highly oxidative environment that promotes tumorigenesis. Understanding the distinct mutation patterns found in the PI3K and Wnt pathways of ovarian and endometrial endometrioid carcinomas may provide future opportunities for stratifying patients for targeted therapeutics.
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- 2014
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38. Histotype-Genotype Correlation in 36 High-grade Endometrial Carcinomas
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Hoang, Lien N., McConechy, Melissa K., Köbel, Martin, Han, Guangming, Rouzbahman, Marjan, Davidson, Ben, Irving, Julie, Ali, Rola H., Leung, Sam, McAlpine, Jessica N., Oliva, Esther, Nucci, Marisa R., Soslow, Robert A., Huntsman, David G., Gilks, C. Blake, and Lee, Cheng-Han
- Abstract
Endometrioid, serous, and clear cell carcinomas are the major types of endometrial carcinoma. Histologic distinction between these different tumor types can be difficult in high-grade cases, in which significant interobserver diagnostic disagreement exists. Endometrioid and clear cell carcinomas frequently harbor ARID1Aandor PTENmutations. Serous carcinoma acquires TP53mutationsinactivation at onset, with a significant subset harboring an additional mutation in PPP2R1A. This study examines the correlation between tumor histotype and genotype in 36 previously genotyped high-grade endometrial carcinomas. This included 23 endometrioidclear cell genotype and 13 serous genotype tumors. Eight subspecialty pathologists reviewed representative online slides and rendered diagnoses before and after receiving p53, p16, and estrogen receptor immunostaining results. statistics for histotype-genotype concordance were calculated. The average values for histotype-genotype concordance was 0.55 (range, 0.30 to 0.67) on the basis of morphologic evaluation alone and it improved to 0.68 (range, 0.54 to 0.81) after immunophenotype consideration (P<0.001). Genotype-incompatible diagnoses were rendered by at least 2 pathologists in 12 of 36 cases (33) (3 cases by 28 pathologists, 2 by 38, 2 by 48, 3 by 68, 1 by 78, and 1 case by 88 pathologists). Six of the 12 were endometrioidclear cell genotype tumors, and the other 6 were serous genotype tumors. The histopathologic features associated with histotype-genotype–discordant cases were reviewed, and specific diagnostic recommendations were made to improve concordance. This study found that although the majority of morphologic diagnoses are genotype concordant, genotype-incompatible diagnoses are made in a significant subset of cases. Judicious use and interpretation of p53 immunohistochemistry in selected scenarios can improve histotype-genotype concordance.
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- 2013
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39. BRCA1and BRCA2mutations correlate with TP53abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma
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McAlpine, Jessica N, Porter, Henry, Köbel, Martin, Nelson, Brad H, Prentice, Leah M, Kalloger, Steve E, Senz, Janine, Milne, Katy, Ding, Jiarui, Shah, Sohrab P, Huntsman, David G, and Gilks, C Blake
- Abstract
We characterized BRCA1and BRCA2status (mutation/methylation) in a consecutive series of cases of ovarian carcinoma in order to identify differences in clinicopathological features, molecular characteristics, and outcome between the pelvic high-grade serous cancers with (i) germline or somatic mutations in BRCA1or BRCA2, (ii) methylation of BRCA1, and (iii) normal BRCA1or BRCA2. In all, 131 women were identified prospectively, who were undergoing surgical staging and agreed to germline testing for BRCA1and BRCA2 mutations. Histopathology, germline and somatic BRCA1or BRCA2 mutations, BRCA1methylation, and BRCA1and BRCA2mRNA expression levels distinguished four subgroups. In all, 103 cases were high-grade serous carcinoma and of these 31 (30%) had germline or somatic BRCA1 or BRCA2mutations (20% BRCA1and 10% BRCA2) (group 1), 21 (20%) had methylation of BRCA1(group 2), and in 51 (50%) there was no BRCA loss (group 3). Group 4 consisted of 28 cases of non-high-grade serous, none of which had BRCA loss. BRCA1and BRCA2mRNA expression levels correlated with designated group (P=0.0008). Among high-grade serous carcinomas, there were no differences between groups 1–3 with respect to stage, ascites, CA125 level, platinum sensitivity, cytoreduction rate, neoadjuvant chemotherapy, or survival. Tumors with BRCA1or BRCA2mutations had increased immune infiltrates (CD20 and TIA-1) compared with high-grade serous without mutations (P=0.034, 0.027). TP53expression differed between groups (P<0.0001), with abnormal TP53expression in 49/50 tumors from groups 1 and 2. Wild-type TP53expression was associated with worse outcome in high-grade serous (P<0.001). BRCA loss (mutation/methylation) is a common event in the pelvic high-grade serous (50%). TP53abnormalities and increased immune cell infiltrates are significantly more common in high-grade serous with germline and somatic mutations in BRCA1or BRCA2, compared with tumors lacking BRCA abnormalities.
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- 2012
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40. BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma
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McAlpine, Jessica N, Porter, Henry, Köbel, Martin, Nelson, Brad H, Prentice, Leah M, Kalloger, Steve E, Senz, Janine, Milne, Katy, Ding, Jiarui, Shah, Sohrab P, Huntsman, David G, and Gilks, C Blake
- Abstract
We characterized BRCA1 and BRCA2 status (mutation/methylation) in a consecutive series of cases of ovarian carcinoma in order to identify differences in clinicopathological features, molecular characteristics, and outcome between the pelvic high-grade serous cancers with (i) germline or somatic mutations in BRCA1 or BRCA2, (ii) methylation of BRCA1, and (iii) normal BRCA1 or BRCA2. In all, 131 women were identified prospectively, who were undergoing surgical staging and agreed to germline testing for BRCA1 and BRCA2 mutations. Histopathology, germline and somatic BRCA1 or BRCA2 mutations, BRCA1 methylation, and BRCA1 and BRCA2 mRNA expression levels distinguished four subgroups. In all, 103 cases were high-grade serous carcinoma and of these 31 (30%) had germline or somatic BRCA1 or BRCA2 mutations (20% BRCA1 and 10% BRCA2) (group 1), 21 (20%) had methylation of BRCA1 (group 2), and in 51 (50%) there was no BRCA loss (group 3). Group 4 consisted of 28 cases of non-high-grade serous, none of which had BRCA loss. BRCA1 and BRCA2 mRNA expression levels correlated with designated group (P=0.0008). Among high-grade serous carcinomas, there were no differences between groups 1–3 with respect to stage, ascites, CA125 level, platinum sensitivity, cytoreduction rate, neoadjuvant chemotherapy, or survival. Tumors with BRCA1 or BRCA2 mutations had increased immune infiltrates (CD20 and TIA-1) compared with high-grade serous without mutations (P=0.034, 0.027). TP53 expression differed between groups (P<0.0001), with abnormal TP53 expression in 49/50 tumors from groups 1 and 2. Wild-type TP53 expression was associated with worse outcome in high-grade serous (P<0.001). BRCA loss (mutation/methylation) is a common event in the pelvic high-grade serous (50%). TP53 abnormalities and increased immune cell infiltrates are significantly more common in high-grade serous with germline and somatic mutations in BRCA1 or BRCA2, compared with tumors lacking BRCA abnormalities.
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- 2012
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41. Risk-Reducing Bilateral Salpingo-Oophorectomy and Sexual Health: A Qualitative Study
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Brotto, Lori A., Branco, Nadia, Dunkley, Cara, McCullum, Mary, and McAlpine, Jessica N.
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To examine the impact of risk-reducing bilateral salpingooophorectomy (RRBSO) on sexual function in BRCA gene mutation carriers, compared with the effect on women undergoing BSO (bilateral salpingo-oophorectomy) for benign indications from a qualitative perspective.
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- 2012
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42. Opportunistic Salpingectomy: We Chose to Act, Not Wait
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McAlpine, Jessica N., Tone, Alicia A., and Hanley, Gillian E.
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- 2016
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43. Subpubic Cartilaginous Cyst: A Rare Sub-Clitoral Mass
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Healy, Ciaran F., Pang, Emily, Bakhsh, Salwa, White, Laura, McAlpine, Jessica N., Yee, Will C., Harris, Alison C., Healy, Ciaran F., Pang, Emily, Bakhsh, Salwa, White, Laura, McAlpine, Jessica N., Yee, Will C., and Harris, Alison C.
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- 2016
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44. Dissociation of solid tumor tissues with cold active protease for single-cell RNA-seq minimizes conserved collagenase-associated stress responses
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O’Flanagan, Ciara H., Campbell, Kieran R., Zhang, Allen W., Kabeer, Farhia, Lim, Jamie L. P., Biele, Justina, Eirew, Peter, Lai, Daniel, McPherson, Andrew, Kong, Esther, Bates, Cherie, Borkowski, Kelly, Wiens, Matt, Hewitson, Brittany, Hopkins, James, Pham, Jenifer, Ceglia, Nicholas, Moore, Richard, Mungall, Andrew J., McAlpine, Jessica N., Shah, Sohrab P., and Aparicio, Samuel
- Abstract
Background: Single-cell RNA sequencing (scRNA-seq) is a powerful tool for studying complex biological systems, such as tumor heterogeneity and tissue microenvironments. However, the sources of technical and biological variation in primary solid tumor tissues and patient-derived mouse xenografts for scRNA-seq are not well understood. Results: We use low temperature (6?°C) protease and collagenase (37?°C) to identify the transcriptional signatures associated with tissue dissociation across a diverse scRNA-seq dataset comprising 155,165 cells from patient cancer tissues, patient-derived breast cancer xenografts, and cancer cell lines. We observe substantial variation in standard quality control metrics of cell viability across conditions and tissues. From the contrast between tissue protease dissociation at 37?°C or 6?°C, we observe that collagenase digestion results in a stress response. We derive a core gene set of 512 heat shock and stress response genes, including FOS and JUN, induced by collagenase (37?°C), which are minimized by dissociation with a cold active protease (6?°C). While induction of these genes was highly conserved across all cell types, cell type-specific responses to collagenase digestion were observed in patient tissues. Conclusions: The method and conditions of tumor dissociation influence cell yield and transcriptome state and are both tissue- and cell-type dependent. Interpretation of stress pathway expression differences in cancer single-cell studies, including components of surface immune recognition such as MHC class I, may be especially confounded. We define a core set of 512 genes that can assist with the identification of such effects in dissociated scRNA-seq experiments.
- Published
- 2019
- Full Text
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45. Costs and Benefits of Opportunistic Salpingectomy as an Ovarian Cancer Prevention Strategy
- Author
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Kwon, Janice S., McAlpine, Jessica N., Hanley, Gillian E., Finlayson, Sarah J., Cohen, Trevor, Miller, Dianne M., Gilks, C. Blake, and Huntsman, David G.
- Abstract
Evidence accumulated over the past decade suggests that the majority of ovarian cancers arise in the fallopian tube and not the ovary. This led to the recommendation that opportunistic salpingectomy be offered as an elective concurrent procedure for premenopausal women at average risk of ovarian cancer who undergo either hysterectomy for benign gynecologic conditions or surgical sterilization. It has been estimated that opportunistic salpingectomy could reduce the ovarian cancer risk by 20 to 40 over the next 20 years. There are few hard data, however, on the long-term risks and benefits associated with this procedure. Because a clinical trial is not feasible, a population-based cohort study is essential to establish the long-term risks, benefits, and cost-effectiveness of opportunistic salpingectomy. Such a cohort study would take many years to yield results; more timely data on the likely costs and benefits of this strategy could be obtained from a decision analytic model.
- Published
- 2015
- Full Text
- View/download PDF
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