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Last Updated: 01/29/18

2016-2017 SPORE Advances

[+] Bladder

Colin Dinney, M.D. and David McConkey, Ph.D. — UT/MD Anderson SPORE in Genitourinary Cancer

Intravesical rAd-IFNα/Syn3 for patients with high-grade, bacillus calmette-guerin-refractory or relapsed non-muscle-invasive bladder cancer: a phase 2 randomized study.

Lead by: David McConkey, Colin Dinney, and Arlene Siefker-Radtke (Project 3)

This open-label, multicenter, parallel-arm, phase 2 study assessed the efficacy and safety of recombinant adenovirus interferon alfa (rAd-IFN α) with Syn3, a surfactant, for patients with high-grade BCG-refractory or relapsed non-muscle invasive bladder cancer. Results showed the of the forty patients who received rAd-IFN α-Syn3, 35% remained free of high grade recurrence 12 months after initial treatment, and only two of these complete responders experienced recurrence at 21 and 28 months. This study showed that rAd-IFN α/Syn3 was well tolerated and demonstrated promising efficacy for patients with high-grade non-muscle invasive bladder cancer after BCG therapy who were not able or not willing to undergo radical cystectomy. Based on these results rAd-IFN α/Syn3 is being advanced to a phase 3 study, sponsored by FKD Therapies Oy (Kuopio, Finland).

Publication:
Shore ND, Boorjian SA, Canter DJ, Ogan K, Karsh LI, Downs TM, Gomella LG, Kamat AM, Lotan Y, Svatek RS, Bivalacqua TJ, Grubb RL 3rd, Krupski TL, Lerner SP, Woods ME, Inman BA, Milowsky MI, Boyd A, Treasure FP, Gregory G, Sawutz DG, Yla-Herttuala S, Parker NR, Dinney CPN. J Clin Oncol. 2017 Oct 20;35(30):3410-3416. doi: 10.1200/JCO.2017.72.3064. Epub 2017 Aug 23. PMID: 28834453.

Aurora kinase a is a biomarker for bladder cancer detection and contributes to its aggressive behavior.

Lead by: Bogdan Czerniak and H. Barton Grossman (Project 1)

This study confirmed that overexpression of Aurora kinase A (AURKA) and activation of its downstream pathway was enriched in the basal subtype of primary human bladder cancer, a highly aggressive subtype of the disease.  Whole genome mRNA expression profiling identified nicotinamide N-methyltransferase (NNMT) as a downstream target of AURKA, attenuating NNMT blockage of tumor cell invasion in vitro.  The study also showed that the  FISH test for the AURKA gene copy number in urine yielded a specificity and sensitivity with an AUC of 0.901, a high level of test performance which implicates AURKA as an effective biomarker for bladder cancer for non-invasive detection and monitoring, as well  as a potential therapeutic target, especially for the basal subtype of bladder cancer.  

Publication:
Mobley A, Zhang S, Bondaruk J, Wang Y, Majewski T, Caraway NP, Huang L, Shoshan E, Velazquez-Torres G, Nitti G, Lee S, Lee JG, Fuentes-Mattei E, Willis D, Zhang L, Guo CC, Yao H, Baggerly K, Lotan Y, Lerner SP, Dinney C, McConkey D, Bar-Eli M, Czerniak B. Sci Rep. 2017 Jan 19;7:40714. doi: 10.1038/srep40714. PMID: 28102366.

[+] Brain

Tracy Batchelor, M.D. — Mass General Hospital SPORE: Targeted Therapies for Glioma

Volumetric relationship between 2- hydroxyglutarate and FLAIR hyperintensity has potential implications for radiotherapy planning of mutant IDH glioma patients.

Lead by: Dan Cahill and William Kaelin (Project 3)

Glioma patients with the isocitrate dehydrogenase mutation (IDH mt) receiving adjuvant radiation and chemotherapy can be monitored noninvasively in a prospective longitudinal imaging study. Monitoring progression and planning treatment is augmented by the IDH mt tumor production of high levels of 2-hydroxyglutarate (2HG) which can be measured by 3D magnetic resonance spectroscopic imaging (MRSI). MRI is also used for imaging which depends on Fluid Attenuated Inversion Recovery (FLAIR). This work explores the relationship between 2HG and FLAIR in mutant IDH glioma patients to determine whether 2HG mapping is valuable for radiotherapy planning. IDH mt gliomas were imaged for 2HG volume vs. FLAIR volume. They found for many patients that assessing tumor burden by 2HG volumetric is more extensive than FLAIR volume and may assist in defining tumor regions for radiotherapy treatment and subsequent monitoring.

Publications:
Jafari-Khouzani K, Loebel F, Bogner W, Rapalino O, Gonzalez GR, Gerstner E, Chi AS, Batchelor TT, Rosen BR, Unkelbach J, Shih HA, Cahill DP, Andronesi OC. Neuro Oncol. 2016 Nov;18(11):1569-1578. Epub 2016 Jul 5. PMID: 27382115.

Andronesi OC, Loebel F, Bogner W, Marjańska M, Vander Heiden MG, Iafrate AJ, Dietrich J, Batchelor TT, Gerstner ER, Kaelin WG, Chi AS, Rosen BR, Cahill DP. Treatment Response Assessment in IDH-Mutant Glioma Patients by Noninvasive 3D Functional Spectroscopic Mapping of 2-Hydroxyglutarate. Clin Cancer Res. 2016 Apr 1;22(7):1632-41. doi: 10.1158/1078-0432.CCR-15-0656. Epub 2015 Nov 3. PMID: 26534967.

Mitchel S. Berger, M.D. — University of California, San Francisco Brain Tumor SPORE
Brian O’Neill, M.D. — Mayo Clinic Brain SPORE (Collaboration)

Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT.

Lead by: Margaret Wrench and Kathleen Egan (UCSF, Project 1) and Jeanette Eckel-Passow, Daniel Lachance, and Robert Jenkins (Mayo Clinic, Project 4)

The WHO 2016 Classification of brain tumors has contributed molecular classification and histology to provide an integrated diagnosis, including IDH mutations and 1p/19q codeletion, forming five major WHO 2016 diagnostic categories. This collaboration between the UCSF and Mayo brain SPOREs contributed significantly to this work. Using data from 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) they showed survival for each group and whether or not additional information on tumor TERT mutation or ATRX alteration was significantly associated with survival and could provide additional prognostic information.

Publication:
Pekmezci M, Rice T, Molinaro AM, Walsh KM, Decker PA, Hansen H, Sicotte H, Kollmeyer TM, McCoy LS, Sarkar G, Perry A, Giannini C, Tihan T, Berger MS, Wiemels JL, Bracci PM, Eckel-Passow JE, Lachance DH, Clarke J, Taylor JW, Luks T, Wiencke JK, Jenkins RB, Wrensch MR. Acta Neuropathol. 2017 Jun;133(6):1001-1016. doi: 10.1007/s00401-017-1690-1. Epub 2017 Mar 2. PMID: 28255664.

Mitchel S. Berger, M.D. — University of California, San Francisco Brain Tumor SPORE

Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas.

Lead by: Hideho Okada and Nicholas Butowski (Project 4)

The investigators have demonstrated a mechanism of IDH mutation-mediated immunosuppression where IDH-mutated (IDH-MUT) tumors down-regulate STAT1 expression through overproduction of the oncometabolite R-2-hydroxyglutarate (2HG). Analysis of clinical samples and gene expression data from The Cancer Genome Atlas (TCGA) in IDH-MUT tumors compared with IDH-WT tumors also demonstrated reduced expression of T cell-associated genes and IFN-γ-inducible chemokines, including CXCL10. Preclinical models showed inhibition by IDH-C35, a specific inhibitor of mutant IDH1 reversed the suppression of CXCL10 and resulted in increased T cell accumulation. IDH-C35 also improved the efficacy of vaccine immunotherapy in mice bearing IDH-MUT gliomas. 

Publication:
Kohanbash G, Carrera DA, Shrivastav S, Ahn BJ, Jahan N, Mazor T, Chheda ZS, Downey KM, Watchmaker PB, Beppler C, Warta R, Amankulor NA, Herold-Mende C, Costello JF, Okada H. J Clin Invest. 2017 Apr 3;127(4):1425-1437. doi: 10.1172/JCI90644. Epub 2017 Mar 20. PMID: 28319047.

[+] Breast

Eric Winer, M.D. — Dana-Farber/Harvard SPORE in Breast Cancer

CDK4/6 inhibition triggers anti-tumour immunity.

Lead by: Thomas Roberts and Ian Krop (Project 2)

Drivers of the cell cycle typically are involved in the initiation and progression of various malignancies and thus, ideal targets for therapy. In particular, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors can induce cell cycle arrest in tumor cells. In this study, researchers identify the molecular mechanisms of action involved in preclinical mouse models and confirm this phenomenon through biopsies of ER+/HER2+ breast cancer patients treated with CDK4/6 inhibitor. Their results show that CDK4/6 inhibitors increase tumor immunogenicity and provide a rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer treatment.

Publication:
Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, Khan N, Ubellacker JM, Xie S, Metzger-Filho O, Hoog J, Ellis MJ, Ma CX, Ramm S, Krop IE, Winer EP, Roberts TM, Kim HJ, McAllister SS, Zhao JJ. Nature. 2017 Aug 24;548(7668):471-475. doi: 10.1038/nature23465. Epub 2017 Aug 16. PMID: 28813415.

Matthew Goetz, M.D. — Mayo Clinic, Rochester SPORE in Breast Cancer
Jennifer Pietenpol, Ph.D. and Ingrid Mayer, M.D., M.S.C.I. — Vanderbilt University Breast SPORE (Collaboration)

Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women.

Lead by: Jennifer Pietenpol and Scott Hiebert (Vanderbilt, Developmental Research Program) and James Ingle (Mayo Clinic Rochester, Developmental Research Program)

Atypical hyperplasia (AH) has been recognized as a group that has increased risk for breast cancer. This study included 708 Mayo and 466 Nashville AH subjects. Histology review quantified the number of foci of atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH). BC risk was stratified for number of AH foci within AH subtypes. In two independent cohort studies of benign breast disease (Mayo cohort and Nashville cohort), extent of atypia stratifies long-term breast cancer risk for ADH and ALH.

Publication:
Degnim AC, Dupont WD, Radisky DC, Vierkant RA, Frank RD, Frost MH, Winham SJ, Sanders ME, Smith JR, Page DL, Hoskin TL, Vachon CM, Ghosh K, Hieken TJ, Denison LA, Carter JM, Hartmann LC, Visscher DW. Cancer. 2016 October;122(19):2971-8. PMID: 27352219.

Jennifer Pietenpol, Ph.D. and Ingrid Mayer, M.D., M.S.C.I. — Vanderbilt University Breast SPORE

Extracellular matrix/integrin signaling promotes resistance to combined inhibition of HER2 and PI3K in HER2(+) breast cancer.

Lead by: Carlos Arteaga and Ingrid Mayer (Project 1)

Understanding the molecular nature of resistance to HER-2 targeted therapies could improve breast cancer therapies. Although PIK3CA mutations are associated with resistance to HER2-targeted therapies, HER2+/PIK3CAH1047R transgenic mammary tumors respond to PI3K inhibitor buparlisib (TPB). Researchers sought to identified mechanisms of resistance to combined inhibition of HER2 and PI3K. Data suggest that upregulation of collagen/integrin/Src signaling contributes to resistance to combinatorial HER2 and PI3K inhibition.

Publication:
Hanker AB, Estrada MV, Bianchini G, Moore PD, Zhao J, Cheng F, Koch JP, Gianni L, Tyson DR, Sánchez V, Rexer BN, Sanders ME, Zhao Z, Stricker TP, Arteaga CL. Cancer Res. 2017 Jun 15;77(12):3280-3292. doi: 10.1158/0008-5472.CAN-16-2808. Epub 2017 Apr 10. PMID: 28396358; PMCID: PMC5482178.

[+] Gastrointestinal

Sanford Markowitz, M.D., Ph.D. — Case Western GI Cancer SPORE

Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer

Lead by: Jennifer Eads and Zenghe Wange (Project 4)

Recent studies from the Case GI SPORE has led to a better understanding of the mechanism by which cancer cells (colorectal cancer cells in particular) leverage glutamine as an energy source to replenish the TCA cycle and generate ATP. The investigators show that oncogenic PIK3CA mutations reprogram metabolism in colorectal cancer cells so that they are more dependent on glutamine and suggest that targeting glutamine metabolism may be an effective therapy.

Publication:
Hao Y, Samuels Y, Li Q, Krokowski D, Guan BJ, Wang C, Jin Z, Dong B, Cao B, Feng X, Xiang M, Xu C, Fink S, Meropol NJ, Xu Y, Conlon RA, Markowitz S, Kinzler KW, Velculescu VE, Brunengraber H, Willis JE, LaFramboise T, Hatzoglou M, Zhang GF, Vogelstein B, Wang Z. Nat Commun. 2016 Jun 20;7:11971. doi: 10.1038/ncomms11971. PMID: 27321283.

Adverse clinical outcome associated with mutations that typify African American colorectal cancers.

Lead by: Joseph Willis, Zenghe Wang, and Li Li (Project 2)

These investigators recently described a panel of 15 genes that are significantly more likely to be mutated in colorectal cancers from African Americans than from Caucasians. This study focused on the outcomes associated with these mutations in African American colorectal cancer patients. Carriers of mutations in these genes were more likely to have poor outcomes, such as metastatic disease and relapse, than African American patients who were not carrying these mutations.

Publication:
Wang Z, Li L, Guda K, Chen Z, Barnholtz-Sloan J, Park YS, Markowitz SD, Willis J. J Natl Cancer Inst. 2016 Aug 31;108(12). pii: djw164. doi: 10.1093/jnci/djw164. Print 2016 Dec. PMID: 27582379.

Robert Coffey, MD — Vanderbilt GI Cancer SPORE

Development of a glutamine transport inhibitor: a novel therapeutic strategy in oncology.

Lead by: Jordan Berlin and Charles Manning (Project 2)

This study is capitalizing on new information regarding the role of glutamine metabolism in colorectal cancer. Investigators from the Vanderbilt SPORE have developed a new drug, V-9302, that targets the glutamine transporter ASCT2 and blocks transmembrane glutamine flux. They show that this agent arrests tumor growth in multiple mouse models of colorectal cancer.

Publication:
Schulte M, Fu A, Zhao P, Li J, Geng L, Smith st, Kondo J, Coffey RJ, Johnson MO, Rathmell JC, Sharick JT, Skala MC, Smith JA, Berlin J, Washington MK, Nickels ML, Manning HC. Nature Medicine, in press.

Mechanism of cetuximab resistance in colorectal cancer.

Lead by: Robert Coffey and Ken Lau (Project 2)

The investigators found that colorectal cancer cells growing in vitro in the presence of collagen exhibit either a cystic colony morphology or spiky colony morphology. The anti-EGFR antibody cetuximab inhibited growth of the cystic type of colonies, but the spiky colonies were resistant. Spiky colony resistance was associated with tyrosine phosphorylation of Met and Ron as well as upregulation of VCAN. VCAN expression strongly correlated with reduced survival and could potentially be used as a prognostic marker. In a separate study they showed that another form of colorectal cancer acquired resistance to cetuximab involves an epigenetic cause that has therapeutic implications.

Publications:
Li C, Singh B, Graves-Deal R, Ma H, Starchenko A, Fry WH, Lu Y, Wang Y, Bogatcheva G, Khan MP, Milne GL, Zhao S, Ayers GD, Li N, Hu H, Washington MK, Yeatman TJ, McDonald OG, Liu Q, Coffey RJ. Three-dimensional culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer. Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):E2852-E2861. doi: 10.1073/pnas.1618297114. Epub 2017 Mar 20. PMID: 28320945.

Lu Y, Zhao X, Liu Q, Li C, Graves-Deal R, Cao Z, Singh B, Franklin JL, Wang J, Hu H, Wei T, Yang M, Yeatman TJ, Lee E, Saito-Diaz K, Hinger S, Patton JG, Chung CH, Emmrich S, Klusmann JH, Fan D, Coffey RJ. lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling. Nat Med. 2017 Oct 16. doi: 10.1038/nm.4424. [Epub ahead of print] PMID: 29035371.

Adam Bass, M.D. and Nabeel Bardeesy, PhD — Dana Farber/Harvard Cancer Center GI Cancer SPORE

Tumor heterogeneity and lesion-specific response to targeted therapy in colorectal cancer.

Lead by: Ryan Corcoran and Jeffrey Clark (Project 4)

This study focused on understanding how genomic heterogeneity in colorectal cancer (CRC) associated with acquired resistance to targeted agents affects response. Next generation sequencing was used to investigate metastatic biopsies and circulating tumor DNA from a CRC patient undergoing EGFR blockade via cetuximab. The patient subsequently underwent therapy targeting identified oncogenic drivers found via these analyses. These data showed that lesion-specific responses can be driven by distinct resistance mechanisms independently arising within separate tumor lesions within the same patient.

Publication:
Russo M, Siravegna G, Blaszkowsky LS, Corti G, Crisafulli G, Ahronian LG, Mussolin B, Kwak EL, Buscarino M, Lazzari L, Valtorta E, Truini M, Jessop NA, Robinson HE, Hong TS, Mino-Kenudson M, Di Nicolantonio F, Thabet A, Sartore-Bianchi A, Siena S, Iafrate AJ, Bardelli A, Corcoran RB. Cancer Discov. 2016 Feb;6(2):147-153. doi: 10.1158/2159-8290.CD-15-1283. Epub 2015 Dec 7. PMID: 26644315.

[+] Kidney

James Brugarolas, M.D., Ph.D. — UT Southwestern Kidney SPORE

Modeling renal cell carcinoma in mice: BAP1 and PBRM1 inactivation drive tumor grade.

Lead by: Payal Kapur, Thomas Carroll, and Yonghao Yu (Project 2)

Clear cell renal cell carcinoma (ccRCC) is characterized by BAP1 and PBRM1 mutations, which are associated with tumors of different grade and prognosis. BAP1 and PBRM1 conditionally targeted in the mouse with VHL failed to cause tumorigenesis. In contrast, targeting with PAX8, a transcription factor frequently overexpressed in ccRCC, led to ccRCC of different grades. Using ccRCC as a model, the investigators show that BAP1 and PBRM1 loss drives tumor grade, and that the conversion from low grade to high grade can be promoted by activation of mTORC1.

Publication:
Gu YF, Cohn S, Christie A, McKenzie T, Wolff N, Do QN, Madhuranthakam AJ, Pedrosa I, Wang T, Dey A, Busslinger M, Xie XJ, Hammer RE, McKay RM, Kapur P, Brugarolas J. Cancer Discov. 2017 Aug;7(8):900-917. doi:10.1158/2159-8290.CD-17-0292. Epub 2017 May 4. PMID: 28473526.

Targeting HIF-2 for the treatment of clear-cell renal cell carcinoma with a HIF-2 antagonist.

Lead by: James Brugarolas, Kevin Courtney, and Ivan Pedrosa (Project 1)

Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumor suppressor gene (VHL). VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been regarded as undruggable. Here this group uses a tumor graft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. Some VHL-mutant ccRCCs were resistant to PT2399 despite HIF-2 dissociation in tumors and evidence of Hif-2 inhibition. Here a HIF-2-dependent gene signature in sensitive tumors has been identified. Binding site and second site suppressor mutations in HIF-2 α and HIF-1β have been identified. Both mutations preserved HIF-2 dimers despite treatment with PT2399.

Publication:
Chen W, Hill H, Christie A, Kim MS, Holloman E, Pavia-Jimenez A, Homayoun F, Ma Y, Patel N, Yell P, Hao G, Yousuf Q, Joyce A, Pedrosa I, Geiger H, Zhang H, Chang J, Gardner KH, Bruick RK, Reeves C, Hwang TH, Courtney K, Frenkel E, Sun X, Zojwalla N, Wong T, Rizzi JP, Wallace EM, Josey JA, Xie Y, Xie XJ, Kapur P, McKay RM, Brugarolas J. Nature. 2016 Nov 3;539(7627):112-117. doi: 10.1038/nature19796. Epub 2016 Sep 5. PMID: 27595394.

David McDermott, M.D. and William Kaelin Jr., M.D. — Dana-Farber/Harvard Cancer Center Kidney SPORE

Survival analyses of patients with metastatic renal cancer treated with targeted therapy with or without cytoreductive nephrectomy: a National Cancer Data Base Study.

Lead by: Sabina Signoretti, Toni Choueiri, and Rupal Bhatt (Project 3)

The role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) has become unclear since the introduction of targeted therapies (TT). The National Cancer Data Base was used to identify patients with clinical mRCC treated with TT between 2006 and 2013. It was found that CN is performed in three of 10 patients with mRCC who are receiving TT. Several patient and sociodemographic characteristics were associated with receipt of CN. When feasible, CN may offer an OS benefit when combined with TT.

Publication:
Hanna N, Sun M, Meyer CP, Nguyen PL, Pal SK, Chang SL, de Velasco G, Trinh QD, Choueiri TK. J Clin Oncol. 2016 Sep 20;34(27):3267-75. doi: 10.1200/JCO.2016.66.7931. Epub 2016 Jun 20. PMID: 27325852.

[+] Leukemia

Hagop Kantarjian, M.D. — UT/MD Anderson Leukemia SPORE

Incorporating FLT3 inhibitors into acute myeloid leukemia (AML) treatment regimens.

Lead by: Mark Levis and Donald Small (Project 4)

Internal tandem duplication mutations in FLT3 are common in acute myeloid leukemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). The investigators aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukemia. 252 adults with relapsed or refractory acute myeloid leukemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated. One hundred (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete hematological recovery, and 25 (10%) partial remission. Based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials sponsored by Astellas Pharma Inc.

Publication:
Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, Claxton D, Erba HP, Gill S, Goldberg S, Jurcic JG, Larson RA, Liu C, Ritchie E, Schiller G, Spira AI, Strickland SA, Tibes R, Ustun C, Wang ES, Stuart R, Röllig C, Neubauer A, Martinelli G, Bahceci E, Levis M. Lancet Oncol. 2017 Aug;18(8):1061-1075. doi: 10.1016/S1470-2045(17)30416-3. Epub 2017 Jun 20 PMID: 28645776.

Daniel Link, M.D. — Washington University Leukemia SPORE

RNA splicing modulators for MDS/AML.

Lead by: Timothy Graubert and Matthew Walter (Project 3)

Somatic mutations in spliceosome genes are detectable in ~50% of patients with myelodysplastic syndromes (MDS). Here the investigators utilize sudemycin compounds that modulate pre-mRNA splicing. Hematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, had an increased sensitivity to in vitro sudemycin treatment relative to controls. The data suggest a potential for treating hematological cancers harboring U2AF1 mutations with pre-mRNA splicing modulators like sudemycins.

Publication:
Shirai CL, White BS, Tripathi M, Tapia R, Ley JN, Ndonwi M, Kim S, Shao J, Carver A, Saez B, Fulton RS, Fronick C, O'Laughlin M, Lagisetti C, Webb TR, Graubert TA, Walter MJ. Nat Commun. 2017 Jan 9;8:14060. doi: 10.1038/ncomms14060. PMID: 28067246.

[+] Lung

Roy Herbst, M.D. — Yale Lung Cancer SPORE

Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer.

Lead by: Lieping Chin, Scott Gettinger, and David Rimm (Project 1)

The project attempts to demonstrate PD-L1 protein distribution in NSCLC tumors using both conventional immunohistochemistry and quantitative immunofluorescence and compare results obtained using 2 different PD-L1 antibodies. Objective determination of PD-L1 protein levels in NSCLC reveals heterogeneity within tumors and prominent interassay variability or discordance. This could be due to different antibody affinities, limited specificity, or distinct target epitopes. Efforts to determine the clinical value of these observations are under way.

Publication:
McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, Velcheti V, Herbst R, LoRusso P, Rimm DL. JAMA Oncol. 2016 Jan;2(1):46-54. doi: 10.1001/jamaoncol.2015.3638. Erratum in: JAMA Oncol. 2016 Jan;2(1):146. PMID: 26562159.

Roy Herbst, M.D. — Yale Lung Cancer SPORE
Ruth Halaban, Ph.D. — Yale SPORE in Skin Cancer (Collaboration)

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.

Lead by: Leiping Chen (Lung Project 1, Melanoma Project 2), Scott Gettinger and David Rimm (Lung Project 1), and Mario Sznol (Melanoma Project 2)

In this collaborative clinical trial between the Yale Lung Cancer and Melanoma SPOREs pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases.

Publication:
Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, Tsiouris AJ, Cohen J, Vortmeyer A, Jilaveanu L, Yu J, Hegde U, Speaker S, Madura M, Ralabate A, Rivera A, Rowen E, Gerrish H, Yao X, Chiang V, Kluger HM. Lancet Oncol. 2016 Jul;17(7):976-983. doi: 10.1016/S1470-2045(16)30053-5. Epub 2016 Jun 3. PMID: 27267608.

Paul Bunn, M.D. — University of Colorado Lung Cancer SPORE
(Collaboration with former Moffitt Lung Cancer SPORE led by Eric Haura)

ZEB1 mediates acquired resistance to the epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer.

Lead by: Harry Drabkin, Robert Gemill, and Daniel Chan (University of Colorado, Project 1)

In this collaboration between the Colorado and Moffitt Lung Cancer SPOREs a new mechanism of acquired resistance to epidermal growth factor tyrosine kinase inhibitors is described. Epithelial-mesenchymal transition (EMT) is one mechanism of acquired resistance to inhibitors of the epidermal growth factor receptor-tyrosine kinases (EGFR-TKIs) in non-small cell lung cancer (NSCLC). The precise mechanisms of EMT-related acquired resistance to EGFR-TKIs in NSCLC remain unclear. Using gene expression arrays in cell lines and patrient specimens, the team established a role of the ZEB1, a zinc-finger E-box-binding transcription factor that regulates expression of E- and N-cadherins.

Publication:
Yoshida T, Song L, Bai Y, Kinose F, Li J, Ohaegbulam KC, Muñoz-Antonia T, Qu X, Eschrich S, Uramoto H, Tanaka F, Nasarre P, Gemmill RM, Roche J, Drabkin HA, Haura EB. PLoS One. 2016 Jan 20;11(1):e0147344. doi: 10.1371/journal.pone.0147344. eCollection 2016. PMID: 26789630.

John Minna, M.D. and Jack Roth, M.D. — UT Southwestern and M. D. Anderson Cancer Center Lung Cancer SPORE

Metabolic heterogeneity in human lung tumors.

Lead by: John Minna and Gao Bonning (Project 1)

Non-small cell lung cancer (NSCLC) is heterogeneous in the genetic and environmental parameters that influence cell metabolism in culture. The work assessed the impact of these factors on human NSCLC metabolism in vivo using intraoperative (13)C-glucose infusions in nine NSCLC patients to compare metabolism between tumors and benign lung. While enhanced glycolysis and glucose oxidation were common among these tumors, the authors observed evidence for oxidation of multiple nutrients in each of them, including lactate as a potential carbon source. Moreover, metabolically heterogeneous regions were identified within and between tumors, and surprisingly, the data suggested potential contributions of non-glucose nutrients in well-perfused tumor areas. The findings not only demonstrate the heterogeneity in tumor metabolism in vivo but also highlight the strong influence of the microenvironment on this feature.

Publication:
Hensley CT, Faubert B, Yuan Q, Lev-Cohain N, Jin E, Kim J, Jiang L, Ko B, Skelton R, Loudat L, Wodzak M, Klimko C, McMillan E, Butt Y, Ni M, Oliver D, Torrealba J, Malloy CR, Kernstine K, Lenkinski RE, DeBerardinis RJ. Cell. 2016 Feb 11;164(4):681-94. doi: 10.1016/j.cell.2015.12.034. Epub 2016 Feb 4. PMID: 26853473.

[+] Lymphoma

Helen Heslop, M.D. — Baylor College of Medicine Lymphoma SPORE

Tonic 4-1BB costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent.

Lead by: Ann Leen, Juan Vera, George Carrum, and Premal Lulla (Project 1)

Antigen-independent tonic signaling by chimeric antigen receptors (CARs) can increase differentiation and exhaustion of T cells, limiting their potency. Incorporating 4-1BB costimulation in CARs may enable T cells to resist this functional exhaustion; however, the potential ramifications of tonic 4-1BB signaling in CAR T cells remain unclear. Here, the investigators found that tonic CAR-derived 4-1BB signaling can produce toxicity in T cells via continuous TRAF2-dependent activation of the nuclear factor κB (NF-κB) pathway and augmented FAS-dependent cell death. This mechanism was amplified in a non-self-inactivating gammaretroviral vector through positive feedback on the long terminal repeat (LTR) promoter, further enhancing CAR expression and tonic signaling. Attenuating CAR expression by substitution with a self-inactivating lentiviral vector minimized tonic signaling and improved T cell expansion and anti-tumor function.

Publication:
Gomes-Silva D, Mukherjee M, Srinivasan M, Krenciute G, Dakhova O, Zheng Y, Cabral JMS, Rooney CM, Orange JS, Brenner MK, Mamonkin M. Cell Rep. 2017 Oct 3;21(1):17-26. doi: 10.1016/j.celrep.2017.09.015. PMID: 28978471.

George Weiner, M.D. and Thomas Witzig, M.D. — University of Iowa Lymphoma SPORE

Everolimus combined with R-CHOP-21 for new, untreated, diffuse large B-cell lymphoma (NCCTG 1085 [Alliance]): safety and efficacy results of a phase 1 and feasibility trial.

Lead by: George Weiner, Yi Lin, Brian Link, Haidong Dong, John Houtman, and Thomas Witzig (Project 2)

The PI3K-mTORC pathway is upregulated in diffuse large B-cell lymphoma (DLBCL) and can be targeted with the mTOR complex 1 (mTORC1) inhibitor everolimus. Everolimus has activity in relapsed DLBCL. These data provide the rationale to combine everolimus with standard treatment for DLBCL of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone delivered in a 21-day cycle (R-CHOP-21) for six cycles. A phase 1 and feasibility study (NCCTG 1085) of oral everolimus 10 mg/day plus R-CHOP-21 was performed in patients aged at least 18 years with new, untreated, CD20-positive DLBCL (stages II-IV) in the NCCTG (Alliance) National Cancer Institute National Clinical Trials Network (USA). The mTORC1 inhibitor everolimus given for 14 days in combination with R-CHOP-21 for patients with DLBCL is safe. These findings suggest that drugs that target the PI3K-mTORC pathway add benefit when combined with standard R-CHOP. The everolimus with R-CHOP regimen should be tested against standard R-CHOP alone in a randomised trial, to support the benefits of this novel combination noted in this study.

Publication:
Johnston PB, LaPlant B, McPhail E, Habermann TM, Inwards DJ, Micallef IN, Colgan JP, Nowakowski GS, Ansell SM, Witzig TE. Lancet Haematol. 2016 Jul;3(7):e309-16. doi: 10.1016/S2352-3026(16)30040-0. Epub 2016 Jun 5. PMID: 27374464.

Anas Younes M.D. and Andrew Zelenetz, M.D., Ph.D. — Memorial Sloan Kettering SPORE in Lymphoma

Ibrutinib unmasks critical role of bruton tyrosine kinase in primary CNS lymphoma.

Lead by: John Leonard and Ari Melnick (Project 3)

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. The investigators performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs.

Publication:
Grommes C, Pastore A, Palaskas N, Tang SS, Campos C, Schartz D, Codega P, Nichol D, Clark O, Hsieh WY, Rohle D, Rosenblum M, Viale A, Tabar VS, Brennan CW, Gavrilovic IT, Kaley TJ, Nolan CP, Omuro A, Pentsova E, Thomas AA, Tsyvkin E, Noy A, Palomba ML, Hamlin P, Sauter CS, Moskowitz CH, Wolfe J, Dogan A, Won M, Glass J, Peak S, Lallana EC, Hatzoglou V, Reiner AS, Gutin PH, Huse JT, Panageas KS, Graeber TG, Schultz N, DeAngelis LM, Mellinghoff IK. Cancer Discov. 2017 Sep;7(9):1018-1029. doi: 10.1158/2159-8290.CD-17-0613. Epub 2017 Jun 15. PMID: 28619981.

[+] Myeloma

Peter L. Bergsagel, M.D. — Mayo Clinic Multiple Myeloma SPORE

IAP antagonists induce anti-tumor immunity in multiple myeloma.

Lead by: Martha Chesi and Asher Chanan-Khan (Project 2)

Small-molecule IAP (inhibitors of apoptosis) antagonists have entered clinical trials for their ability to induce tumor necrosis factor (TNF)-mediated apoptosis of cancer cells. However, cIAP1 and cIAP2 are recurrently homozygously deleted in multiple myeloma (MM), resulting in constitutive activation of the noncanonical nuclear factor (NF)-κB pathway. In this study a robust in vivo anti-myeloma activity of an IAP antagonist in a transgenic myeloma mouse model and in patients with relapsed-refractory MM was observed, where the addition of cyclophosphamide resulted in a median progression-free-survival of 10 months. This effect was not a result of direct induction of tumor cell death, but rather of upregulation of tumor-cell-autonomous type I interferon (IFN) signaling and a strong inflammatory response that resulted in the activation of macrophages and dendritic cells, leading to phagocytosis of tumor cells. Treatment of a MM mouse model with LCL161 established long-term anti-tumor protection and induced regression in a fraction of the mice. Notably, combination of LCL161 with the immune-checkpoint inhibitor anti-PD1 was curative in all of the treated mice.

Publication:
Chesi M, Mirza NN, Garbitt VM, Sharik ME, Dueck AC, Asmann YW, Akhmetzyanova I, Kosiorek HE, Calcinotto A, Riggs DL, Keane N, Ahmann GJ, Morrison KM, Fonseca R, Lacy MQ, Dingli D, Kumar SK, Ailawadhi S, Dispenzieri A, Buadi F, Gertz MA, Reeder CB, Lin Y, Chanan-Khan AA, Stewart AK, Fooksman D, Bergsagel PL. Nat Med. 2016 Dec;22(12):1411-1420. doi: 10.1038/nm.4229. Epub 2016 Nov 14. PMID: 27841872.

Kenneth Anderson, M.D. — Dana-Farber/Harvard Cancer Center Myeloma SPORE

MUC1-C drives MYC in multiple myeloma (MM).

Lead by: Donald Kuffe and Teru Hideshima (Project 3)

The present studies demonstrate that targeting MUC1-C with silencing by clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 editing or with the GO-203 inhibitor is associated with downregulation of MYC messenger RNA and protein. The results show that MUC1-C occupies the MYC promoter and thereby activates the MYC gene by a β-catenin/transcription factor 4 (TCF4)-mediated mechanism. The findings collectively provide convincing evidence that MUC1-C drives MYC expression in MM.

Publication:
Tagde A, Rajabi H, Bouillez A, Alam M, Gali R, Bailey S, Tai YT, Hideshima T, Anderson K, Avigan D, Kufe D. Blood. 2016 May 26;127(21):2587-97. doi: 10.1182/blood-2015-07-659151. Epub 2016 Feb 23. PMID: 26907633.

Anti-CD38 antibody SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide.

Lead by: Kenneth Anderson and Dharminder Chauhan (Project 1)

The anti-CD38 monoclonal antibody SAR650984 (SAR) is showing promising clinical activity in treatment of relapsed and refractory multiple myeloma (MM). Besides effector-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, the authors define molecular mechanisms of SAR-directed MM cell death and enhanced anti-MM activity triggered by SAR with Pomalidomide (Pom). SAR is the first therapeutic monoclonal antibody mediating direct cytotoxicity against MM cells via multiple mechanisms of action. The data show that Pom augments both direct and effector cell-mediated MM cytotoxicity of SAR, providing the framework for combination clinical trials.

Publication:
Jiang H, Acharya C, An G, Zhong M, Feng X, Wang L, Dasilva N, Song Z, Yang G, Adrian F, Qiu L, Richardson P, Munshi NC, Tai YT, Anderson KC. Leukemia. 2016 Feb;30(2):399-408. doi: 10.1038/leu.2015.240. Epub 2015 Sep 4. PMID: 26338273.

[+] Ovarian

Scott Kaufmann, M.D., Ph.D. — Mayo Clinic, Rochester SPORE in Ovarian Cancer

Pooled clustering of high-grade serous ovarian cancer gene expression leads to novel consensus subtypes associated with survival and surgical outcomes.

Lead by: Ellen Goode and Lynn Hartmann (Career Enhancement Program)

Researchers assess whether molecular subtyping identifies biological features of tumors that correlate with survival and surgical outcomes of high-grade serous ovarian cancer (HGSOC). Consensus clustering of pooled mRNA expression data from over 2,000 HGSOC cases was used to define 5 molecular subtypes (mesenchymal, immunoreactive, proliferative, differentiated, anti-mesenchymal) of HGSOCs. This de novo classification scheme was then applied to 381 Mayo Clinic HGSOC patients with detailed survival and surgical outcome information. Molecular subtypes were significantly associated with overall survival and with rate of optimal surgical debulking. Mesenchymal tumors may have features that were associated with less favorable surgical outcome while immunoreactive and anti-mesenchymal were associated with better prognosis. Thus, molecular subtyping may have future utility in guiding neoadjuvant treatment decisions for women with HGSOC.

Wang C, Armasu SM, Kalli KR, Maurer MJ, Heinzen EP, Keeney GL, Cliby WA, Oberg AL, Kaufmann SH, Goode EL. Clin Cancer Res. 2017 Aug 1;23(15):4077-4085. doi: 10.1158/1078-0432.CCR-17-0246. Epub 2017 Mar 9. PMID: 28280090.

[+] Pancreatic

Tony Hollingsworth, Ph.D. — University of Nebraska Pancreatic Cancer SPOR

MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer.

Lead by: Pankaj Singh and Jean Grem (Project 4)

The investigators discovered a common mechanism for gemcitabine resistance in pancreatic cancers that involves increased glycolytic flux which leads to glucose addiction. Associated with this is an increase in pyrimidine biosynthesis to boost dCTP levels which, in turn, reduce effect levels of gemcitabine through molecular competitition. MUC-1 regulated stabilization of HIF-1alpha appears to mediate the necessary metabolic reprogramming.

Publication:
Shukla SK, Purohit V, Mehla K, Gunda V, Chaika NV, Vernucci E, King RJ, Abrego J, Goode GD, Dasgupta A, Illies AL, Gebregiworgis T, Dai B, Augustine JJ, Murthy D, Attri KS, Mashadova O, Grandgenett PM, Powers R, Ly QP, Lazenby AJ, Grem JL, Yu F, Matés JM, Asara JM, Kim JW, Hankins JH, Weekes C, Hollingsworth MA, Serkova NJ, Sasson AR, Fleming JB, Oliveto JM, Lyssiotis CA, Cantley LC, Berim L, Singh PK. Cancer Cell. 2017 Sep 11;32(3):392. doi: 10.1016/j.ccell.2017.08.008. PMID: 28898700.

[+] Prostate

Howard Scher, M.D. — Memorial Sloan Kettering Cancer Center Prostate SPORE

SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer.

Lead by: Charles Sawyers and Howard Scher (Project 3)

Using in vitro and in vivo human prostate cancer models this study revealed that tumors can develop resistance to enzalutamide, a second generation anti-androgen, by a phenotypic shift from androgen receptor (AR) dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity, which occurs with the functional loss TP53 and RB1, was found to be enabled by SOX2 expression and could be reversed by restoring the function of TP53 and RB1 or by inhibiting SOX2 expression.

Publication:
Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen CC, Wongvipat J, Ku SY, Gao D, Cao Z, Shah N, Adams EJ, Abida W, Watson PA, Prandi D, Huang CH, de Stanchina E, Lowe SW, Ellis L, Beltran H, Rubin MA, Goodrich DW, Demichelis F, Sawyers CL. Science. 2017 Jan 6;355(6320):84-88. doi: 10.1126/science.aah4307. PMID: 28059768.

[+] Skin

Patrick Hwu, M.D. and Elizabeth Grimm, Ph.D. — The University of Texas MD Anderson Cancer Center SPORE in Melanoma

Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual.

Lead by: Jeffrey Gershenwald, Victor Prieto, Alexander Lazar, Lauren Haydu (Pathology Core)

A revised manual by the American Joint Committee on Cancer (AJCC) for staging melanoma was issued based on an international database housed at MD Anderson and headed by members of the SPORE biospecimen core. Samples were collected worldwide since 1998 of melanoma tumors at stages I-III from over 49,000 patients. The revised staging includes updated nomenclature and several important changes to the Tumor, Nodes, Metastasis (TNM) classification and stage grouping criteria. This evidence-based revision of the AJCC melanoma staging system will guide prognosis, planning treatments, and stratifying patients for clinical trials. Also, it supports a centralized cancer registry for the design, conduct, and analysis of clinical trials.

Publication:
Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, Lazar AJ, Faries MB, Kirkwood JM, McArthur GA, Haydu LE, Eggermont AMM, Flaherty KT, Balch CM, Thompson JF; for members of the American Joint Committee on Cancer Melanoma Expert Panel and the International Melanoma Database and Discovery Platform. CA Cancer J Clin. 2017 Oct 13. doi: 10.3322/caac.21409. [Epub ahead of print] PMID: 29028110.

[+] Thyroid

James A. Fagin, M.D. — MSKCC SPORE in Thyroid Cancer

Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.

Lead by: James Fagin and Steve Larson (Project 2)

This study determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer. A small increase in ERK inhibition markedly increased the expression of thyroid differentiation genes, increased iodide accumulation in cancer cells, and thereby improved responses to Radioiodide (RAI) therapy. Only a short exposure to the drug was necessary to obtain a maximal response to RAI. These data suggest that potent inhibition of ERK signaling is required to adequately induce iodide uptake and indicate that this is a promising strategy for the treatment of BRAF-mutant thyroid cancer.

Publication:
Nagarajah J, Le M, Knauf JA, Ferrandino G, Montero-Conde C, Pillarsetty N, Bolaender A, Irwin C, Krishnamoorthy GP, Saqcena M, Larson SM, Ho AL, Seshan V, Ishii N, Carrasco N, Rosen N, Weber WA, Fagin JA. 2016 Nov 1;126(11):4119-4124. doi: 10.1172/JCI89067. Epub 2016 Sep 26. PMID: 27669459.

Matthew Ringel, M.D. — Ohio State University SPORE in Thyroid Cancer

A genome-wide association study yields five novel thyroid cancer risk loci.

Lead by: Albert de la Chapelle and Rebecca Nagy (Project 1)

This collaborative GWAS study included a total of 3,001 patients and 287,550 controls from five study groups of European descent. The Ohio cohort of 1580 cases/1628 controls was used in the discovery phase. The results produced five novel risk loci (all with P values <3 × 10-8): 1q42.2 (rs12129938 in PCNXL2), 3q26.2 (rs6793295 a missense mutation in LRCC34 near TERC), 5q22.1 (rs73227498 between NREP and EPB41L4A), 10q24.33 (rs7902587 near OBFC1), and two independently risk associated variants at 15q22.33 (rs2289261 and rs56062135; both in SMAD3). The study also confirmed recently published association results from a Chinese study of a variant on 5p15.33 (rs2736100 near the TERT gene) and presented a stronger association result for a moderately correlated variant (rs10069690; OR=1.20, P=3.2 × 10-7) based on our study of individuals of European ancestry. In combination, these results create ample opportunities for future studies into the pathogenesis of thyroid cancer and clinical implications thereof.

Publication:
Gudmundsson J, Thorleifsson G, Sigurdsson JK, Stefansdottir L, Jonasson JG, Gudjonsson SA, Gudbjartsson DF, Masson G, Johannsdottir H, Halldorsson GH, Stacey SN, Helgason H, Sulem P, Senter L, He H, Liyanarachchi S, Ringel MD, Aguillo E, Panadero A, Prats E, Garcia-Castaño A, De Juan A, Rivera F, Xu L, Kiemeney LA, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Kristvinsson H, Netea-Maier RT, Jonsson T, Mayordomo JI, Plantinga TS, Hjartarson H, Hrafnkelsson J, Sturgis EM, Thorsteinsdottir U, Rafnar T, de la Chapelle A, Stefansson K. Nat Commun. 2017 Feb 14;8:14517. doi: 10.1038/ncomms14517. PMID: 28195142.

Papillary thyroid carcinoma: association between germline DNA variant markers and clinical parameters.

Lead by: Albert de la Chapelle and Rebecca Nagy (Project 1)

To determine the utility of germline genetic analyses in papillary thyroid carcinoma (PTC) management, the genotypes of five GWAS SNPs (rs965513, rs944289, rs116909374, rs2439302, and rs966423) were determined in 1216 PTC patients and 1416 controls. Additionally, the expression of seven genes harboring or proximal to these variants (PTCSC3, MBIP, NKX2-1, FOXE1, DIRC3, PTCSC2, and NRG1) was measured in 73 PTC paired tumor/normal tissues, respectively. Association analyses were performed between the genotypes of the germline variants and the levels of gene expression with clinical/pathological features such as age, sex, TNM staging, multifocality status, extrathyroidal expansion, and MACIS score. The results demonstrated that the studied germline risk alleles predisposing to PTC were associated with a more aggressive disease course reflected by higher tumor diameter, multifocality rate, and advanced N stage at the time of diagnosis. Ultimately, these results demonstrated that germline variants not only predispose to PTC but also might impact clinical course.

Publication:
Jendrzejewski J, Liyanarachchi S, Nagy R, Senter L, Wakely PE, Thomas A, Nabhan F, He H, Li W, Sworczak K, Ringel MD, Kirschner LS, de la Chapelle A. Thyroid. 2016 Sep;26(9):1276-84. doi: 10.1089/thy.2015.0665. Epub 2016 Jul 22. PMID: 27342578.