Sir Peter MacCallum Department of Oncology - Research Publications

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    BRCA1 Promoter Methylation and Clinical Outcomes in Ovarian Cancer: An Individual Patient Data Meta-Analysis
    Kalachand, RD ; Stordal, B ; Madden, S ; Chandler, B ; Cunningham, J ; Goode, EL ; Ruscito, I ; Braicu, E ; Sehouli, J ; Ignatov, A ; Yu, H ; Katsaros, D ; Mills, GB ; Lu, KH ; Carey, MS ; Timms, KM ; Kupryjanczyk, J ; Rzepecka, IK ; Podgorska, A ; McAlpine, JN ; Swisher, EM ; Bernards, SS ; O'Riain, C ; O'Toole, S ; O'Leary, JJ ; Bowtell, DD ; Thomas, DM ; Prieske, K ; Joosse, SA ; Woelber, L ; Chaudhry, P ; Hafner, N ; Runnebaum, IB ; Hennessy, BT (OXFORD UNIV PRESS INC, 2020-12-01)
    BACKGROUND: BRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal and ovarian cancer (OC) do not consistently support improved survival following platinum chemotherapy. We examine the characteristics of BRCA1-methylated OC in a meta-analysis of individual participant data. METHODS: Data of 2636 participants across 15 studies were analyzed. BRCA1-methylated tumors were defined according to their original study. Associations between BRCA1 methylation and clinicopathological characteristics were evaluated. The effects of methylation on overall survival (OS) and progression-free survival (PFS) were examined using mixed-effects models. All statistical tests were 2-sided. RESULTS: 430 (16.3%) tumors were BRCA1-methylated. BRCA1 methylation was associated with younger age and advanced-stage, high-grade serous OC. There were no survival differences between BRCA1-methylated and non-BRCA1-methylated OC (median PFS = 20.0 vs 18.5 months, hazard ratio [HR] = 1.01, 95% CI = 0.87 to 1.16; P = .98; median OS = 46.6 vs 48.0 months, HR = 1.02, 95% CI = 0.87 to 1.18; P = .96). Where BRCA1/2 mutations were evaluated (n = 1248), BRCA1 methylation displayed no survival advantage over BRCA1/2-intact (BRCA1/2 wild-type non-BRCA1-methylated) OC. Studies used different methods to define BRCA1 methylation. Where BRCA1 methylation was determined using methylation-specific polymerase chain reaction and gel electrophoresis (n = 834), it was associated with improved survival (PFS: HR = 0.80, 95% CI = 0.66 to 0.97; P = .02; OS: HR = 0.80, 95% CI = 0.63 to 1.00; P = .05) on mixed-effects modeling. CONCLUSION: BRCA1-methylated OC displays similar clinicopathological features to BRCA1-mutated OC but is not associated with survival. Heterogeneity within BRCA1 methylation assays influences associations. Refining these assays may better identify cases with silenced BRCA1 function and improved patient outcomes.
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    Glucagonoma Masquerading as a Mucinous Cancer of the Ovary: Lessons from Cell Biology
    Ho, GY ; Ananda, S ; Vandenberg, CJ ; McNally, O ; Tie, J ; Gorringe, K ; Bowtell, D ; Pyman, J ; Wakefield, MJ ; Scott, CL ; Ho, GY ; Frentzas, S (IntechOpen, 2020-06-17)
    High-grade mucinous ovarian cancer (HGMOC) is often a misnomer as the majority of cases are metastatic disease with a gastro-intestinal origin. The standard platinum-based ovarian cancer (OC) chemotherapy regimens are often ineffective, and there are insufficient data to support the use of colorectal cancer (CRC) chemotherapy regimens due to the rarity of HGMOC. We described a cohort of four consecutive suspected HGMOC cases treated at the Royal Women’s Hospital, Melbourne in 2012. Two cases were treated as primary MOC, whereas the other two were considered to be metastatic CRC based on histopathological and clinical evidence. From the RNAseq analysis, we identified two cases of HGMOC whose gene expression profiles were consistent with mucinous epithelial OC, one case that was treated as metastatic CRC with gene expression profile correlated with CRC and one case with neuroendocrine (NET) gene expression features. Interestingly, glucagon was over-expressed in this tumor that was subsequently confirmed by immunohistochemistry. These findings suggest a rare glucagonoma-like NET appendiceal tumor that had metastasized to the surface of ovary and were unresponsive to CRC chemotherapy regimens. In summary, a carefully curated panel of expression markers and selected functional genomics could provide diagnosis and treatment guidance for patients with possible HGMOC.
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    Signal Transduction Pathway Activity in High-Grade, Serous Ovarian Carcinoma Reveals a More Favorable Prognosis in Tumors with Low PI3K and High NF-kappa B Pathway Activity: A Novel Approach to a Long-Standing Enigma
    van Lieshout, L ; van de Stolpe, A ; van der Ploeg, P ; Bowtell, D ; de Hullu, J ; Piek, J (MDPI, 2020-09-01)
    We investigated signal transduction pathway (STP) activity in high-grade serous ovarian carcinoma (HGSC) in relation to progression-free survival (PFS) and overall survival (OS). We made use of signal transduction pathway activity analysis (STA analysis), a novel method to quantify functional STP activity. Activity of the following pathways was measured: androgen receptor (AR), estrogen receptor (ER), phosphoinositide 3-kinase (PI3K), Hedgehog (Hh), Notch, nuclear factor-kappa B (NF-κB), transforming growth factor beta (TGF-β), and Wnt. We selected HGSC samples from publicly available datasets of ovarian cancer tissue, and used repeated k-means clustering to identify pathway activity clusters. PFS and OS of the clusters were analyzed. We used a subset of publicly available dataset GSE9891 (n = 140), where repeated k-means clustering based on PI3K and NF-κB pathway activity in HGSC samples resulted in two stable clusters. The cluster with low PI3K and high NF-κB pathway activity (n = 72) had a more favorable prognosis for both PFS (p = 0.004) and OS (p = 0.001) compared to the high-PI3K and low-NF-κB pathway activity cluster (n = 68). The low PI3K and high NF-κB pathway activity of the favorable prognosis cluster may indicate a more active immune response, while the high PI3K and low NF-κB pathway activity of the unfavorable prognosis cluster may indicate high cell division.
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    Genomic analysis of low-grade serous ovarian carcinoma to identify key drivers and therapeutic vulnerabilities
    Cheasley, D ; Nigam, A ; Zethoven, M ; Hunter, S ; Etemadmoghadam, D ; Semple, T ; Allan, P ; Carey, MS ; Fernandez, ML ; Dawson, A ; Kobel, M ; Huntsman, DG ; Le Page, C ; Mes-Masson, A-M ; Provencher, D ; Hacker, N ; Gao, Y ; Bowtell, D ; deFazio, A ; Gorringe, KL ; Campbell, IG (WILEY, 2020-10-28)
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    ABCC4/MRP4 contributes to the aggressiveness of Myc-associated epithelial ovarian cancer
    Jung, M ; Gao, J ; Cheung, L ; Bongers, A ; Somers, K ; Clifton, M ; Ramsay, EE ; Russell, AJ ; Valli, E ; Gifford, AJ ; George, J ; Kennedy, CJ ; Wakefield, MJ ; Topp, M ; Ho, G-Y ; Scott, CL ; Bowtell, DD ; deFazio, A ; Norris, MD ; Haber, M ; Henderson, MJ (WILEY, 2020-05-08)
    Epithelial ovarian cancer (EOC) is a complex disease comprising discrete histological and molecular subtypes, for which survival rates remain unacceptably low. Tailored approaches for this deadly heterogeneous disease are urgently needed. Efflux pumps belonging to the ATP-binding cassette (ABC) family of transporters are known for roles in both drug resistance and cancer biology and are also highly targetable. Here we have investigated the association of ABCC4/MRP4 expression to clinical outcome and its biological function in endometrioid and serous tumors, common histological subtypes of EOC. We found high expression of ABCC4/MRP4, previously shown to be directly regulated by c-Myc/N-Myc, was associated with poor prognosis in endometrioid EOC (P = .001) as well as in a subset of serous EOC with a "high-MYCN" profile (C5/proliferative; P = .019). Transient siRNA-mediated suppression of MRP4 in EOC cells led to reduced growth, migration and invasion, with the effects being most pronounced in endometrioid and C5-like serous cells compared to non-C5 serous EOC cells. Sustained knockdown of MRP4 also sensitized endometrioid cells to MRP4 substrate drugs. Furthermore, suppression of MRP4 decreased the growth of patient-derived EOC cells in vivo. Together, our findings provide the first evidence that MRP4 plays an important role in the biology of Myc-associated ovarian tumors and highlight this transporter as a potential therapeutic target for EOC.
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    Therapeutic options for mucinous ovarian carcinoma
    Gorringe, KL ; Cheasley, D ; Wakefield, MJ ; Ryland, GL ; Allan, PE ; Alsop, K ; Amarasinghe, KC ; Ananda, S ; Bowtell, DDL ; Christie, M ; Chiew, Y-E ; Churchman, M ; DeFazio, A ; Fereday, S ; Gilks, CB ; Gourley, C ; Hadley, AM ; Hendley, J ; Hunter, SM ; Kaufmann, SH ; Kennedy, CJ ; Kobel, M ; Le Page, C ; Li, J ; Lupat, R ; McNally, OM ; McAlpine, JN ; Pyman, J ; Rowley, SM ; Salazar, C ; Saunders, H ; Semple, T ; Stephens, AN ; Thio, N ; Torres, MC ; Traficante, N ; Zethoven, M ; Antill, YC ; Campbell, IG ; Scott, CL (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2020-03-01)
    OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.
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    Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D
    Yang, X ; Song, H ; Leslie, G ; Engel, C ; Hahnen, E ; Auber, B ; Horvath, J ; Kast, K ; Niederacher, D ; Turnbull, C ; Houlston, R ; Hanson, H ; Loveday, C ; Dolinsky, JS ; LaDuca, H ; Ramus, SJ ; Menon, U ; Rosenthal, AN ; Jacobs, I ; Gayther, SA ; Dicks, E ; Nevanlinna, H ; Aittomaeki, K ; Pelttari, LM ; Ehrencrona, H ; Borg, A ; Kvist, A ; Rivera, B ; Hansen, TVO ; Djursby, M ; Lee, A ; Dennis, J ; Bowtell, DD ; Traficante, N ; Diez, O ; Balmana, J ; Gruber, SB ; Chenevix-Trench, G ; Jensen, A ; Kjaer, SK ; Hogdall, E ; Castera, L ; Garber, J ; Janavicius, R ; Osorio, A ; Golmard, L ; Vega, A ; Couch, FJ ; Robson, M ; Gronwald, J ; Domchek, SM ; Culver, JO ; de la Hoya, M ; Easton, DF ; Foulkes, WD ; Tischkowitz, M ; Meindl, A ; Schmutzler, RK ; Pharoah, PDP ; Antoniou, AC (OXFORD UNIV PRESS INC, 2020-12-01)
    BACKGROUND: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. CONCLUSIONS: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.
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    Prognostic gene expression signature for high-grade serous ovarian cancer
    Millstein, J ; Budden, T ; Goode, EL ; Anglesio, MS ; Talhouk, A ; Intermaggio, MP ; Leong, HS ; Chen, S ; Elatre, W ; Gilks, B ; Nazeran, T ; Volchek, M ; Bentley, RC ; Wang, C ; Chiu, DS ; Kommoss, S ; Leung, SCY ; Senz, J ; Lum, A ; Chow, V ; Sudderuddin, H ; Mackenzie, R ; George, J ; Fereday, S ; Hendley, J ; Traficante, N ; Steed, H ; Koziak, JM ; Kobel, M ; McNeish, IA ; Goranova, T ; Ennis, D ; Macintyre, G ; De Silva, DS ; Ramon y Cajal, T ; Garcia-Donas, J ; Hernando Polo, S ; Rodriguez, GC ; Cushing-Haugen, KL ; Harris, HR ; Greene, CS ; Zelaya, RA ; Behrens, S ; Fortner, RT ; Sinn, P ; Herpel, E ; Lester, J ; Lubinski, J ; Oszurek, O ; Toloczko, A ; Cybulski, C ; Menkiszak, J ; Pearce, CL ; Pike, MC ; Tseng, C ; Alsop, J ; Rhenius, V ; Song, H ; Jimenez-Linan, M ; Piskorz, AM ; Gentry-Maharaj, A ; Karpinskyj, C ; Widschwendter, M ; Singh, N ; Kennedy, CJ ; Sharma, R ; Harnett, PR ; Gao, B ; Johnatty, SE ; Sayer, R ; Boros, J ; Winham, SJ ; Keeney, GL ; Kaufmann, SH ; Larson, MC ; Luk, H ; Hernandez, BY ; Thompson, PJ ; Wilkens, LR ; Carney, ME ; Trabert, B ; Lissowska, J ; Brinton, L ; Sherman, ME ; Bodelon, C ; Hinsley, S ; Lewsley, LA ; Glasspool, R ; Banerjee, SN ; Stronach, EA ; Haluska, P ; Ray-Coquard, I ; Mahner, S ; Winterhoff, B ; Slamon, D ; Levine, DA ; Kelemen, LE ; Benitez, J ; Chang-Claude, J ; Gronwald, J ; Wu, AH ; Menon, U ; Goodman, MT ; Schildkraut, JM ; Wentzensen, N ; Brown, R ; Berchuck, A ; Chenevix-Trench, G ; DeFazio, A ; Gayther, SA ; Garcia, MJ ; Henderson, MJ ; Rossing, MA ; Beeghly-Fadiel, A ; Fasching, PA ; Orsulic, S ; Karlan, BY ; Konecny, GE ; Huntsman, DG ; Bowtell, DD ; Brenton, JD ; Doherty, JA ; Pharoah, PDP ; Ramus, SJ (ELSEVIER, 2020-09-01)
    BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
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    Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium
    Martins, FC ; Couturier, D-L ; Paterson, A ; Karnezis, AN ; Christine, C ; Nazeran, TM ; Odunsi, A ; Gentry-Maharaj, A ; Vrvilo, A ; Hein, A ; Talhouk, A ; Osorio, A ; Hartkopf, AD ; Brooks-Wilson, A ; DeFazio, A ; Fischer, A ; Hartmann, A ; Hernandez, BY ; McCauley, BM ; Karpinskyj, C ; de Sousa, CB ; Hogdall, C ; Tiezzi, DG ; Herpel, E ; Taran, FA ; Modugno, F ; Keeney, G ; Nelson, G ; Steed, H ; Song, H ; Luk, H ; Benitez, J ; Alsop, J ; Koziak, JM ; Lester, J ; Rothstein, JH ; de Andrade, JM ; Lundvall, L ; Paz-Ares, L ; Robles-Diaz, L ; Wilkens, LR ; Garcia, MJ ; Intermaggio, MP ; Alcaraz, M-L ; Brett, MA ; Beckmann, MW ; Jimenez-Linan, M ; Anglesio, M ; Carney, ME ; Schneider, M ; Traficante, N ; Pejovic, N ; Singh, N ; Le, N ; Sinn, P ; Ghatage, P ; Erber, R ; Edwards, R ; Vierkant, R ; Ness, RB ; Leung, S ; Orsulic, S ; Brucker, SY ; Kaufmann, SH ; Fereday, S ; Gayther, S ; Winham, SJ ; Kommoss, S ; Pejovic, T ; Longacre, TA ; McGuire, V ; Rhenius, V ; Sieh, W ; Shvetsov, YB ; Whittemore, AS ; Staebler, A ; Karlan, BY ; Rodriguez-Antona, C ; Bowtell, DD ; Goode, EL ; Hogdall, E ; Candido dos Reis, FJ ; Gronwald, J ; Chang-Claude, J ; Moysich, KB ; Kelemen, LE ; Cook, LS ; Goodman, MT ; Fasching, PA ; Crawford, R ; Deen, S ; Menon, U ; Huntsman, DG ; Kobel, M ; Ramus, SJ ; Pharoah, PDP ; Brenton, JD (SPRINGERNATURE, 2020-06-18)
    BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
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    Genomic footprints of activated telomere maintenance mechanisms in cancer
    Sieverling, L ; Hong, C ; Koser, SD ; Ginsbach, P ; Kleinheinz, K ; Hutter, B ; Braun, DM ; Cortes-Ciriano, I ; Xi, R ; Kabbe, R ; Park, PJ ; Eils, R ; Schlesner, M ; Brors, B ; Rippe, K ; Jones, DTW ; Feuerbach, L (NATURE PUBLISHING GROUP, 2020-02-05)
    Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXXtrunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.