Sir Peter MacCallum Department of Oncology - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 10 of 106
  • Item
    Thumbnail Image
    Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8(+) TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas
    Heinze, K ; Nazeran, TM ; Lee, S ; Kramer, P ; Cairns, ES ; Chiu, DS ; Leung, SCY ; Kang, EY ; Meagher, NS ; Kennedy, CJ ; Boros, J ; Kommoss, F ; Vollert, H-W ; Heitze, F ; du Bois, A ; Harter, P ; Grube, M ; Kraemer, B ; Staebler, A ; Kommoss, FKF ; Heublein, S ; Sinn, H-P ; Singh, N ; Laslavic, A ; Elishaev, E ; Olawaiye, A ; Moysich, K ; Modugno, F ; Sharma, R ; Brand, AH ; Harnett, PR ; DeFazio, A ; Fortner, RT ; Lubinski, J ; Lener, M ; Toloczko-Grabarek, A ; Cybulski, C ; Gronwald, H ; Gronwald, J ; Coulson, P ; El-Bahrawy, MA ; Jones, ME ; Schoemaker, MJ ; Swerdlow, AJ ; Gorringe, KL ; Campbell, I ; Cook, L ; Gayther, SA ; Carney, ME ; Shvetsov, YB ; Hernandez, BY ; Wilkens, LR ; Goodman, MT ; Mateoiu, C ; Linder, A ; Sundfeldt, K ; Kelemen, LE ; Gentry-Maharaj, A ; Widschwendter, M ; Menon, U ; Bolton, KL ; Alsop, J ; Shah, M ; Jimenez-Linan, M ; Pharoah, PDP ; Brenton, JD ; Cushing-Haugen, KL ; Harris, HR ; Doherty, JA ; Gilks, B ; Ghatage, P ; Huntsman, DG ; Nelson, GS ; Tinker, A ; Lee, C-H ; Goode, EL ; Nelson, BH ; Ramus, SJ ; Kommoss, S ; Talhouk, A ; Kobel, M ; Anglesio, MS (Wiley, 2022-04)
  • Item
    No Preview Available
    Estimating the proportion of pathogenic variants from breast cancer case-control data: Application to calibration of ACMG/AMP variant classification criteria
    James, PA ; Fortuno, C ; Li, N ; Lim, BWX ; Campbell, IG ; Spurdle, AB (WILEY-HINDAWI, 2022-07)
    For genes with reliable estimates of disease risk associated with loss-of-function variants, case-control data can be used to estimate the proportion of variants of typical risk effect for defined groups of variants, of relevance for variant classification. A calculation was derived for a maximum likelihood estimate of the proportion of pathogenic variants of typical effect from case-control data and applied to rare variant counts for ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, and RAD51D from published breast cancer studies: BEACCON (5770 familial cases and 5741 controls) and breast cancer risk after diagnostic sequencing (60,466 familial and population-based cases and 53,461 controls). There was significant evidence of pathogenic variants among rare noncoding variants, in particular deeper intronic variants, for BRCA1 (13%, p = 8.3 × 10-7 ), BRCA2 (6%, p = 0.016) and PALB2 (13%, p = 0.001). The estimated proportion of pathogenic missense variants varied markedly between genes, generally with enrichment in familial cases, for example, 9% for BRCA2 versus 60%-90% for CHEK2. Stratifying missense variants by position indicated that, for most genes, location within a functional domain significantly predicted pathogenicity, whereas location outside domains provided robust evidence against pathogenicity. Our approach provides novel insights into the spectrum of pathogenic variants of specific breast cancer genes and has wider application to inform gene-focused specifications of American College of Medical Genetics and Genomics (ACMG)/Association of Molecular Pathology (AMP) codes for variant curation.
  • Item
    Thumbnail Image
    Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes
    Meagher, NS ; Gorringe, KL ; Wakefield, M ; Bolithon, A ; Pang, CNI ; Chiu, DS ; Anglesio, MS ; Mallitt, K-A ; Doherty, JA ; Harris, HR ; Schildkraut, JM ; Berchuck, A ; Cushing-Haugen, KL ; Chezar, K ; Chou, A ; Tan, A ; Alsop, J ; Barlow, E ; Beckmann, MW ; Boros, J ; Bowtell, DDL ; Brand, AH ; Brenton, JD ; Campbell, I ; Cheasley, D ; Cohen, J ; Cybulski, C ; Elishaev, E ; Erber, R ; Farrell, R ; Fischer, A ; Fu, Z ; Gilks, B ; Gill, AJ ; Gourley, C ; Grube, M ; Harnett, PR ; Hartmann, A ; Hettiaratchi, A ; Hogdall, CK ; Huzarski, T ; Jakubowska, A ; Jimenez-Linan, M ; Kennedy, CJ ; Kim, B-G ; Kim, J-W ; Kim, J-H ; Klett, K ; Koziak, JM ; Lai, T ; Laslavic, A ; Lester, J ; Leung, Y ; Li, N ; Liauw, W ; Lim, BWX ; Linder, A ; Lubinski, J ; Mahale, S ; Mateoiu, C ; McInerny, S ; Menkiszak, J ; Minoo, P ; Mittelstadt, S ; Morris, D ; Orsulic, S ; Park, S-Y ; Pearce, CL ; Pearson, J ; Pike, MC ; Quinn, CM ; Mohan, GR ; Rao, J ; Riggan, MJ ; Ruebner, M ; Salfinger, S ; Scott, CL ; Shah, M ; Steed, H ; Stewart, CJR ; Subramanian, D ; Sung, S ; Tang, K ; Timpson, P ; Ward, RL ; Wiedenhoefer, R ; Thorne, H ; Cohen, PA ; Crowe, P ; Fasching, PA ; Gronwald, J ; Hawkins, NJ ; Hogdall, E ; Huntsman, DG ; James, PA ; Karlan, BY ; Kelemen, LE ; Kommoss, S ; Konecny, GE ; Modugno, F ; Park, SK ; Staebler, A ; Sundfeldt, K ; Wu, AH ; Talhouk, A ; Pharoah, PDP ; Anderson, L ; DeFazio, A ; Kobel, M ; Friedlander, ML ; Ramus, SJ (AMER ASSOC CANCER RESEARCH, 2022-12-15)
    PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
  • Item
    Thumbnail Image
    Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
    DeVries, AA ; Dennis, J ; Tyrer, JP ; Peng, P-C ; Coetzee, SG ; Reyes, AL ; Plummer, JT ; Davis, BD ; Chen, SS ; Dezem, FS ; Aben, KKH ; Anton-Culver, H ; Antonenkova, NN ; Beckmann, MW ; Beeghly-Fadiel, A ; Berchuck, A ; Bogdanova, N ; Bogdanova-Markov, N ; Brenton, JD ; Butzow, R ; Campbell, I ; Chang-Claude, J ; Chenevix-Trench, G ; Cook, LS ; DeFazio, A ; Doherty, JA ; Dork, T ; Eccles, DM ; Eliassen, AH ; Fasching, PA ; Fortner, RT ; Giles, GG ; Goode, EL ; Goodman, MT ; Gronwald, J ; Hakansson, N ; Hildebrandt, MAT ; Huff, C ; Huntsman, DG ; Jensen, A ; Kar, S ; Karlan, BY ; Khusnutdinova, EK ; Kiemeney, LA ; Kjaer, SK ; Kupryjanczyk, J ; Labrie, M ; Lambrechts, D ; Le, ND ; Lubinski, J ; May, T ; Menon, U ; Milne, RL ; Modugno, F ; Monteiro, AN ; Moysich, KB ; Odunsi, K ; Olsson, H ; Pearce, CL ; Pejovic, T ; Ramus, SJ ; Riboli, E ; Riggan, MJ ; Romieu, I ; Sandler, DP ; Schildkraut, JM ; Setiawan, VW ; Sieh, W ; Song, H ; Sutphen, R ; Terry, KL ; Thompson, PJ ; Titus, L ; Tworoger, SS ; Van Nieuwenhuysen, E ; Edwards, DV ; Webb, PM ; Wentzensen, N ; Whittemore, AS ; Wolk, A ; Wu, AH ; Ziogas, A ; Freedman, ML ; Lawrenson, K ; Pharoah, PDP ; Easton, DF ; Gayther, SA ; Jones, MR (OXFORD UNIV PRESS INC, 2022-11)
    BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
  • Item
    Thumbnail Image
    Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers
    Hakkaart, C ; Pearson, JF ; Marquart, L ; Dennis, J ; Wiggins, GAR ; Barnes, DR ; Robinson, BA ; Mace, PD ; Aittomaki, K ; Andrulis, IL ; Arun, BK ; Azzollini, J ; Balmana, J ; Barkardottir, RB ; Belhadj, S ; Berger, L ; Blok, MJ ; Boonen, SE ; Borde, J ; Bradbury, AR ; Brunet, J ; Buys, SS ; Caligo, MA ; Campbell, I ; Chung, WK ; Claes, KBM ; Collonge-Rame, M-A ; Cook, J ; Cosgrove, C ; Couch, FJ ; Daly, MB ; Dandiker, S ; Davidson, R ; de la Hoya, M ; de Putter, R ; Delnatte, C ; Dhawan, M ; Diez, O ; Ding, YC ; Domchek, SM ; Donaldson, A ; Eason, J ; Easton, DF ; Ehrencrona, H ; Engel, C ; Evans, DG ; Faust, U ; Feliubadalo, L ; Fostira, F ; Friedman, E ; Frone, M ; Frost, D ; Garber, J ; Gayther, SA ; Gehrig, A ; Gesta, P ; Godwin, AK ; Goldgar, DE ; Greene, MH ; Hahnen, E ; Hake, CR ; Hamann, U ; Hansen, TVO ; Hauke, J ; Hentschel, J ; Herold, N ; Honisch, E ; Hulick, PJ ; Imyanitov, EN ; Isaacs, C ; Izatt, L ; Izquierdo, A ; Jakubowska, A ; James, PA ; Janavicius, R ; John, EM ; Joseph, V ; Karlan, BY ; Kemp, Z ; Kirk, J ; Konstantopoulou, I ; Koudijs, M ; Kwong, A ; Laitman, Y ; Lalloo, F ; Lasset, C ; Lautrup, C ; Lazaro, C ; Legrand, C ; Leslie, G ; Lesueur, F ; Mai, PL ; Manoukian, S ; Mari, V ; Martens, JWM ; McGuffog, L ; Mebirouk, N ; Meindl, A ; Miller, A ; Montagna, M ; Moserle, L ; Mouret-Fourme, E ; Musgrave, H ; Nambot, S ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Yie, JNY ; Nguyen-Dumont, T ; Nikitina-Zake, L ; Offit, K ; Olah, E ; Olopade, OI ; Osorio, A ; Ott, C-E ; Park, SK ; Parsons, MT ; Pedersen, IS ; Peixoto, A ; Perez-Segura, P ; Peterlongo, P ; Pocza, T ; Radice, P ; Ramser, J ; Rantala, J ; Rodriguez, GC ; Ronlund, K ; Rosenberg, EH ; Rossing, M ; Schmutzler, RK ; Shah, PD ; Sharif, S ; Sharma, P ; Side, LE ; Simard, J ; Singer, CF ; Snape, K ; Steinemann, D ; Stoppa-Lyonnet, D ; Sutter, C ; Tan, YY ; Teixeira, MR ; Teo, SH ; Thomassen, M ; Thull, DL ; Tischkowitz, M ; Toland, AE ; Trainer, AH ; Tripathi, V ; Tung, N ; van Engelen, K ; van Rensburg, EJ ; Vega, A ; Viel, A ; Walker, L ; Weitzel, JN ; Wevers, MR ; Chenevix-Trench, G ; Spurdle, AB ; Antoniou, AC ; Walker, LC (NATURE PORTFOLIO, 2022-10-06)
    The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.
  • Item
    Thumbnail Image
    The Clinical and Psychosocial Outcomes for Women Who Received Unexpected Clinically Actionable Germline Information Identified through Research: An Exploratory Sequential Mixed-Methods Comparative Study
    Forrest, LE ; Shepherd, RF ; Tutty, E ; Pearce, A ; Campbell, I ; Devereux, L ; Trainer, AH ; James, PA ; Young, M-A (MDPI, 2022-07)
    Background Research identifying and returning clinically actionable germline variants offer a new avenue of access to genetic information. The psychosocial and clinical outcomes for women who have received this ‘genome-first care’ delivering hereditary breast and ovarian cancer risk information outside of clinical genetics services are unknown. Methods: An exploratory sequential mixed-methods case-control study compared outcomes between women who did (cases; group 1) and did not (controls; group 2) receive clinically actionable genetic information from a research cohort in Victoria, Australia. Participants completed an online survey examining cancer risk perception and worry, and group 1 also completed distress and adaptation measures. Group 1 participants subsequently completed a semi structured interview. Results: Forty-five participants (group 1) and 96 (group 2) completed the online survey, and 31 group 1 participants were interviewed. There were no demographic differences between groups 1 and 2, although more of group 1 participants had children (p = 0.03). Group 1 reported significantly higher breast cancer risk perception (p < 0.001) compared to group 2, and higher cancer worry than group 2 (p < 0.001). Some group 1 participants described how receiving their genetic information heightened their cancer risk perception and exacerbated their cancer worry while waiting for risk-reducing surgery. Group 1 participants reported a MICRA mean score of 27.4 (SD 11.8, range 9−56; possible range 0−95), and an adaptation score of 2.9 (SD = 1.1). Conclusion: There were no adverse psychological outcomes amongst women who received clinically actionable germline information through a model of ‘genome-first’ care compared to those who did not. These findings support the return of clinically actionable research results to research participants.
  • Item
    Thumbnail Image
    Molecular characterization of low-grade serous ovarian carcinoma identifies genomic aberrations according to hormone receptor expression
    Cheasley, D ; Fernandez, ML ; Kobel, M ; Kim, H ; Dawson, A ; Hoenisch, J ; Bittner, M ; Chiu, DS ; Talhouk, A ; Gilks, CB ; Jayawardana, MW ; Pishas, K ; Mes-Masson, A-M ; Provencher, D ; Nigam, A ; Hacker, NF ; Gorringe, KL ; Campbell, IG ; Carey, MS (NATURE PORTFOLIO, 2022-06-29)
    Hormone receptor expression is a characteristic of low-grade serous ovarian carcinoma (LGSOC). Studies investigating estrogen receptor (ER) and progesterone receptor (PR) expression levels suggest its prognostic and predictive significance, although their associations with key molecular aberrations are not well understood. As such, we sought to describe the specific genomic profiles associated with different ER/PR expression patterns and survival outcomes in a cohort of patients with advanced disease. The study comprised fifty-five advanced-staged (III/IV) LGSOCs from the Canadian Ovarian Experimental Unified Resource (COEUR) for which targeted mutation sequencing, copy-number aberration, clinical and follow-up data were available. ER, PR, and p16 expression were assessed by immunohistochemistry. Tumors were divided into low and high ER/PR expression groups based on Allred scoring. Copy number analysis revealed that PR-low tumors (Allred score <2) had a higher fraction of the genome altered by copy number changes compared to PR-high tumors (p = 0.001), with cancer genes affected within specific loci linked to altered peptidyl-tyrosine kinase, MAP-kinase, and PI3-kinase signaling. Cox regression analysis showed that ER-high (p = 0.02), PR-high (p = 0.03), stage III disease (p = 0.02), low residual disease burden (p = 0.01) and normal p16 expression (p<0.001) were all significantly associated with improved overall survival. This study provides evidence that genomic aberrations are linked to ER/PR expression in primary LGSOC.
  • Item
    Thumbnail Image
    Polygenic risk modeling for prediction of epithelial ovarian cancer risk (vol 30, pg 349, 2021)
    Dareng, EO ; Tyrer, JP ; Barnes, DR ; Jones, MR ; Yang, X ; Aben, KKH ; Adank, MA ; Agata, S ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Aravantinos, G ; Arun, BK ; Augustinsson, A ; Balmana, J ; Bandera, EV ; Barkardottir, RB ; Barrowdale, D ; Beckmann, MW ; Beeghly-Fadiel, A ; Benitez, J ; Bermisheva, M ; Bernardini, MQ ; Bjorge, L ; Black, A ; Bogdanova, NV ; Bonanni, B ; Borg, A ; Brenton, JD ; Budzilowska, A ; Butzow, R ; Buys, SS ; Cai, H ; Caligo, MA ; Campbell, I ; Cannioto, R ; Cassingham, H ; Chang-Claude, J ; Chanock, SJ ; Chen, K ; Chiew, Y-E ; Chung, WK ; Claes, KBM ; Colonna, S ; Cook, LS ; Couch, FJ ; Daly, MB ; Dao, F ; Davies, E ; de la Hoya, M ; de Putter, R ; Dennis, J ; DePersia, A ; Devilee, P ; Diez, O ; Ding, YC ; Doherty, JA ; Domchek, SM ; Dork, T ; du Bois, A ; Durst, M ; Eccles, DM ; Eliassen, HA ; Engel, C ; Evans, GD ; Fasching, PA ; Flanagan, JM ; Fortner, RT ; Machackova, E ; Friedman, E ; Ganz, PA ; Garber, J ; Gensini, F ; Giles, GG ; Glendon, G ; Godwin, AK ; Goodman, MT ; Greene, MH ; Gronwald, J ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hamann, U ; Hansen, TVO ; Harris, HR ; Hartman, M ; Heitz, F ; Hildebrandt, MAT ; Hogdall, E ; Hogdall, CK ; Hopper, JL ; Huang, R-Y ; Huff, C ; Hulick, PJ ; Huntsman, DG ; Imyanitov, EN ; Isaacs, C ; Jakubowska, A ; James, PA ; Janavicius, R ; Jensen, A ; Johannsson, OT ; John, EM ; Jones, ME ; Kang, D ; Karlan, BY ; Karnezis, A ; Kelemen, LE ; Khusnutdinova, E ; Kiemeney, LA ; Kim, B-G ; Kjaer, SK ; Komenaka, I ; Kupryjanczyk, J ; Kurian, AW ; Kwong, A ; Lambrechts, D ; Larson, MC ; Lazaro, C ; Le, ND ; Leslie, G ; Lester, J ; Lesueur, F ; Levine, DA ; Li, L ; Li, J ; Loud, JT ; Lu, KH ; Lubinski, J ; Mai, PL ; Manoukian, S ; Marks, JR ; Matsuno, RK ; Matsuo, K ; May, T ; McGuffog, L ; McLaughlin, JR ; McNeish, IA ; Mebirouk, N ; Menon, U ; Miller, A ; Milne, RL ; Minlikeeva, A ; Modugno, F ; Montagna, M ; Moysich, KB ; Munro, E ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Yie, JNY ; Nielsen, HR ; Nielsen, FC ; Nikitina-Zake, L ; Odunsi, K ; Offit, K ; Olah, E ; Olbrecht, S ; Olopade, OI ; Olson, SH ; Olsson, H ; Osorio, A ; Papi, L ; Park, SK ; Parsons, MT ; Pathak, H ; Pedersen, IS ; Peixoto, A ; Pejovic, T ; Perez-Segura, P ; Permuth, JB ; Peshkin, B ; Peterlongo, P ; Piskorz, A ; Prokofyeva, D ; Radice, P ; Rantala, J ; Riggan, MJ ; Risch, HA ; Rodriguez-Antona, C ; Ross, E ; Rossing, MA ; Runnebaum, I ; Sandler, DP ; Santamarina, M ; Soucy, P ; Schmutzler, RK ; Setiawan, VW ; Shan, K ; Sieh, W ; Simard, J ; Singer, CF ; Sokolenko, AP ; Song, H ; Southey, MC ; Steed, H ; Stoppa-Lyonnet, D ; Sutphen, R ; Swerdlow, AJ ; Tan, YY ; Teixeira, MR ; Teo, SH ; Terry, KL ; Terry, MB ; Thomassen, M ; Thompson, PJ ; Thomsen, LCV ; Thull, DL ; Tischkowitz, M ; Titus, L ; Toland, AE ; Torres, D ; Trabert, B ; Travis, R ; Tung, N ; Tworoger, SS ; Valen, E ; van Altena, AM ; van der Hout, AH ; Van Nieuwenhuysen, E ; van Rensburg, EJ ; Vega, A ; Edwards, DV ; Vierkant, RA ; Wang, F ; Wappenschmidt, B ; Webb, PM ; Weinberg, CR ; Weitzel, JN ; Wentzensen, N ; White, E ; Whittemore, AS ; Winham, SJ ; Wolk, A ; Woo, Y-L ; Wu, AH ; Yan, L ; Yannoukakos, D ; Zavaglia, KM ; Zheng, W ; Ziogas, A ; Zorn, KK ; Kleibl, Z ; Easton, D ; Lawrenson, K ; DeFazio, A ; Sellers, TA ; Ramus, SJ ; Pearce, CL ; Monteiro, AN ; Cunningham, JM ; Goode, EL ; Schildkraut, JM ; Berchuck, A ; Chenevix-Trench, G ; Gayther, SA ; Antoniou, AC ; Pharoah, PDP (SPRINGERNATURE, 2022-05)
  • Item
    Thumbnail Image
    Polygenic risk modeling for prediction of epithelial ovarian cancer risk
    Dareng, EO ; Tyrer, JP ; Barnes, DR ; Jones, MR ; Yang, X ; Aben, KKH ; Adank, MA ; Agata, S ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Aravantinos, G ; Arun, BK ; Augustinsson, A ; Balmana, J ; Bandera, E ; Barkardottir, RB ; Barrowdale, D ; Beckmann, MW ; Beeghly-Fadiel, A ; Benitez, J ; Bermisheva, M ; Bernardini, MQ ; Bjorge, L ; Black, A ; Bogdanova, N ; Bonanni, B ; Borg, A ; Brenton, JD ; Budzilowska, A ; Butzow, R ; Buys, SS ; Cai, H ; Caligo, MA ; Campbell, I ; Cannioto, R ; Cassingham, H ; Chang-Claude, J ; Chanock, SJ ; Chen, K ; Chiew, Y-E ; Chung, WK ; Claes, KBM ; Colonna, S ; Cook, LS ; Couch, FJ ; Daly, MB ; Dao, F ; Davies, E ; de la Hoya, M ; de Putter, R ; Dennis, J ; DePersia, A ; Devilee, P ; Diez, O ; Ding, YC ; Doherty, JA ; Domchek, SM ; Dork, T ; du Bois, A ; Durst, M ; Eccles, DM ; Eliassen, HA ; Engel, C ; Evans, GD ; Fasching, PA ; Flanagan, JM ; Fortner, R ; Machackova, E ; Friedman, E ; Ganz, PA ; Garber, J ; Gensini, F ; Giles, GG ; Glendon, G ; Godwin, AK ; Goodman, MT ; Greene, MH ; Gronwald, J ; Group, OS ; AOCSGroup, ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hamann, U ; Hansen, TVO ; Harris, HR ; Hartman, M ; Heitz, F ; Hildebrandt, MAT ; Hogdall, E ; Hogdall, CK ; Hopper, JL ; Huang, R-Y ; Huff, C ; Hulick, PJ ; Huntsman, DG ; Imyanitov, EN ; Isaacs, C ; Jakubowska, A ; James, PA ; Janavicius, R ; Jensen, A ; Johannsson, OT ; John, EM ; Jones, ME ; Kang, D ; Karlan, BY ; Karnezis, A ; Kelemen, LE ; Khusnutdinova, E ; Kiemeney, LA ; Kim, B-G ; Kjaer, SK ; Komenaka, I ; Kupryjanczyk, J ; Kurian, AW ; Kwong, A ; Lambrechts, D ; Larson, MC ; Lazaro, C ; Le, ND ; Leslie, G ; Lester, J ; Lesueur, F ; Levine, DA ; Li, L ; Li, J ; Loud, JT ; Lu, KH ; Mai, PL ; Manoukian, S ; Marks, JR ; KimMatsuno, R ; Matsuo, K ; May, T ; McGuffog, L ; McLaughlin, JR ; McNeish, IA ; Mebirouk, N ; Menon, U ; Miller, A ; Milne, RL ; Minlikeeva, A ; Modugno, F ; Montagna, M ; Moysich, KB ; Munro, E ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Yie, JNY ; Nielsen, HR ; Nielsen, FC ; Nikitina-Zake, L ; Odunsi, K ; Offit, K ; Olah, E ; Olbrecht, S ; Olopade, O ; Olson, SH ; Olsson, H ; Osorio, A ; Papi, L ; Park, SK ; Parsons, MT ; Pathak, H ; Pedersen, IS ; Peixoto, A ; Pejovic, T ; Perez-Segura, P ; Permuth, JB ; Peshkin, B ; Peterlongo, P ; Piskorz, A ; Prokofyeva, D ; Radice, P ; Rantala, J ; Riggan, MJ ; Risch, HA ; Rodriguez-Antona, C ; Ross, E ; Rossing, MA ; Runnebaum, I ; Sandler, DP ; Santamarina, M ; Soucy, P ; Schmutzler, RK ; Setiawan, VW ; Shan, K ; Sieh, W ; Simard, J ; Singer, CF ; Sokolenko, AP ; Song, H ; Southey, MC ; Steed, H ; Stoppa-Lyonnet, D ; Sutphen, R ; Swerdlow, AJ ; Tan, YY ; Teixeira, MR ; Teo, SH ; Terry, KL ; BethTerry, M ; Thomassen, M ; Thompson, PJ ; Thomsen, LCV ; Thull, DL ; Tischkowitz, M ; Titus, L ; Toland, AE ; Torres, D ; Trabert, B ; Travis, R ; Tung, N ; Tworoger, SS ; Valen, E ; van Altena, AM ; van der Hout, AH ; Nieuwenhuysen, E ; van Rensburg, EJ ; Vega, A ; Edwards, DV ; Vierkant, RA ; Wang, F ; Wappenschmidt, B ; Webb, PM ; Weinberg, CR ; Weitzel, JN ; Wentzensen, N ; White, E ; Whittemore, AS ; Winham, SJ ; Wolk, A ; Woo, Y-L ; Wu, AH ; Yan, L ; Yannoukakos, D ; Zavaglia, KM ; Zheng, W ; Ziogas, A ; Zorn, KK ; Kleibl, Z ; Easton, D ; Lawrenson, K ; DeFazio, A ; Sellers, TA ; Ramus, SJ ; Pearce, CL ; Monteiro, AN ; Cunningham, J ; Goode, EL ; Schildkraut, JM ; Berchuck, A ; Chenevix-Trench, G ; Gayther, SA ; Antoniou, AC ; Pharoah, PDP (SPRINGERNATURE, 2022-03)
    Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
  • Item
    Thumbnail Image
    Common variants in breast cancer risk loci predispose to distinct tumor subtypes
    Ahearn, TU ; Zhang, H ; Michailidou, K ; Milne, RL ; Bolla, MK ; Dennis, J ; Dunning, AM ; Lush, M ; Wang, Q ; Andrulis, IL ; Anton-Culver, H ; Arndt, V ; Aronson, KJ ; Auer, PL ; Augustinsson, A ; Baten, A ; Becher, H ; Behrens, S ; Benitez, J ; Bermisheva, M ; Blomqvist, C ; Bojesen, SE ; Bonanni, B ; Borresen-Dale, A-L ; Brauch, H ; Brenner, H ; Brooks-Wilson, A ; Bruening, T ; Burwinkel, B ; Buys, SS ; Canzian, F ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Chenevix-Trench, G ; Clarke, CL ; Collee, JM ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Dork, T ; Dwek, M ; Eccles, DM ; Evans, DG ; Fasching, PA ; Figueroa, J ; Floris, G ; Gago-Dominguez, M ; Gapstur, SM ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Goldberg, MS ; Gonzalez-Neira, A ; Alnaes, GIG ; Grip, M ; Guenel, P ; Haiman, CA ; Hall, P ; Hamann, U ; Harkness, EF ; Heemskerk-Gerritsen, BAM ; Holleczek, B ; Hollestelle, A ; Hooning, MJ ; Hoover, RN ; Hopper, JL ; Howell, A ; Jakimovska, M ; Jakubowska, A ; John, EM ; Jones, ME ; Jung, A ; Kaaks, R ; Kauppila, S ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Ko, Y-D ; Koutros, S ; Kristensen, VN ; Kruger, U ; Kubelka-Sabit, K ; Kurian, AW ; Kyriacou, K ; Lambrechts, D ; Lee, DG ; Lindblom, A ; Linet, M ; Lissowska, J ; Llaneza, A ; Lo, W-Y ; MacInnis, RJ ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; Martinez, ME ; McLean, C ; Meindl, A ; Menon, U ; Nevanlinna, H ; Newman, WG ; Nodora, J ; Offit, K ; Olsson, H ; Orr, N ; Park-Simon, T-W ; Patel, A ; Peto, J ; Pita, G ; Plaseska-Karanfilska, D ; Prentice, R ; Punie, K ; Pylkas, K ; Radice, P ; Rennert, G ; Romero, A ; Ruediger, T ; Saloustros, E ; Sampson, S ; Sandler, DP ; Sawyer, EJ ; Schmutzler, RK ; Schoemaker, MJ ; Schottker, B ; Sherman, ME ; Shu, X-O ; Smichkoska, S ; Southey, MC ; Spinelli, JJ ; Swerdlow, AJ ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Teras, LR ; Terry, MB ; Torres, D ; Troester, MA ; Vachon, CM ; van Deurzen, CHM ; van Veen, EM ; Wagner, P ; Weinberg, CR ; Wendt, C ; Wesseling, J ; Winqvist, R ; Wolk, A ; Yang, XR ; Zheng, W ; Couch, FJ ; Simard, J ; Kraft, P ; Easton, DF ; Pharoah, PDP ; Schmidt, MK ; Garcia-Closas, M ; Chatterjee, N (BMC, 2022-01-04)
    BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.