• p27KIP1 phosphorylation by PKB/Akt leads to poor breast cancer prognosis.

      Clarke, Robert B; Breast Biology Group, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester, UK. RClarke@PICR.man.ac.uk (2003)
    • The p38 alpha stress kinase suppresses aneuploidy tolerance by inhibiting Hif-1 alpha.

      Simoes-Sousa, Susana; Littler, Samantha; Thompson, Sarah L; Minshall, Paul; Whalley, Helen J; Bakker, B; Belkot, Klaudyna; Moralli, D; Bronder, Daniel; Tighe, Anthony; et al. (2018)
      Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically, however, karyotype heterogeneity drives tumor evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate glycolysis and avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones. We also show that p38 deficiency upregulates the hypoxia-inducible transcription factor Hif-1? and that inhibiting Hif-1? restores apoptosis in p38-deficent cells. Because hypoxia and aneuploidy are both barriers to tumor progression, the ability of Hif-1? to promote cell survival following chromosome missegregation raises the possibility that aneuploidy tolerance coevolves with adaptation to hypoxia.
    • p53 and related proteins in epithelial ovarian cancer.

      Sengupta, P S; McGown, Alan T; Bajaj, V; Blackhall, Fiona H; Swindell, Ric; Bromley, Michael; Shanks, Jonathan H; Ward, Timothy H; Buckley, C H; Reynolds, K; et al. (2000-12)
      We conducted a retrospective immunohistochemical evaluation of the prognostic significance of the expression of p53 and the related proteins Bax, Bcl-2, growth arrest and DNA damage (Gadd45), murine double minute 2 (Mdm2) and p21(WAF1/CIP1) in chemonaive tumours taken from 66 patients with ovarian cancer. Ki-67 expression (a marker of cell proliferation) was also evaluated immunohistochemically, while apoptosis within malignant cells was determined with the terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling (TUNEL) assay. The expression of each of the following proteins was significantly associated in the tumours (P < 0.05 unless otherwise stated): Bax with Bcl-2 (P < 0.01); Bax with Mdm2; p21(WAF1/CIP1) with Gadd45 (P < 0.01); p21(WAF1/CIP1) with p53; p53 with Mdm2. Univariate analysis showed that expression of p53, Bax, bulk residual disease and International Federation of Gynecology and Obstetricians (FIGO) stage were all strongly correlated with response to chemotherapy (P < 0.01). Similarly, the FIGO stage and Ki-67 expression (P < 0.01), as well as pathological subtype and bulk residual disease (P < 0.05), were prognostic factors for disease progression. The FIGO stage and Ki-67 expression were significant prognostic factors for overall survival (P < 0.01), with Gadd45 expression and pathological subtype also significant (P < 0.05) in a univariate analysis. Multivariate analysis for response to chemotherapy showed that expression of p53, Bax and FIGO stage were all independent prognostic factors (P < 0.01). The FIGO stage was the most important independent prognostic factor for progression and survival on multivariate analysis (P < 0.01). However, Ki-67 expression was also an independent prognostic factor for disease progression (P < 0.05) and approached significance for survival (P = 0.055). Taken together, these data suggest that determination of Ki-67 expression could supplement established prognostic factors.
    • p53 deficiency sensitizes clonogenic cells to irradiation in the large but not the small intestine.

      Hendry, Jolyon H; Cai, W B; Roberts, Stephen A; Potten, Christopher S; CRC Department of Experimental Radiation Oncology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, United Kingdom. (1997-09)
      The role of p53 in the survival of irradiated crypts in the small intestine and three regions of the large intestine (cecum, mid-colon and rectum) was assessed by comparing the responses in p53 null, p53 heterozygous and wild-type mice. There was no difference in the levels of crypt survival in the small intestine between the three genotypes, although the rate of cell depletion and regeneration in the null mice appeared slower. In the large intestine, crypt survival was lowest in the null mice compared to the other genotypes, in particular after high doses. The levels of crypt survival in the heterozygotes were not significantly different from those in the wild-type mice. Hence the greater radioresistance of crypts in the colon than in the small intestine, reported previously by us and others using various other mouse strains, may be partly attributable to the presence of p53. This effect is not readily explained by current knowledge concerning the decreased p53 expression and the greater expression of the survival gene Bcl2 in the stem cell zone of crypts in the colon compared to those in the small intestine. Reduced repair associated with the lack of a G2-phase checkpoint delay, the predominant arrest point for intestinal cells, is a possible explanation for the decrease in survival.
    • p53 overexpression as a marker of malignancy in gastric biopsies.

      Starzynska, T; Marsh, P J; Stern, Peter L; Department of Gastroenterology, Medical Pomeranian Academy, Szczecin, Poland. (1993-12)
      Inactivation of the p53 tumour-suppressor gene is the commonest genetic abnormality in human cancers. This results in a conformational change in the p53 protein, and a consequent prolongation in its half-life; thereby permitting the identification of p53 immunoreactivity in malignant cells. Such reactivity is observed in up to 57% of gastric carcinomas, and is a proven indicator of poor prognosis. We have investigated the use of p53 immunohistochemistry in the diagnosis of malignancy in pre-operative gastric biopsy specimens. Using a three-stage immunoperoxidase technique, p53 expression was examined in 117 gastric biopsies obtained during flexible upper gastrointestinal endoscopy: 80 of these biopsies were from known gastric carcinomas, 20 from benign gastric disorders and 17 from normal gastric mucosa. Of the gastric cancers 40% (n = 32) exhibited overexpression of p53. No reactivity was observed in any of the biopsies of gastric ulcers, polyps or normal mucosa. The expression of p53 by gastric carcinomas improved the diagnostic accuracy of conventional histopathology from 86% to 92.5%; with 5% of biopsies incorrectly diagnosed and 2.5% of an equivocal appearance. These results demonstrate that the detection of p53 is a highly specific marker of gastric malignancy, and that such a technique can easily be performed on biopsies obtained at endoscopy.
    • Pan-cancer analysis of whole genomes

      Campbell, P. J.; Getz, G.; Korbel, J. O.; Stuart, J. M.; Jennings, J. L.; Stein, L. D.; Perry, M. D.; Nahal-Bose, H. K.; Ouellette, B. F. F.; Li, C. H.; et al. (2020)
      Fibrosis and fat replacement in skeletal muscle are major complications that lead to a loss of mobility in chronic muscle disorders, such as muscular dystrophy. However, the in vivo properties of adipogenic stem and precursor cells remain unclear, mainly due to the high cell heterogeneity in skeletal muscles. Here, we use single-cell RNA sequencing to decomplexify interstitial cell populations in healthy and dystrophic skeletal muscles. We identify an interstitial CD142-positive cell population in mice and humans that is responsible for the inhibition of adipogenesis through GDF10 secretion. Furthermore, we show that the interstitial cell composition is completely altered in muscular dystrophy, with a near absence of CD142-positive cells. The identification of these adipo-regulatory cells in the skeletal muscle aids our understanding of the aberrant fat deposition in muscular dystrophy, paving the way for treatments that could counteract degeneration in patients with muscular dystrophy.
    • Papillomavirus vaccines.

      Duggan-Keen, Margaret F; Brown, Michael D; Stacey, Simon N; Stern, Peter L; Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, United Kingdom. (1998-12-01)
      The considerable morbidity and mortality associated with certain human papillomaviruses (HPV) has provided the impetus for HPV vaccine development. The design of such vaccines has evolved from an understanding of the nature of HPV infections and their consequences, together with evaluation of the efficacy of different approaches to vaccination in animal models. These studies have culminated in the production of several different vaccine preparations which are currently undergoing Phase I and II clinical trials. The justification for the widespread implementation of prophylactic HPV vaccines will depend on the outcome of larger scale studies of vaccine efficacy that take into account the epidemiology of HPV infections and associated disease. The usefulness of therapeutic HPV vaccines will require evidence that they can substantially augment or substitute for the effectiveness of currently available treatments.
    • Paradoxical elevations in serum IGF-II and IGF binding protein-2 in acromegaly: insights into the regulation of these peptides.

      Renehan, Andrew G; Toogood, Andy; Ryder, W David J; Jones, Jenny; Potten, Christopher S; O'Dwyer, Sarah T; Shalet, Stephen M; Department of Surgery, Christie Hospital NHS Trust, Manchester, UK. arenehan@picr.man.ac.uk (2001-10)
      OBJECTIVE: Circulating insulin-like growth factor (IGF)-II and IGF binding protein-2 (IGFBP-2) are frequently altered, often in parallel, in numerous pathologies including neoplastic disease but little is known about their normal regulation. This study compared serum IGF-II and IGFBP-2 distributions between acromegalics and a large normal adult population to explore possible determinants. PATIENTS: Sixty acromegalic patients undergoing screening colonoscopy (age range 25-81 years); normative data from 306 healthy adults (age range 20-89 years). MEASUREMENTS: Serum IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were measured in healthy adults and acromegalics. Mean growth hormone (GH) levels were obtained for acromegalic patients. Differences were compared using t-tests (unadjusted) and multiple regression models (adjusted for age and gender). Correlations were expressed as Pearson's coefficient (r). RESULTS: For acromegalic patients, GH was significantly correlated with IGF-I (r = 0.50; P < 0.001) and IGFBP-3 (r = 0.29; P = 0.03) but not IGF-II or IGFBP-2. Contrary to expectations, mean IGF-II and IGFBP-2 levels were significantly raised in the acromegalics compared with normals [adjusted mean difference (95% CI) = 226 (181, 271) microg/l and 305 (200, 410) microg/l, respectively]. Ten acromegalic patients had colorectal neoplasia but their presence did not contribute to the elevations in serum IGF-II and IGFBP-2. The (IGF-I + IGF-II)/IGFBP-3 molar ratios were remarkably constant in both healthy adults and acromegalics, but the relationships of the ligands individually with IGFBP-3 were not linear: as IGFBP-3 increased, IGF-I also increased whereas IGF-II initially increased but then decreased. IGFBP-2 did not correlate with IGF-II, but molar concentration significantly correlated with the IGF-II/IGFBP-3 molar ratio (r = 0.40; P = 0.001). CONCLUSIONS: Serum IGF-II and IGFBP-2 levels were paradoxically elevated in acromegalics, independent of the presence of colorectal neoplasia. The (IGF-I + IGF-II)/IGFBP-3 molar ratio appears to be pivotal in determining IGF-II values, which, in turn, expressed as a ratio of IGFBP-3, is related to IGFBP-2. These observations offer new insights into the regulation of these peptides.
    • Parallel evaluation of circulating tumor DNA and circulating tumor cells in metastatic colorectal cancer.

      Germano, G; Mauri, G; Siravegna, G; Dive, Caroline; Pierce, Jackie; Di Nicolantonio, F; D'Incalci, M; Bardelli, A; Siena, S; Sartore-Bianchi, A; et al. (2017-11-01)
      Tissue biopsy is the gold standard for tumor genotyping, but it is an invasive procedure providing a single snapshot into tumor heterogeneity. Liquid biopsy approaches, encompassing the analysis of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs), have been proposed as an alternative, with the potential of providing a comprehensive portrait of the tumor molecular landscape. In metastatic colorectal cancer (mCRC), both CTCs and ctDNA analysis have been investigated, but comparative analyses are limited.
    • A parallel proteomic and metabolomic analysis of the hydrogen peroxide- and Sty1p-dependent stress response in Schizosaccharomyces pombe.

      Weeks, Mark E; Sinclair, John; Butt, Amna; Chung, Yuen-Li; Worthington, Jessica L; Wilkinson, Caroline R M; Griffiths, John R; Jones, Nic; Waterfield, Michael D; Timms, John F; et al. (2006-05)
      Using an integrated approach incorporating proteomics, metabolomics and published mRNA data, we have investigated the effects of hydrogen peroxide on wild type and a Sty1p-deletion mutant of the fission yeast Schizosaccharomyces pombe. Differential protein expression analysis based on the modification of proteins with matched fluorescent labelling reagents (2-D-DIGE) is the foundation of the quantitative proteomics approach. This study identifies 260 differentially expressed protein isoforms from 2-D-DIGE gels using MALDI MS and reveals the complexity of the cellular response to oxidative stress and the dependency on the Sty1p stress-activated protein kinase. We show the relationship between these protein changes and mRNA expression levels identified in a parallel whole genome study, and discuss the regulatory mechanisms involved in protecting cells against hydrogen peroxide and the involvement of Sty1p-dependent stress-activated protein kinase signalling. Metabolomic profiling of 29 intermediates using 1H NMR was also conducted alongside the protein analysis using the same sample sets, allowing examination of how the protein changes might affect the metabolic pathways and biological processes involved in the oxidative stress response. This combined analysis identifies a number of interlinked metabolic pathways that exhibit stress- and Sty1-dependent patterns of regulation.
    • The paralogous hematopoietic regulators Lyl1 and Scl are coregulated by Ets and GATA factors, but Lyl1 cannot rescue the early Scl-/- phenotype.

      Chan, Wan Y I; Follows, George A; Lacaud, Georges; Pimanda, John E; Landry, Josette-Renee; Kinston, Sarah; Knezevic, Kathy; Piltz, Sandie; Donaldson, Ian J; Gambardella, Laure; et al. (2007-03-01)
      Transcription factors are key regulators of hematopoietic stem cells (HSCs), yet the molecular mechanisms that control their expression are largely unknown. Previously, we demonstrated that expression of Scl/Tal1, a transcription factor required for the specification of HSCs, is controlled by Ets and GATA factors. Here we characterize the molecular mechanisms controlling expression of Lyl1, a paralog of Scl also required for HSC function. Two closely spaced promoters directed expression to hematopoietic progenitor, megakaryocytic, and endothelial cells in transgenic mice. Conserved binding sites required for promoter activity were bound in vivo by GATA-2 and the Ets factors Fli1, Elf1, Erg, and PU.1. However, despite coregulation of Scl and Lyl1 by the same Ets and GATA factors, Scl expression was initiated prior to Lyl1 in embryonic stem (ES) cell differentiation assays. Moreover, ectopic expression of Scl but not Lyl1 rescued hematopoietic differentiation in Scl-/- ES cells, thus providing a molecular explanation for the vastly different phenotypes of Scl-/- and Lyl1-/- mouse embryos. Furthermore, coregulation of Scl and Lyl1 later during development may explain the mild phenotype of Scl-/- adult HSCs.
    • PARG inhibition: development of novel compounds and a biomarker strategy to determine cell line sensitivity in breast cancer

      Waddell, Ian D; James, Dominic I; Smith, Kate M; Holt, Sarah V; Acton, Ben; Fairweather, Emma E; Hamilton, Niall M; Hamilton, Nicola S; Hitchin, James R; Huttom, Colin; et al. (2015)
    • PARG inhibitors exhibit synthetic lethality with XRCC1 deficiency and a cellular mechanism of action that is distinct from PARP inhibition

      Martin, Leenus; Cheng, Tzuling; James, Dominic I; Begum, Habiba; Smith, Kate M; Jordan, Allan M; Waddell, Ian D; Vaidya, Kedar; Fischer, Marcus; Yao, Bing; et al. (2018)
    • Partial trisomy 14q-- and pseudoxanthoma elasticum.

      Muldal, S; Enoch, B A; Ahmed, A; Harris, R; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1973-06)
    • Pathbase: a database of mutant mouse pathology.

      Schofield, Paul N; Bard, Jonathan B L; Booth, Catherine; Boniver, Jacques; Covelli, Vincenzo; Delvenne, Philippe; Ellender, Michele; Engstrom, Wilhelm; Goessner, Wolfgang; Gruenberger, Michael; et al. (2004-01-01)
      Pathbase is a database that stores images of the abnormal histology associated with spontaneous and induced mutations of both embryonic and adult mice including those produced by transgenesis, targeted mutagenesis and chemical mutagenesis. Images of normal mouse histology and strain-dependent background lesions are also available. The database and the images are publicly accessible (http://www.pathbase.net) and linked by anatomical site, gene and other identifiers to relevant databases; there are also facilities for public comment and record annotation. The database is structured around a novel ontology of mouse disorders (MPATH) and provides high-resolution downloadable images of normal and diseased tissues that are searchable through orthogonal ontologies for pathology, developmental stage, anatomy and gene attributes (GO terms), together with controlled vocabularies for type of genetic manipulation or mutation, genotype and free text annotation for mouse strain and additional attributes. The database is actively curated and data records assessed by pathologists in the Pathbase Consortium before publication. The database interface is designed to have optimal browser and platform compatibility and to interact directly with other web-based mouse genetic resources.
    • Patient age and risk of recurrence of primary melanoma at high risk of spread

      Ghiasvand, R.; Khosrotehrani, K.; Hughes, M. C. B.; von Schuckmann, L. A.; Beesley, V. L.; Malt, M.; Smithers, B. M.; Green, Adèle C; Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway. (2020)
      Melanoma is more aggressive with poorer outcomes in older than younger patients. Older age has been associated with greater tumour thickness, higher rates of ulceration, and high mitotic rates,1,2 but it is not clear whether poorer outcomes in the elderly are solely due to these tumour-specific features or to additional effects of age-related decline in in immune surveillance, greater comorbidity, and age-related behaviours such as delayed diagnosis.
    • Patient-derived xenograft (PDX) models in basic and translational breast cancer research.

      Dobrolecki, L; Airhart, S; Alférez, Denis G; Aparicio, S; Behbod, F; Bentires-Alj, M; Brisken, C; Bult, C; Cai, S; Clarke, R; et al. (2016-12)
      Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and "Triple-negative" (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward "credentialing" of PDX models as surrogates to represent individual patients for use in preclinical and co-clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research.
    • The pattern of expression of the 5T4 oncofoetal antigen on normal, dysplastic and malignant oral mucosa.

      Ali, A; Langdon, J; Stern, Peter L; Partridge, M; Maxillofacial Unit/Molecular Oncology, King's College Hospital, Denmark Hill, SE5 8RX, London, UK. (2001-01)
      The human 5T4 oncofoetal antigen is expressed by all types of trophoblast in pregnancy but is not detected on most adult tissues, although low levels are found on some epithelia. However, this antigen is strongly expressed by many cancers and tumour-associated labelling correlates with metastatic spread and poor clinical outcome for patients with gastric and colon cancer. Over-expression of the gene influences cell adhesion, shape and motility, which may be related to changes in the cellular localisation of the 5T4 oncofoetal antigen as malignancy develops. To establish whether the 5T4 oncofoetal antigen can serve as a tumour-specific marker for oral cancer and precancer, we have evaluated the pattern of expression on biopsies of normal, inflamed and dysplastic oral mucosa using immunohistochemistry. Oral mucosa, taken from different sites in the mouth, expressed the 5T4 oncofoetal antigen with varying intensity and pattern. The majority of the immunoreactivity was detected in the basal and suprabasal layers, with expression extending into the spinous cells at fully keratinised sites and when inflammation was present. This antigen was also detected in the underlying connective tissue. Oral squamous cell carcinoma showed a variety of patterns and intensity of staining corresponding to those found for normal mucosa. However, 21 of 41 cases showed no stromal labelling, a finding also observed for dysplastic lesions. The alterations in the pattern and intensity of 5T4 oncofoetal antigen expression were not related to clinicopathological features of the tumours examined. These data show that the 5T4 oncofoetal antigen is expressed on normal oral mucosa, such that this target cannot be used for detection of neoplastic or preneoplastic cells, although altered expression may contribute to the pathogenesis of these lesions.
    • Patterns of mortality after prolonged follow-up of a randomised controlled trial using granulocyte colony-stimulating factor to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma.

      Clamp, Andrew R; Ryder, W David J; Bhattacharya, Soumo; Pettengell, Ruth; Radford, John A; Department of Medical Oncology, Cancer Research UK, University of Manchester, Christie Hospital, Wilmslow Rd., Manchester M20 4BX, UK. Andrew.clamp@christie.nhs.uk (2008-07-22)
      The effect of utilising granulocyte colony-stimulating factor (G-CSF) to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma (NHL) on long-term mortality patterns has not been formally evaluated. We analysed prolonged follow-up data from the first randomised controlled trial investigating this approach. Data on 10-year overall survival (OS), progression-free survival (PFS), freedom from progression (FFP) and incidence of second malignancies were collected for 80 patients with aggressive subtypes of NHL, who had been randomised to receive either VAPEC-B chemotherapy or VAPEC-B+G-CSF. Median follow-up was 15.7 years for surviving patients. No significant differences were found in PFS or OS. However, 10-year FFP was better in the G-CSF arm (68 vs 47%, P=0.037). Eleven deaths from causes unrelated to NHL or its treatment occurred in the G-CSF arm compared to five in controls. More deaths occurred from second malignancies (4 vs 2) and cardiovascular causes (5 vs 0) in the G-CSF arm. Although this pharmacovigilance study has insufficient statistical power to draw conclusions and is limited by the lack of data on smoking history and other cardiovascular risk factors, these unique long-term outcome data generate hypotheses that warrant further investigation.
    • Patterns of omega-3 and omega-6 fatty acid dietary intake and melanoma thickness at diagnosis

      Mahamat-Saleh, Y.; Hughes, M. C. B.; Miura, K.; Malt, M. K.; von Schuckmann, L.; Khosrotehrani, K.; Smithers, B. M.; Green, Adèle C; Centre for Research in Epidemiology and Population Health (CESP) School of Medicine, Universite Paris Sud School of Medicine, Universite Versailles Saint-Quentin-en-Yvelines (UVSQ); INSERM French National Institute for Health and Medical Research, Universite Paris Saclay, Villejuif, France. (2020)
      Background: Experimental evidence suggests that dietary intakes of omega-3 and omega-6 polyunsaturated fatty acids have divergent effects on melanoma growth, but epidemiologic evidence on their combined effect is lacking. Methods: In 634 Australian patients with primary melanoma, we assessed prediagnosis consumption of 39 food groups by food frequency questionnaires completed within 2 months of diagnosis. We derived, by reduced rank regression, dietary patterns that explained variability in selected omega-3 and omega-6 fatty acid intakes. Prevalence ratios (PR) and 95% confidence intervals (CI) for the association between tertiles of dietary patterns and melanoma thickness >2 mm versus ≤2 mm were estimated using Poisson regression. Results: Overall omega-3 fatty acid intakes were low. Two major fatty acid dietary patterns were identified: "meat, fish, and fat," positively correlated with intakes of all fatty acids; and "fish, low-meat, and low-fat," positively correlated with long-chain omega-3 fatty acid intake, and inversely with medium-chain omega-3 and omega-6 fatty acid intakes. Prevalence of thick melanomas was significantly higher in those in the highest compared with lowest tertile of the "meat, fish, and fat" pattern (PR, 1.40; 95% CI, 1.01-1.94), especially those with serious comorbidity (PR, 1.83; 95% CI, 1.15-2.92) or a family history (PR, 2.32; 95% CI, 1.00-5.35). The "fish, low-meat, and low-fat" pattern was not associated with melanoma thickness. Conclusions: People with high meat, fish, and fat intakes, who thus consumed relatively high levels of omega-3 and high omega-6 fatty acid intakes, are more likely to be diagnosed with thick than thin melanomas.