Sir Peter MacCallum Department of Oncology - Research Publications

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    BRCA1 polymorphisms
    Campbell, IG ; Schroff, R ; Englefield, P ; Eccles, DM (CHURCHILL LIVINGSTONE, 1997)
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    LOSS OF HETEROZYGOSITY AND AMPLIFICATION ON CHROMOSOME-11Q IN HUMAN OVARIAN-CANCER
    FOULKES, WD ; CAMPBELL, IG ; STAMP, GWH ; TROWSDALE, J (STOCKTON PRESS, 1993-02)
    The 11q13 chromosomal region encodes oncogenes relevant to a variety of human cancers as well as a tumour suppressor gene implicated in multiple endocrine neoplasia type 1. In addition, high affinity folate receptor (FOLR1), which maps to 11q13.3-13.5, is expressed at an elevated level on the surface of over 80% of nonmucinous epithelial ovarian cancers. Further telomeric, 11q breakpoints are found in many cancers. We studied the involvement of 11q markers in ovarian cancer by looking for tumour-specific loss of heterozygosity (LOH), as well as amplification or rearrangements that might explain the overexpression of FOLR1. Twenty eight epithelial ovarian cancers, along with lymphocyte DNA from the same individual were used for Southern blotting with polymorphic probes from 11q. PCR primers from 11q23.3 were also used. The 11q13 band was amplified in four out of 28 cancers. The amplicon included the probe D11S146 as well as FGF3 (formerly INT2) and FOLR1 in one out of these four cases, thus crossing the bcl1 translocation breakpoint. LOH was seen in three out of 16 cases with FGF3 (11q13). A much higher frequency of LOH (8/12) was found at 11q23.3-qter, implying the presence of a tumour suppressor gene in this region.
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    MDM2 OVEREXPRESSION IS RARE IN OVARIAN-CARCINOMA IRRESPECTIVE OF TP53 MUTATION STATUS
    FOULKES, WD ; STAMP, GWH ; AFZAL, S ; LALANI, N ; MCFARLANE, CP ; TROWSDALE, J ; CAMPBELL, IG (STOCKTON PRESS, 1995-10)
    Somatic mutations in TP53 are seen in many human cancers. In addition, the protein product of the wild-type TP53 can be sequestered by the protein MDM2 (murine double minute 2). This protein is commonly overexpressed in human sarcomas and gliomas, usually as a result of gene amplification. In this study, 43 ovarian carcinomas (OCs) were analysed for aberrations in the TP53 gene by immunohistochemistry (IHC), loss of heterozygosity (LOH) or mutation analysis. The MDM2 gene and its product was studied by Southern blotting and IHC. Over 50% of the OCs studied showed mutations in TP53 by either direct sequencing (19/36, 53%), positive IHC (23,43, 53%) or both, whereas 0/32 had amplification of MDM2 and only 1/37 tumours had positive IHC using the anti-MDM2 antibody IF-2. The solitary example of positive IHC in this series was seen in a mixed müllerian tumour with sarcomatous differentiation and was not accompanied by MDM2 DNA amplification. These results support previous data showing that around 50% of OCs have mutations in TP53 and in addition, suggest that MDM2 is not amplified in OC, but the presence of sarcomatous features in mixed müllerian tumours may result in positive immunohistochemistry with IF-2.
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    TP53 intron 6 polymorphism and the risk of ovarian and breast cancer
    Mavridou, D ; Gornall, R ; Campbell, IG ; Eccles, DM (CHURCHILL LIVINGSTONE, 1998-02)
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    LOSS OF HETEROZYGOSITY ON CHROMOSOME-22 IN OVARIAN-CARCINOMA IS DISTAL TO AND IS NOT ACCOMPANIED BY MUTATIONS IN NF2 AT 22Q12
    ENGLEFIELD, P ; FOULKES, WD ; CAMPBELL, IG (STOCKTON PRESS, 1994-11)
    Frequent loss of heterozygosity (LOH) has been reported on 22q in ovarian carcinoma, implying the presence of a tumour-suppressor gene. The neurofibromatosis type 2 gene (NF2) at 22q12 is a plausible candidate. Analysis of 9 of the 17 exons of NF2 by single-strand conformational polymorphism (SSCP) in 67 ovarian carcinomas did not detect any somatic mutations, suggesting that NF2 is not involved in the pathogenesis of ovarian carcinoma. LOH data support this conclusion and that the putative tumour-suppressor gene lies distal to NF2, beyond D22S283.
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    Allele loss and mutation screen at the Peutz-Jeghers (LKB1) locus (19p13.3) in sporadic ovarian tumours
    Wang, ZJ ; Churchman, M ; Campbell, IG ; Xu, WH ; Yan, ZY ; McCluggage, WG ; Foulkes, WD ; Tomlinson, IPM (CHURCHILL LIVINGSTONE, 1999-04)
    Germline mutations in the LKB1 (STK11) gene (chromosome sub-band 19p13.3) cause characteristic hamartomas and pigmentation to develop in patients with Peutz-Jeghers syndrome. Peutz-Jeghers syndrome carries an overall risk of cancer that may be up to 20 times that of the general population and Peutz-Jeghers patients are at increased risk of benign and malignant ovarian tumours, particularly granulosa cell tumours. Loss of heterozygosity (allele loss, LOH) has been reported in about 50% of ovarian cancers on 19p13.3. LKB1 is therefore a candidate tumour suppressor gene for sporadic ovarian tumours. We found allele loss at the marker D19S886 (19p13.3) in 12 of 49 (24%) sporadic ovarian adenocarcinomas. Using SSCP analysis, we screened ten ovarian cancers with LOH, 35 other ovarian cancers and 12 granulosa cell tumours of the ovary for somatic mutations in LKB1. No variants were detected in any of the adenocarcinomas. Two mutations were detected in one of the granulosa cell tumours: a mis-sense mutation affecting the putative 'start' codon (ATG --> ACG, M1T); and a silent change in exon 7 (CTT --> CTA, leucine). Like BRCA1 and BRCA2, therefore, it appears that LKB1 mutations can cause ovarian tumours when present in the germline, but occur rarely in the soma. The allele loss on 19p13.3 in ovarian cancers almost certainly targets a different gene from LKB1.
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    BRCA1 mutations in southern England
    Eccles, DM ; Englefield, P ; Soulby, MA ; Campbell, IG (CHURCHILL LIVINGSTONE, 1998-06)
    If genetic testing for breast and ovarian cancer predisposition is to become available within a public health care system there needs to be a rational and cost-effective approach to mutation analysis. We have screened for BRCA1 mutations in 230 women with breast cancer, all from the Wessex region of southern England, in order to establish the parameters on which to base a cost-effective regional mutation analysis strategy. Truncating mutations were detected in 10/155 (6.5%) consecutive cases selected only for diagnosis under the age of 40 (nine of these ten women had a strong family history of breast or ovarian cancer), 3/61 (4.9%) bilateral-breast cancer cases (all three mutations occurring among women for whom the first cancer was diagnosed under 40 years) and 8/30 (26.6%) breast cancer cases presenting to the genetics clinic (for whom a strong family history of breast and/or ovarian cancer was present). Ten different mutations were detected in 17 families, but three of these accounted for 10/17 (59%) of the families. The cost of screening the population for mutations in the entire BRCA1 gene is unacceptably high. However, the cost of screening a carefully selected patient cohort is low, the risk of misinterpretation much less and the potential clinical benefits clearer.
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    No association of a 306-bp insertion polymorphism in the progesterone receptor gene with ovarian and breast cancer
    Manolitsas, TP ; Englefield, P ; Eccles, DM ; Campbell, IG (CHURCHILL LIVINGSTONE, 1997-05)
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    Loss of heterozygosity on chromosome 5q in ovarian cancer is frequently accompanied by TP53 mutation and identifies a tumour suppressor gene locus at 5q13.1-21
    Tavassoli, M ; Steingrimsdottir, H ; Pierce, E ; Jiang, X ; Alagoz, M ; Farzaneh, F ; Campbell, IG (STOCKTON PRESS, 1996-07)
    Forty-nine ovarian tumours were examined for loss of heterozygosity (LOH) on chromosome 5 using eight microsatellite markers spanning both arms, including one at the APC locus. LOH on 5q was a frequent event, detectable in 23 of 49 (47%) tumours, whereas 5p LOH was detected in only 1 of 22 tumours (5%). Six tumours showed partial LOH on 5q, enabling the candidate region to be localised to a 22 cM region proximal to APC, flanked by D5S424 and D5S644. An association was found between 5q LOH and TP53 mutation, with 18 of 23 (78%) tumours with LOH on 5q also harbouring a TP53 mutation. LOH on 5q was observed in 6 of 18 (33%) stage I tumours, suggesting that it may be an early event in the molecular pathogenesis of certain ovarian carcinomas.
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    Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma
    Kader, T ; Hill, P ; Zethoven, M ; Goode, DL ; Elder, K ; Thio, N ; Doyle, M ; Semple, T ; Sufyan, W ; Byrne, DJ ; Pang, J-MB ; Murugasu, A ; Miligy, IM ; Green, AR ; Rakha, EA ; Fox, SB ; Mann, GB ; Campbell, IG ; Gorringe, KL (WILEY, 2019-07)