Charmaine Smith

Multiple newly identified loci associated with prostate cancer susceptibility

Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at ≤60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 × 10−8 to P = 8.7 × 10−29). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3.

Prostate cancer segregation analyses using 4390 families from UK and Australian population-based studies.

Familial aggregation of prostate cancer is likely to be due to multiple susceptibility loci, perhaps acting in conjunction with shared lifestyle risk factors. Models that assume a single mode of inheritance may be unrealistic. We analyzed genetic models of susceptibility to prostate cancer using segregation analysis of occurrence in families ascertained through population‐based series totaling 4390 incident cases. We investigated major gene models (dominant, recessive, general, X‐linked), polygenic models, and mixed models of susceptibility using the pedigree analysis software MENDEL. The hypergeometric model was used to approximate polygenic inheritance. The best‐fitting model for the familial aggregation of prostate cancer was the mixed recessive model. The frequency of the susceptibility allele in the population was estimated to be 0.15 (95% confidence interval (CI) 0.11–0.20), with a relative risk for homozygote carriers of 94 (95% CI 46–192), and a polygenic standard deviation of 2.01 (95% CI 1.72–2.34). These analyses suggest that one or more genes having a strong recessively inherited effect on risk, as well as a number of genes with variants having small multiplicative effects on risk, may account for the genetic susceptibility to prostate cancer. The recessive component would predict the observed higher familial risk for siblings of cases than for fathers, but this could also be due to other factors such as shared lifestyle by siblings, targeted screening effects, and/or non‐additive effects of one or more genes. Genet. Epidemiol. 34:42–50, 2010.

Anti-Müllerian hormone serum concentrations of women with germline BRCA1 or BRCA2 mutations

STUDY QUESTION Do women with BRCA1 or BRCA2 mutations have reduced ovarian reserve, as measured by circulating anti-Müllerian hormone (AMH) concentration? SUMMARY ANSWER Women with a germline mutation in BRCA1 have reduced ovarian reserve as measured by AMH. WHAT IS KNOWN ALREADY The DNA repair enzymes encoded by BRCA1 and BRCA2 are implicated in reproductive aging. Circulating AMH is a biomarker of ovarian reserve and hence reproductive lifespan. STUDY DESIGN, SIZE, DURATION This was a cross-sectional study of AMH concentrations of 693 women at the time of enrolment into the Kathleen Cuningham Foundation Consortium for research in the Familial Breast Cancer (kConFab) cohort study (recruitment from 19 August 1997 until 18 September 2012). AMH was measured on stored plasma samples between November 2014 and January 2015 using an electrochemiluminescence immunoassay platform. PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible women were from families segregating BRCA1 or BRCA2 mutations and had known mutation status. Participants were aged 25–45 years, had no personal history of cancer, retained both ovaries and were not pregnant or breastfeeding at the time of plasma storage. Circulating AMH was measured for 172 carriers and 216 non-carriers from families carrying BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying BRCA2 mutations. Associations between plasma AMH concentration and carrier status were tested by linear regression, adjusted for age at plasma storage, oral contraceptive use, body mass index and cigarette smoking. MAIN RESULTS AND THE ROLE OF CHANCE Mean AMH concentration was negatively associated with age (P < 0.001). Mutation carriers were younger at blood draw than non-carriers (P ≤ 0.031). BRCA1 mutation carriers had, on average, 25% (95% CI: 5%–41%, P = 0.02) lower AMH concentrations than non-carriers and were more likely to have AMH concentrations in the lowest quartile for age (OR 1.84, 95% CI: 1.11–303, P = 0.02). There was no evidence of an association between AMH concentration and BRCA2 mutation status (P = 0.94). LIMITATIONS, REASONS FOR CAUTION AMH does not directly measure the primordial follicle pool. The clinical implications of the lower AMH concentrations seen in BRCA1 mutation carriers cannot be assessed by this study design. WIDER IMPLICATIONS OF THE FINDINGS Women with a germline mutation in BRCA1 may have reduced ovarian reserve. This is consistent with other smaller studies in the literature and has potential implications for fertility and reproductive lifespan. STUDY FUNDING/COMPETING INTEREST(S) kConFab is supported by a grant from the Australian National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. K.A.P. is an Australian National Breast Cancer Foundation Practitioner Fellow. J.L.H. is a NHMRC Senior Principal Research Fellow. M.H. is a NHMRC Practitioner Fellow. R.A.A. reports personal fees from Roche Diagnostics & Beckman Coulter outside the submitted work and C.S. reports other earnings from Melbourne IVF outside the submitted work. The remaining authors have nothing to declare and no conflicts of interest.

A whole of population‐based series of radical prostatectomy in Victoria, 1995 to 2000

Objective: Radical prostatectomy (RP) as a first line treatment of prostate cancer was rare prior to the advent of prostate specific antigen (PSA) testing, yet little is known of its use and outcomes in a population setting. We described baseline characteristics of cases in the Victorian Radical Prostatectomy Register (VRPR), investigated possible associations between demographic characteristics and characteristics at diagnosis and at surgery and trends over time.

Identification of new genetic risk factors for prostate cancer.

There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.

Improved quality of risk-reducing salpingo-oophorectomy in Australasian women at high risk of pelvic serous cancer

ObjectivesThe quality of risk-reducing salpingo-oophorectomy (RRSO) performed in Australasian women was previously reported to be suboptimal. Here we describe the quality of RRSO performed since 2008 in women enrolled in the same cohort and determine whether it has improved.DesignProspective cohort study of women at high risk of pelvic serous cancer (PSC) in kConFab. Eligible women had RRSO between 2008 and 2014 and their RRSO surgical and pathology reports were reviewed. “Adequate” surgery and pathology were defined as complete removal and paraffin embedding of all ovarian and extra-uterine fallopian tube tissue, respectively. Associations between clinical factors and “adequate” pathology were assessed using logistic regression. Data were compared with published cohort data on RRSO performed prior to 2008 using Chi square test.ResultsOf 164 contemporary RRSOs performed in 78 centres, 158/159 (99%) had “adequate” surgery and 108/164 (66%) had “adequate” pathology. Surgery performed by a gynaecologic oncologist rather than a general gynaecologist [OR 8.2, 95%CI (3.6–20.4), p < 0.001], surgery without concurrent hysterectomy [OR 2.5, 95%CI (1.1–6.0), p = 0.03], more recent year of surgery [OR 1.4, 95%CI (1.1–1.8), p = 0.02], and clinical notation that indicated high risk [OR 19.4, 95%CI (3.1–385), p = 0.008] were independently associated with “adequate” pathology. Both surgery and pathology were significantly more likely to be “adequate” (p < 0.001) in this contemporary sample. ConclusionThe quality of RRSOs has significantly improved since our last report. Surgery by a gynaecologic oncologist who informs the pathologist that the woman is at high risk for PSC is associated with optimal RRSO pathology.

Abstract P3-02-03: Breast cancer screening by women from BRCA1 & BRCA2 mutation positive families

Purpose: Breast screening may detect breast cancer (BC) at an early stage but optimal screening depends on a woman’s level of risk and age. This study estimates the contemporary prevalence of BC screening by Australian women from families with a BRCA1/2 mutation identified by Family Cancer Clinics. Methods: Subjects were carriers and true non-carriers from families with a BRCA1/2 mutation enrolled in the nationwide kConFab cohort. They are followed up every 3 years with a questionnaire which includes use of breast ultrasound, mammography (MMG), magnetic resonance imaging (MRI) and clinical breast examination (CBE) over the previous 3 year period. Data from each woman’s most recent questionnaire (completed Oct 2009- March 2014) were used in the analysis. All knew their mutation result. Those who had risk-reducing mastectomy, previous cancer, were evaluated for benign breast disease, pregnant or breastfeeding or received their mutation result in the most recent follow-up round were excluded. Screening behaviour was categorized based on current national guidelines (see table). Associations with underscreening and overscreening were assessed using unconditional logistic regression to estimate odds ratios and 95% confidence intervals. Results: Of 372 eligible participants, there were 92 mutation carriers (42 BRCA1, 50 BRCA2) and 280 true non-carriers. 1% of carriers were overscreening, 86% were screening annually while 13% were underscreening. MRI, which is funded for mutation carriers aged 30-50 years, was used by only 52% (13/27) of carriers aged 50. Underscreening carriers were more likely to be single (OR=2.78, 95%CI=1.28-5.88, P=0.009) while those with a first degree cancer affected relative were less likely to underscreen (OR= 0.40, 0.19-0.85, P=0.017). CBE was undertaken by 79% of carriers at least yearly; 15% had no or irregular CBE. 115/280 (41%) non-carriers were overscreening, 55% were screening appropriately and 5% were underscreening. Underscreening non-carriers were more likely to be single (OR 3.85, 95%CI=1.00-14.9, P=0.05). Predictive of overscreening in non-carriers was having a cancer affected first degree relative (OR=2.92, 1.55-5.51, P=0.001). Non-carriers were less likely to utilise CBE (54%). Conclusion: Most mutation carriers in kConFab are having regular screening MMG, but MRI is underutilised even when funded. The reasons for low usage of MRI requires further research and is concerning given its increased sensitivity over MMG. Overscreening is common in true non-carriers of BRCA mutations. Family cancer history and marital status may predict inappropriate screening behaviour. Citation Format: Melanie Wuttke, Roger Milne, Prue Weideman, Sandra Picken, Charmaine Smith, Michael Friedlander, kConFab Investigators, Sue-Anne McLachlan, John L Hopper, Kelly-Anne Phillips. Breast cancer screening by women from BRCA1 & BRCA2 mutation positive families [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-02-03.

The development and introduction of a written post-radiotherapy information leaflet for prostate cancer patients [Abstract]

Background With rapidly dividing lesions such as non-small cell lung cancer (NSCLC), repopulation of tumour cells during breaks in radiotherapy treatment is recognised as a prohibiting factor for effective tumour eradication. To address this, NICE guidelines advocate continuous hyperfractionated accelerated radiotherapy (CHART) as the standard regimen for the treatment of suitable stage I and II NSCLC. The CHART regimen is, however, more intensive than conventional radiotherapy fractionation and is associated with increased risk of treatment morbidity and radiation induced complications. One complication associated with radiation treatment of lung tissue is radiation induced pneumonitis (RP). This systematic review of literature aimed to compare the incidence and severity of RP in patients receiving CHART with patients receiving conventional fractionation radiotherapy treatment. Method A systematic review of current evidence-based literature was employed, with the scope of the study extending to include a variety of databases such as Medline, PubMED and the Cochrane Library. The evidence was then filtered in order to meet inclusion/exclusion criteria and relevance criteria. Findings A total of 10 studies met the criteria for inclusion in the final review. The main reasons for exclusion of studies included lack of relevance, no provision of quantitative or qualitative data with respect to incidence of RP or evidence of methodological flaws. The review showed decreased incidence of RP amongst patients receiving CHART compared with patients receiving conventional fractionation radiotherapy (13.2% to 19.7% respectively). The study also highlighted several key predicative factors for RP including Mean Lung Dose, volume of lung receiving a dose greater than 20Gy, gender, age and smoking habits. Conclusion A range of variables have an effect on the incidence of RP, of which treatment regimen is one. However, as other predicative factors are present multivariate models would need to be constructed in order to provide an accurate assessment of RP risk.