Genetic Predisposition to Cancer Elena Castro, MD, PhD Prostate Cancer and GU tumours Unit Spanish National Cancer Research Centre Madrid, Spain
Abstract 750O: Early detection of hereditary renal cell cancer by improved evaluation of spontaneous pneumothorax patients Abstract 751O: Prevalence of HOXB13G84E germline mutation in UK prostate cancers; correlation with tumours characteristics and outcomes Abstract 491PD: Lynch-like syndrome: Characterization and comparison with EPCAM deletion carriers Abstract 492PD: Functional analysis of the BRCA1 H1686Q sequence variant: From biology to clinic Abstract 493PD: A survey of genetic counsellors about the need of 18-25 year olds from families with hereditary breast and ovarian cancer syndrome
Abstract 8060P: Genomic alterations in patients showing multiple primary tumors and family history of cancer Abstract 8384P: Contribution of rare germline copy number variants and single nucleotide polymorphisms to familial colorectal cancer Abstract 5253P: A multidisciplinary approach to heredofamilial cancer syndromes: evaluation of the first four years of experience at a Spanish University Hospital Abstract 7924P: Prognosis of BRCA1 and BRCA2-related breast cancers: are there differences?
Abstract 750O Early detection of hereditary renal cell cancer by improved evaluation of spontaneous pneumothorax patients Paul C. Johannesma, MD et al
Birt-Hogg-Dubé Syndrome Birt Hogg Dubé (BHD) syndrome is an autosomal dominant, hereditary cancer syndrome in which affected individuals are at risk for the development of kidney tumours, pulmonary cysts, pneumotorax and cutaneous fibrofolliculomas. 80-90% pulmonary cysts 25-30% pneumotorax 75-90% fibrofolliculomas 25-30% renal cancer
How frequent is BHD among patients with a primary SP? Included patients N=42 Thoracic CT N=2 Not eligible due Bullous emphysema Included patients N=40 Negative family history PSP Positive family history PSP FLCN mutation analysis Dermatological examination FLCN mutation analysis Dermatological examination Pathogenic mutation Pathogenic mutation Renal MRI Renal MRI Family counseling Family counseling 26-30 September Johannesma 2014, PC, Reinhard Madrid, R, Kon Spain Y, et al. The prevalence of Birt-Hogg-Dubé syndrome among patients with apparently primary SP. Respirology (in revision) esmo.org
How frequent is BHD among patients with a primary SP? 7-9% of SP carry a germline FLCN mutation - Ren et al: 10/102 patients with SP - Johannesma: 3/42 patients with SP Thoracic CT Included patients N=42 N=2 Not eligible due Bullous emphysema Included patients N=40 Negative family history PSP Positive family history PSP FLCN mutation analysis Dermatological examination FLCN mutation analysis Dermatological examination Pathogenic mutation Pathogenic mutation Renal MRI Renal MRI Family counseling Family counseling 26-30 September Johannesma 2014, PC, Reinhard Madrid, R, Kon Spain Y, et al. The prevalence of Birt-Hogg-Dubé syndrome among patients with apparently primary SP. Respirology (in revision) esmo.org
Evaluation of clinical and radiological characteristics among 200 FLCN mutation carriers in BHD 55 families. FLCN + N=200 RCC: N=19 SP: N=60 28/55 families (51%) 1 patient with SP RCC + SP in family: N=15* * Including 7 patients with both RCC and SP So far detection of BHD through SP resulted in 15 RCC patients in our cohort with mean FU of 5 years (1-10)
Current advice if BHD is detected 1. Counseling family on pathogenic mutation 2. Follow up mutation carriers with MRI and/or US
Current advice if BHD is detected 1. Counseling family on pathogenic mutation 2. Follow up mutation carriers with MRI and/or US 1. 115 FLCN mutation carriers (Houweling AC, et al. Br. J. Cancer 2011; 105: 1912-1919) 2. Two new cases found during follow up (mean: 5 years follow up) 3. Extrapolating (2/115)x100 = 1.74 new cases per 5 years follow up 4. 0,30 new cases / 100 cases / year 5. 3 new cases of RCC /1000 cases/ year
Theoretical extrapolation current data: 1. Screening for pathogenic FLCN mutation of 3.6 patients per BHD family 2. Diagnosing 100 (new) families > 360 pathogenic FLCN mutation carriers 3. At age 70; 16-25%* lifetime risk to develop RCC will lead to 58-90 new RCC patients * In both studies the observation period is limited and % is based on limited observation Houweling AC, Gijezen LM, et al. Renal cancer and pneumothorax risk in BHDS; an analysis of 115 FLCN mutation carriers from 35 BHD families. Br. J. Cancer 2011; 105: 1912-1919 Toro JR, Pautler SE, Stewart L, et al. Lung cysts, spontaneous pneumothorax and genetic associations in 89 families with BHD. Am J Respir Crit Care Med. 2007;175:1044-53.
Flowchart for spontaneous pneumothorax Spontaneous pneumothorax
Flowchart for spontaneous pneumothorax Spontaneous pneumothorax - RCC in medical history? - Familial SP - Familial RCC Thoracic CT: Basal Lung cysts?
Flowchart for spontaneous pneumothorax Spontaneous pneumothorax - RCC in medical history? - Familial SP - Familial RCC + FLCN mutation analysis Thoracic CT: Basal Lung cysts? +
Flowchart for spontaneous pneumothorax Spontaneous pneumothorax - RCC in medical history? - Familial SP - Familial RCC + FLCN mutation analysis + Thoracic CT: Basal Lung cysts? + Family counseling Renal MRI Dermatological consultation
Conclusion In our pilot study 7.5% of all SP caused by pathogenic FLCN mutation Including (low dose) thoracic CT can lead to identification BHD families Annual renal imaging offered to affected relatives > detection RCC Limited period of observation leads to detection of RCC in early stage
UK 64m population Incidence of pneumotorax: 24 /100.000 / year (men) 10/100.000/year (women) 11,520 PSP/year If 3 RCC/1000 pneumothorax:.35 new cases /year 10.144RCC/ year.0.34% of all cases SPAIN 46.5m population Incidence of pneumothorax: 20/100.000/year (men) 6/100.000/year (women) 6,975 PSP/year If 3 RCC/1000 pneumothorax: 20 new cases/year 4.529 RCC/ year 0.44% of all cases
330 CT scans to diagnose 1 RCC
330 CT scans to diagnose 1 RCC - Larger studies, more relatives, longer screening periods - Better definition of patients that should undergo CT
Can we justify a CT scan for all SP based on this study? 330 CT scans to diagnose 1 RCC - Larger studies, more relatives, longer screening periods - Better definition of patients that should undergo CT
Abstract 751O Prevalence of HOXB13 G84E germline mutation and prostate cancer risk in the UK Christos Mikropoulos MD et al
Screening of 8652 PrCa cases (UKGPCS)and 5252 controls (ProtecT) HOXB13 G84E identified in 0.5% of healthy controls vs. 1.5% of PrCa OR=2.93 (95%CI: 1.94-4.59) relative risk of PrCa OR=4.53 (95%CI:2.86-7.34) relative risk of familial PrCa OR=3.11(95%CI:1.98-5) relative risk of early-onset PrCa (under 55 years)
Patients characteristics Abstract 751O
Patients characteristics Abstract 751O
Survival Data No detrimental impact on overall and prostate cancer specific survival Overall Survival Prostate Cancer Specific Survival controls G84E ca
HOXB13 G84E is a rare but recurrent germline mutation associated to familial PrCa (Ewing et al, N Engl J Med, 2012) Xu et al, Hum Genet, 2013
Shang et al, Eu Urol 2013
Shang et al, Eu Urol 2013
Mutation present in 1.5% of PrCa cases: 134 carriers Based on PSA, Gleason, TNM most cases had an intermediate risk of relapse» 5 years CSS is 95%
Mutation present in 1.5% of PrCa cases: 134 carriers Based on PSA, Gleason, TNM most cases had an intermediate risk of relapse» 5 years CSS is 95% No impact on survival Median follow-up and events (deaths) not disclosed Short follow-up and few events to see a difference
OR=3.11 relative risk of early-onset PrCa (under 55 years) However, no differences on age at diagnosis between carriers and non-carriers were seen in this series
HOXB13 Increased risk of PrCa (OR 3.6-8.5, depending on population) (Shang et al Eu Urol, 2013) Early onset Family History (Ewing et al, N Eng J Med, 2012) (Shang et al, Eu Urol, 2013) No association with aggressiveness has been seen Pseudohyperplastic-type features and markedly low prevalence of ERG + with increased prevalence of SPINK1 cancers (Smith S et al, Am J Surg Pathol, 2014) Impact on PrCa outcomes remains unknown
26-30 September 2014, Madrid, Spain Morrison et al; Oncologist, esmo.org 2010
Chromophobe Chromophobe + oncocytic Mixed pattern Bilateral. Multifocal Clinical implications of FLCN mutations still unknown Treatment as sporadic RCC Nephron sparing surgery Systemic for Metastatic Role of Adjuvant treatment? Lineham et al, Genome research, 2012
26-30 September 2014, Madrid, Spain Menko et al, Lancet Oncol, esmo.org 2010