The role of Clinical Geneticists in Hereditary Cancer Management and Research

AbstractHereditary cancer refers to cancers caused by germline mutations in cancer predisposing genes. These mutations confer a significantly increased risk of cancer, are rare, and are in the majority of cases autosomal dominantly inherited.  Since the eighties of last century more than 115 cancer predisposing genes have been identified. In many Western countries genetic testing of patients and families with clustering of cancers started early, and was often performed by clinical geneticists (MDs performed the counselling and pedigree analyses) and by molecular biologists (in laboratories within departments of clinical genetics).  It turned out to be a long path to fully realize the promise of cancer predisposing genes. The clinical utility of many cancer genetic tests and subsequent risk reducing interventions has not yet been validated and pitfalls in e.g. misinterpretation of genetic variants showed up. However, without doubt genetic testing for mutations will eventually turn out as a strong tool to save lives from early cancer death and will become part of standard cancer care throughout the developed world.  Apart from primary surgical prevention, major progress is to be expected in earlier diagnoses, tailored therapies, and possibly chemoprevention.  Ideally researchers, clinical geneticists, molecular biologists, surgeons, oncologists, gynaecologists and other professionals will work together to reach this goal

HBOC in Europe

AbstractEurope has contributed to the majority of high-impact papers on genes and risk alleles in breast cancer and ovarian cancer susceptibility. Consortia like the Breast Cancer Linkage Consortium, Breast Cancer Association Consortium, and the Consortium of Investigators on Modifying genes in BRCA1/2, started from the nineties of the last century on.  Many highly motivated participants throughout Europe, the US, Australia and elsewhere contributed to the formation of huge datasets. Instrumental of the success of the consortia was also the leadership and knowledge of Dough Easton, UK, on the statistics of cancer genetics. The consortia papers have produced the data on which national guidelines in HBOC were formulated in West-Europe, the US and worldwide.   Genetic testing for HBOC is in most Western-European countries accepted and funded. Two decades after the identification of BRCA1 and BRCA2, attitudes towards genetic testing for HBOC are changing and becoming more ‘common’ practice. This offers opportunities to organize cancer genetic care more efficiently and at lower costs while informed decision making and consent of the patients remain in place

Contralateral breast cancer risk is influenced by the age at onset in BRCA1-associated breast cancer

BRCA1/2 mutation carriers diagnosed with breast cancer have a strongly elevated life-time risk of developing a contralateral tumour. We studied the contralateral breast cancer risk in 164 patients from 83 families with a proven BRCA1 mutation in relation to the age at diagnosis of the first primary breast cancer. In the actuarial outcomes after 10 years’ follow-up, 40% of the 124 BRCA1-patients diagnosed with breast cancer < 50 years had developed contralateral breast cancer, vs 12% of the 40 patients > 50 years at first diagnosis (Plogrank= 0.02). These data suggest that age at diagnosis of the first tumour should be taken into account when prophylactic mastectomy in BRCA1-patients is considered. © 2000 Cancer Research Campaig

Factors influencing uptake and timing of risk reducing salpingo-oophorectomy in women at risk of familial ovarian cancer: a competing risk time to event analysis

Objective To evaluate factors affecting uptake of risk-reducing salpingo-oophorectomy (RRSO) over time in women at high-risk of familial ovarian cancer. Design Prospective observational cohort. Setting Tertiary high-risk familial gynaecological cancer clinic. Population/sample New clinic attendees between March 2004 and November 2009, fulfilling the high-risk criteria for the UK Familial Ovarian Cancer Screening Study. Methods Risk management options discussed included RRSO and ovarian surveillance. Outcome data were analysed from a bespoke database. The competing risk method was used to model the cumulative incidence function (CIF) of RRSO over time, and the sub-hazard ratio (SHR) was used to assess the strength of the association of variables of interest with RRSO. Gray's test was used to evaluate the difference in CIF between two groups and multivariable competing risk regression analysis was used to model the cumulative probabilities of covariates on the CIF. Results Of 1133 eligible women, 265 (21.4%) opted for RRSO and 868 (69.9%) chose screening. Women undergoing RRSO were older (49 years, interquartile range 12.2 years) than those preferring screening (43.4 years, interquartile range 11.9 years) (P < 0.0005). The CIF for RRSO at 5 years was 0.55 (95% CI 0.45-0.64) for BRCA1/2 carriers and 0.22 (95% CI 0.19-0.26) for women of unknown mutation status (P < 0.0001); 0.42 (95% CI 0.36-0.47) for postmenopausal women (P < 0.0001); 0.29 (95% CI 0.25-0.33) for parity ≤1 (P = 0.009) and 0.47 (95% CI 0.39-0.55) for a personal history of breast cancer (P < 0.0001). Variables of significance from the regression analysis were: a BRCA1/2 mutation (SHR 2.31, 95% CI 1.7-3.14), postmenopausal status (SHR 2.16, 95% CI 1.62-2.87)) and a personal history of breast cancer (SHR 1.5, 95% CI 1.09-2.06). Conclusions Decision-making is a complex process and women opt for surgery many years after initial risk assessment. BRCA carriers, postmenopausal women and women who had breast cancer are significantly more likely to opt for preventative surgery. © 2012 RCOG

A novel CCM2 variant in a family with non-progressive cognitive complaints and cerebral microbleeds

Lobar cerebral microbleeds are most often sporadic and associated with Alzheimer's disease. The aim of our study was to identify the underlying genetic defect in a family with cognitive complaints and multiple lobar microbleeds and a positive family history for early onset Alzheimer's disease. We performed exome sequencing followed by Sanger sequencing for validation purposes on genomic DNA of three siblings with cognitive complaints, reduced amyloid-beta-42 in CSF and multiple cerebral lobar microbleeds. We checked for the occurrence of the variant in a cohort of 363 patients with early onset dementia and/or microbleeds. A novel frameshift variant (c.236_237delAC) generating a premature stop codon in the CCM2 gene shared by all three siblings was identified. Pathogenicity of the variant was supported by the presence of cerebral cavernous malformations in two of the siblings and by the absence of the variant exome variant databases. Two siblings were homozygous for APOE-ϵ4; one heterozygous. The cognitive complaints, reduced amyloid-beta-42 in CSF and microbleeds suggest preclinical Alzheimer's disease, but the stability of the cognitive complaints does not. We hypothesize that the phenotype in this family may be due to a combination of the CCM2 variant and the APOE status. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc

Prophylactic Mastectomy in BRCA1/2 Mutation Carriers and Women at Risk of Hereditary Breast Cancer: Long-Term Experiences at the Rotterdam Family Cancer Clinic

Background BRCA1/2 mutation carriers and women from a hereditary breast(/ovarian) cancer family have a highly increased risk of developing breast cancer (BC). Prophylactic mastectomy (PM) results in the greatest BC risk reduction. Long-term data on the efficacy and sequels of PM are scarce. Methods From 358 high-risk women (including 236 BRCA1/2 carriers) undergoing PM between 1994 and 2004, relevant data on the occurrence of BC in relation to PM, complications in relation to breast reconstruction (BR), mutation status, age at PM and preoperative imaging examination results were extracted from the medical records, and analyzed separately for women without (unaffected, n = 177) and with a BC history (affected, n = 181). Results No primary BCs occurred after PM (median follow-up 4.5 years). In one previously unaffected woman, metastatic BC was detected almost 4 years after PM (primary BC not found). Median age at PM was younger in unaffected women (P < .001), affected women more frequently were 50% risk carriers (P < .001). Unexpected (pre)malignant changes at PM were found in 3% of the patients (in 5 affected, and 5 unaffected women, respectively). In 49.6% of the women opting for BR one or more complications were registered, totaling 215 complications, leading to 153 surgical interventions (71%). Complications were mainly related to cosmetic outcome (36%) and capsular formation (24%). Conclusions The risk of developing a primary BC after PM remains low after longer follow-up. Preoperative imaging and careful histological examination is warranted because of potential unexpected (pre)malignant findings. The high complication rate after breast reconstruction mainly concerns cosmetic issues

CHEK2 1100delC in patients with metachronous cancers of the breast and the colorectum

BACKGROUND: Development of multiple primary tumors is a hallmark of hereditary cancer. At least 1/10 of breast cancers and colorectal cancers occur because of heredity and recently the cell cycle kinase 2, CHEK2 1100delC allele has been identified at a particularly high frequency in families with hereditary breast and colorectal cancer. METHODS: We utilized the Southern Sweden population-based cancer registry to identify women with double primary breast and colorectal cancer and sequenced tumor material in order to assess the contribution of the CHEK2 1100delC to the development of such metachronous tumors. RESULTS: Among the 75 patients successfully analyzed, 2 (2.5%) carried the CHEK2 1100delC allele. which was not significantly different (p = 0.26) from the 1% (3/300) carriers identified in the control group. CONCLUSION: In summary, our data suggest that the CHEK2 1100delC is not a major cause of double primary breast and colorectal cancer in Sweden, which suggests that this patient group should not routinely be screened for the CHEK2 1100delC variant

Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers

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