Christina G. Selkirk

Parents’ Perceptions of Autism Spectrum Disorder Etiology and Recurrence Risk and Effects of their Perceptions on Family Planning: Recommendations for Genetic Counselors

Knowledge about the etiology of Autism Spectrum Disorders (ASDs) is increasing, but causes remain elusive for most cases. Genetic counselors are positioned to help families that have children with ASDs despite uncertainty regarding etiology. To determine how genetic counselors might best provide services, an anonymous survey was conducted with 255 parents whose children were diagnosed on the autism spectrum. Questions concerned: 1) their perceptions of ASD cause(s) and 2) recurrence risk, 3) whether perceived risk affected family planning decisions, 4) whether parents had received genetic services, and 5) how genetic counselors might assist families. The most prevalent perceived cause was genetic influences (72.6%). Most parents’ recurrence risk perceptions were inaccurately high and significantly affected family planning. Only 10% had seen a genetic professional related to an ASD. Parents provided several suggestions for genetic counselor best practices. Findings indicate the importance of genetic counselor awareness of parent perceptions in order to best help families who have children with ASDs.

Role of Engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men

Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0 ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals.

Common Genetic Variation at BARD1 Is Not Associated with Breast Cancer Risk in BRCA1 or BRCA2 Mutation Carriers

Background: Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies. Methods: A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser. In a second nonindependent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated. Results: The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 0.90 (95% CI: 0.71–1.15) in BRCA1 carriers and 0.87 (95% CI: 0.59–1.29) in BRCA2 carriers. Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk. Conclusion: Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers. Impact: Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk. Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk. Cancer Epidemiol Biomarkers Prev; 20(5); 1032–8. ©2011 AACR.

Evaluation of laboratory perspectives on hereditary cancer panels

Genetic counseling and testing for hereditary cancer susceptibility is a rapidly evolving field and partly a result of next-generation sequencing (NGS) allowing analysis of multiple cancer susceptibility genes simultaneously. This qualitative study explored laboratory perspectives on hereditary cancer panels. Semi-structured interviews were conducted with representatives of clinical laboratories offering hereditary cancer panels via NGS. Several themes emerged from the responses pertaining to hereditary cancer panel development, the importance of communication of panel properties with patients, variant reporting policies, and the future of hereditary cancer gene testing. Clinical utility was discussed as primary consideration during panel development. In addition, while participants indicated gene and syndrome overlap prompted panel development in general, laboratories differed in their opinions of whether phenotypic overlap warrants offering pan-cancer panels only versus cancer specific panels. Participants stressed the importance of patients understanding implications of panel testing, including what is tested for and limitations of testing. While all laboratories discussed the limitations of a variant of uncertain significance result, they differed significantly in their reporting methods. This study provides healthcare providers information on the laboratory approach to panel testing, highlighting both commonalities and differences in laboratory approaches, and may allow providers to make more informed decisions when ordering hereditary cancer panels.

To PSA or not to PSA? Still a question for men with a family history of prostate cancer.

Family history (FH) has long been known to increase a man’s risk of developing prostate cancer (PCa); there is an approximately twofold increased risk with an affected father and a threefold increased risk with an affected brother [1]. Furthermore, FH may increase the risk of more aggressive disease for family members, although results of studies in the PSA screening era have been inconsistent [2,3]. Using FH as a risk factor, the present analysis of the Swiss arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC) conducted by Randazzo et al. [4] sought to determine whether men with a positive FH of PCa, followed up by PSA screening every 4 years, would have a higher risk of having more aggressive disease.

Prostate-specific antigen velocity as a predictive biomarker in a prospective prostate cancer screening study (IMPACT study).

16 Background: We retrospectively assessed the clinical application of Prostate Specific Antigen Velocity (PSA V) in the IMPACT study (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in men at higher genetic risk and controls). This is a case-control prostate cancer (PrCa) screening study for men with a known genetic predisposition to PrCa; participants with a single PSA reading above 3ng/ml are offered diagnostic TRUS prostate biopsies (PB). Methods: We calculated PSA velocity (PSA V) using all three validated methods, including the arithmetic mean, the linear regression and the first and last readings equations. Pearson chi-square test was used to compare PSA V between four genetic groups: BRCA1 carriers and BRCA1 negative controls and BRCA2 carriers and BRCA2 negative controls. Results: PSA V data were evaluated in 191 men who underwent a PB with a total of 57 PrCas diagnosed. PSA V using both a threshold of 0ng/ml/year and 0.75ng/ml/year in any of the three m...

MP69-05 PSA VALUES AND KINETICS OF BRCA1 AND BRCA2 MUTATION CARRIERS AT HIGH RISK FOR PROSTATE CANCER

METHODS: Overall, 10,311 men aged 55-70 years were randomized 1:1 between 1998 2003 to the screening or control group, respectively. Men with PSA between 1.0 2.99ng/ml and a F/T PSA of 20% underwent prostate biopsy at baseline (initial study during the first screening round) and were analyzed separately. Men were invited every 4 years for PSA-test. A PSA of 3.0ng/ml was used as a trigger for prostate biopsy. Through registry linkages, information on PCa incidence was obtained. Primary outcome measure was PCa diagnosis. PCa risk stratification was defined according to d`Amico criteria, high risk PCa included men with N1 and/or M1. F/T PSA at study entrance was divided into quartiles and Cox regression analysis was used to assess the influence of age, family history, baseline PSA and F/T PSA at study entrance. RESULTS: The median follow-up time was 12.2 years. At baseline, 1371 (31.6%) men had a PSA of 1.0 1.99 and 563 (12.9%) men had 2.0 2.99ng/ml. Mean age was 61.6 and 62.7 years, respectively. The cumulative hazard rate for intermediate or high risk PCa diagnosis among men with baseline PSA values of 1.00 1.99 and 2.00 2.99ng/ml was 6.0 and 7.5 times higher (95%CI 3.9-9.2, p < 0.0001; 95%CI 4.6-12.2, p < 0.0001) as compared tomenwith PSA values of 0 0.99 at study entrance, respectively. Men diagnosed with intermediate/high risk PCa during follow-up had statistically significant lower F/T PSA levels at baseline than those without cancer. After adjusting for age, PSA at baseline and family history on multivariate analysis, baseline F/T PSA was the most important predictor for intermediate or high risk PCa during follow-up. Compared to the highest F/T PSA quartile, the risk was more than doubled in the lowest F/T PSA quartile (HR 2.3, 95%CI 0.4-1.9; p 1⁄4 0.006). CONCLUSIONS: Lower F/T PSA at study entrance was significant predictor for intermediate or high risk PCa throughout the follow-up of 12.2 years. These results support the idea of incorporating F/T PSA as an essential element of the risk based model for the smarter PCa screening.