Tester DJ, and MJ Ackerman. January 16, 2007 . Postmortem Long QT Syndrome Genetic Testing for sudden Unexplained Death in the Young. J. Am. Coll. Cardiol. 49(2):240-246.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester , Minnesota .

OBJECTIVES: This study sought to determine the spectrum and prevalence of long QT syndrome (LQTS)-associated mutations in a large cohort of autopsy-negative sudden unexplained death (SUD). BACKGROUND: Potentially heritable arrhythmia syndromes may explain a significant proportion of SUD in the young. Here, comprehensive postmortem LQTS genetic testing was performed in a cohort of SUD cases. METHODS: From September 1998 to March 2004, 49 cases of SUD (30 male patients, average age at death 14.2 +/- 10.9 years) were referred by medical examiners/coroners to Mayo Clinic's Sudden Death Genomics Laboratory. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, open reading frame/splice site mutational analysis was conducted for all 8 genes implicated in the pathogenesis of either LQTS (LQT1 to LQT6) or multisystem disorders involving either QT or QU prolongation. RESULTS: Ten LQTS-associated mutations (4 novel) were discovered in 10 SUD cases (20%, 8 female patients, average age at death 18.0 +/- 11.8 years). The LQTS susceptibility mutations LQT1 (5), LQT2 (3), and LQT3 (2) were far more common among women (8 of 18, 44%) than men (2 of 30, 6.7%, p < 0.008). The activities at the time of SUD included sleep (5), exertion (2), auditory arousal (1), and undetermined (2). Sudden death was the sentinel event in two-thirds of the cases. CONCLUSIONS: In this cardiac channel-focused molecular autopsy investigation of SUD, over one-third of decedents harbored a putative cardiac channel mutation: 7 previously reported to host mutations in the RyR2-encoded calcium release channel and now 10 with LQTS susceptibility mutations. Accordingly, postmortem cardiac channel genetic testing should be pursued in the evaluation of autopsy-negative SUD.

PMID: 17222736 [PubMed - as supplied by publisher]

Dorval M, Vallee MH, Plante M, Chiquette J, Gaudet M, and J Simard. January 2007. Effect of Women's Health Initiative Study Publication on Hormone Replacement Therapy among Women WHO Have Undergone BRCA1/2 Testing . Cancer Epidemiol. Biomarkers Prev. 16(1):157-160.

Unite de recherche en sante des populations, Centre hospitalier affilie universitaire de Quebec, Hopital du Saint-Sacrement, 1050 chemin Sainte-Foy, Quebec , Quebec , Canada G1S 4L8 . mdorval@uresp.ulaval.ca.

BACKGROUND: Since the publication, in July 2002, of the Women's Health Initiative (WHI) study, use of hormone replacement therapy (HRT) has decreased substantially in the general population. However, little is known about the effect of WHI study results on HRT use among women at high risk of breast cancer. The purpose of this study is to compare HRT use, prepublication versus postpublication of the WHI study, among women tested for BRCA1/2 mutations. METHODS: Participants were >35 years of age and had received their result of genetic testing (delivered within the interdisciplinary research program Interdisciplinary Health Research International Team on Breast Cancer Susceptibility), no later than February 28, 2005 . HRT use was reported in self-administered questionnaires, 1 year after result disclosure. Women returning their questionnaire before July 17, 2002 were classified as pre-WHI, whereas those returning it after October 15, 2002 comprised the post-WHI group. RESULTS: Four hundred fifty-seven women (199 and 258 in the pre-WIH and post-WHI groups, respectively) were included in this analysis. Globally, there was no difference in HRT use between prepublication and postpublication of the WHI study (8% and 11%, respectively; prevalence ratio, 0.74; 95% confidence interval, 0.43-1.28). However, noncarriers of the familial mutation were less likely to use HRT after publication of the WHI study results (9%) than before (21%; P = 0.03). CONCLUSIONS: Overall, HRT use among women tested for BRCA1/2 mutations is relatively low and apparently uninfluenced by the WHI study findings. However, the HRT use reduction among noncarriers is similar to that of women in the general population and consistent with the Canadian Cancer Society's recent HRT use recommendations. (Cancer Epidemiol Biomarkers Prev 2007;16(1):157-60).

PMID: 17220345 [PubMed - as supplied by publisher]

Hwang ES, McLennan JL, Moore DH, Crawford BB, Esserman LJ, and JL Ziegler. January 8, 2007 . Ductal Carcinoma In Situ in BRCA Mutation Carriers . J Clin. Oncol. Epub.

University of California , San Francisco (UCSF) Cancer Risk Program and the Carol Franc Buck Breast Care Center , UCSF Comprehensive Cancer Center , San Francisco CA .

PURPOSE: The current literature suggests that ductal carcinoma in situ (DCIS) of the breast is infrequently diagnosed in patients with BRCA germline mutations. We studied women at high risk of hereditary breast cancer syndromes who underwent testing for BRCA1 and BRCA2 to estimate DCIS prevalence and incidence in known BRCA-positive women compared with high-risk women who were mutation negative. METHODS: We analyzed breast event outcomes in a retrospective cohort of 129 BRCA-positive and 269 BRCA-negative women undergoing genetic testing for a BRCA mutation between September 1996 and December 2003 at University of California , San Francisco . We estimated the frequency of DCIS and invasive cancer and time to breast events from birth using a Cox proportional hazard model for competing risks. Histologic grade of DCIS was also compared between groups. RESULTS: Among BRCA carriers, 48 (37%) had DCIS (with or without invasive cancer) compared with 92 noncarriers (34%). Univariate analysis showed that both DCIS and invasive cancer had an earlier onset in mutation carriers than in noncarriers, although on a per-woman basis, this difference was not statistically significant. High-grade DCIS was more common in BRCA1 mutation carriers than in patients without a mutation (P = .02). CONCLUSION: DCIS is equally as prevalent in patients who carry deleterious BRCA mutations as in high familial-risk women who are noncarriers, but occurs at an earlier age. Our results argue for the consideration of DCIS as a criterion for BRCA risk assessments with appropriate weighting in prediction models such as BRCAPRO.

PMID: 17210933 [PubMed - as supplied by publisher]

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