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Purpose: Some variants identified by multigene panel testing of DNA from blood present with low variant allele fraction (VAF), often a manifestation of clonal hematopoiesis. Research has shown that the proportion of variants with low VAF is especially high in TP53, the Li-Fraumeni syndrome gene. Based on the hypothesis that variants with low VAF are positively selected as drivers of clonal hematopoiesis, we investigated the use of VAF as a predictor of TP53 germline variant pathogenicity., Methods: We used data from 260,681 TP53 variants identified at 2 laboratories to compare the distribution of pathogenic and benign variants at different VAF intervals., Results: Likelihood ratios toward pathogenicity associated with a VAF < 26% equated to the American College of Medical Genetics/Association of Molecular Pathology strong strength level and were applicable for 1 in 5 variants of unknown significance., Conclusion: In conclusion, detection of variants with low VAF in blood can be considered an in vivo functional assay to aid assessment of TP53 variant pathogenicity., Competing Interests: Conflict of Interest Tina Pesaran, Kelly McGoldrick, Jill Dolinsky, and Lily Hoang are paid employees of Ambry Genetics. All other authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Women with triple negative breast cancer (TNBC) have a high prevalence of BRCA1 mutations, and current clinical guidelines recommend genetic testing for patients with TNBC aged ≤60 years. However, studies supporting this recommendation have included few older women with TNBC., Methods: Genetic testing results from women aged >60 years with TNBC enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) registry were included in this analysis. Prevalence of breast cancer-associated pathogenic variants (PVs) was compared across age groups., Results: We identified 151 women with TNBC aged >60 years (median 65 years; SD 5.3). Of these, 130 (86%) underwent genetic testing, and a breast cancer-associated PV was identified in 16 (12.3%; 95% CI 7-19): BRCA1 (n = 6), BRCA2 (n = 5), PALB2 (n = 2), ATM (n = 1) and RAD51C (n = 2). We found no differences in the proportion of patients with close blood relatives with breast (≤50 years) or ovarian cancer (any age) between PV carriers (37.5%) and non-carriers (34.2%) (p = 0.79). Among PV's carriers, the proportion of older women with a BRCA1 PV was lower when compared to younger women (37.5% vs 77.2%; p < 0.01)., Conclusion: Breast cancer-associated PVs were found in an important proportion of women aged >60 years with TNBC undergoing genetic testing, including greater representation of BRCA2. These results suggest that older women with TNBC should be offered genetic testing, and that their exclusion based on chronologic age alone may not be appropriate., Competing Interests: Declaration of Competing Interest Chavarri-Guerra: research support from Roche. Weitzel: Speakers bureau for AstraZeneca., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers., Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort., Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10 -72 ). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10 -50 ). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10 -22 ) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10 -12 ) carriers. The associations in the prospective cohort were similar., Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

Earlier age at onset is one characteristic of hereditary cancer syndromes, so most studies of genetic testing have focused on young patients with cancer. However, recent studies of multigene panel tests in unselected cancer populations have detected a considerable proportion of older patients with germline pathogenic variants (PVs) in cancer susceptibility genes. As the number of older patients with cancer continues to rise, clinicians should be aware of genetic/genomic cancer risk assessment (GCRA) criteria in both young and older adults. Identifying individuals with a germline PV in a cancer susceptibility gene may be important for precision therapy of current cancers and screening and prevention of new primary cancers, as well as cascade testing to identify high cancer risks for family members. Typically, hereditary predisposition germline genetic testing has been recommended for patients with early onset cancers and/or a family history of cancer. However, more recently international guidelines recommend testing for potential therapeutic intervention regardless of age for some tumors frequently seen in older patients, such as epithelial ovarian, pancreatic, and metastatic prostate and breast cancers. GCRA in older patients may present challenges including: clonal hematopoiesis (CH) confounding test interpretation, ethical aspects (autonomy, nonmaleficence, beneficence), patient health status, comorbidities, as well as lack of insurance coverage. These factors should be considered during genetic counseling and when considering cancer screening and risk reduction procedures. This manuscript reviews available data on common hereditary cancer syndromes in older patients and provides tools to help providers perform GCRA in this population., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Objective: Our goal was to identify pathogenic variants (PV) associated with germline cancer predisposition in an unselected cohort of older breast cancer survivors. Older patients with cancer may also be at higher risk for clonal hematopoiesis (CH) due to their age and chemotherapy exposure. Therefore, we also explored the prevalence of PVs suggestive of CH., Methods: We evaluated 44 older adults (65 years or older) diagnosed with breast cancer who survived at least two years after diagnosis from a prospective study, compared to healthy controls over the age of 65 (n = 36). DNA extracted from blood samples and a multi-gene panel test was used to evaluate for common hereditary cancer predisposition and CH PVs. Fisher's exact test was used to compare PV rates between groups., Results: Eight PVs in ATM, BRCA2 (x2), PALB2, RAD51D, BRIP1, and MUTYH (x2) were identified in 7 of 44 individuals with breast cancer (15.9%, 95% CI: 7-30%), whereas none were identified in healthy controls (p = .01). Results remained statistically significant after removal of MUTYH carriers (p = .045). PVs indicative of CH (ATM, NBN, and PPM1D [x2]) were identified in three of 27 individuals with breast cancer who received chemotherapy and in one healthy control., Conclusion: Moderate-risk and later disease onset high-risk hereditary cancer predisposition PVs were statistically significantly enriched in our survivorship cohort compared to controls. Because age- and chemotherapy-related CH are more frequent in this population, care must be taken to differentiate potential CH PVs from germline cancer predisposition PVs., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome, is caused by mismatch repair (MMR) gene mutations. However, data about MMR mutations in Hispanics are limited. This study aims to describe the spectrum of MMR mutations in Hispanics with LS and explore ancestral origins. This case series involved an IRB-approved retrospective chart review of self-identified Hispanic patients (n = 397) seen for genetic cancer risk assessment at four collaborating academic institutions in California, Texas, and Puerto Rico who were evaluated by MMR genotyping and/or tumor analysis. A literature review was conducted for all mutations identified. Of those who underwent clinical genetic testing (n = 176), 71 had MMR gene mutations. Nine mutations were observed more than once. One third (3/9) of recurrent mutations and two additional mutations (seen only once) were previously reported in Spain, confirming the influence of Spanish ancestry on MMR mutations in Hispanic populations. The recurrent mutations identified (n = 9) included both previously reported mutations as well as unique mutations not in the literature. This is the largest report of Hispanic MMR mutations in North America; however, a larger sample and haplotype analyses are needed to better understand recurrent MMR mutations in Hispanic populations., (Copyright © 2017. Published by Elsevier Inc.)

Germline mutations in BRCA1 or BRCA2 (BRCA) are responsible for 5-15% of breast (BC) and ovarian cancers (OC), predisposing to the development of early onset and often multiple primary tumors. Since mutation carriers can benefit from risk-reducing interventions, the identification of individuals with hereditary breast and ovarian cancer (HBOC) syndrome has a significant clinical impact. We assessed whether a panel assay for recurrent Hispanic BRCA mutations (HISPANEL) has an adequate breadth of coverage to be suitable as a cost effective screening tool for HBOC in a cohort of patients from Southern Brazil. A multiplex, PCR-based panel was used to genotype 232 unrelated patients for 114 germline BRCA mutations, finding deleterious mutations in 3.5% of them. This mutation prevalence is within the range detected by the HISPANEL among BC patients unselected for family history in other Latin American settings. The HISPANEL would have accounted for 27% of the BRCA mutations detected by complete sequencing in a comparison cohort (n = 193). This prevalence may be region-specific since significant differences in population structure exist in Brazil. Comprehensive analysis of BRCA in a larger set of HBOC patients from different Brazilian regions is warranted, and the results could inform customization of the HISPANEL as an affordable mutation screening tool., (Copyright © 2016. Published by Elsevier Inc.)

Germ-line mutations in MLH1, MSH2, MSH6, and PMS2 have been shown to cause Lynch syndrome. The penetrance of the cancer and tumor spectrum has been repeatedly studied, and multiple professional societies have proposed clinical management guidelines for affected individuals. Several studies have demonstrated a reduced penetrance for monoallelic carriers of PMS2 mutations compared with the other mismatch repair (MMR) genes, but clinical management guidelines have largely proposed the same screening recommendations for all MMR gene carriers. The authors considered whether enough evidence existed to propose new screening guidelines specific to PMS2 mutation carriers with regard to age at onset and frequency of colonic screening. Published reports of PMS2 germ-line mutations were combined with unpublished cases from the authors' research registries and clinical practices, and a discussion of potential modification of cancer screening guidelines was pursued. A total of 234 monoallelic PMS2 mutation carriers from 170 families were included. Approximately 8% of those with colorectal cancer (CRC) were diagnosed before age 30, and each of these tumors presented on the left side of the colon. As it is currently unknown what causes the early onset of CRC in some families with monoallelic PMS2 germline mutations, the authors recommend against reducing cancer surveillance guidelines in families found having monoallelic PMS2 mutations in spite of the reduced penetrance.Genet Med 18 1, 13-19.

Heterozygous loss-of-function SMAD4 mutations are associated with juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia. Some carriers exhibit symptoms of both conditions, leading to juvenile polyposis-hereditary hemorrhagic telangiectasia syndrome. Three families have been reported with connective tissue abnormalities. To better understand the spectrum and extent of clinical findings in SMAD4 carriers, medical records of 34 patients (20 families) from five clinical practices were reviewed. Twenty-one percent of the patients (7/34) had features suggesting a connective tissue defect: enlarged aortic root (n = 3), aortic and mitral insufficiency (n = 2), aortic dissection (n = 1), retinal detachment (n = 1), brain aneurysms (n = 1), and lax skin and joints (n = 1). Juvenile polyposis-specific findings were almost uniformly present but variable. Ninety-seven percent of the patients had colon polyps that were generally pan-colonic and of variable histology and number. Forty-eight percent of the patients (15/31) had extensive gastric polyposis. Hereditary hemorrhagic telangiectasia features, including epistaxis (19/31, 61%), mucocutaneous telangiectases (15/31, 48%), liver arteriovenous malformation (6/16, 38%), brain arteriovenous malformation (1/26, 4%), pulmonary arteriovenous malformation (9/17, 53%), and intrapulmonary shunting (14/23, 61%), were documented in 76% of the patients. SMAD4 carriers should be managed for juvenile polyposis and hereditary hemorrhagic telangiectasia because symptoms of both conditions are likely yet unpredictable. Connective tissue abnormalities are an emerging component of juvenile polyposis-hereditary hemorrhagic telangiectasia syndrome, and larger studies are needed to understand these manifestations.

Previous studies have suggested that BRCA-related epithelial ovarian cancer (EOC) conveys improved survival compared with that of sporadic EOC, but few studies have evaluated differences between BRCA genotypes. We compared characteristics and outcome by genotype in BRCA-associated EOC. Patients with BRCA-associated EOC who were diagnosed between January 30,1981, and December 30, 2008, were retrospectively identified through institutional review board-approved registry studies. We examined clinical characteristics, including event-free survival (EFS) and overall survival (OS), for BRCA1 versus BRCA2 patients. We identified 197 cases (148 BRCA1 cases; 49 BRCA2 cases); the median follow-up period was 63 months. BRCA2 patients were older (55.4 vs. 51.1 y; P < 0.01) and had fewer poorly differentiated tumors (67% vs. 82%; P < 0.05). No difference in EFS was observed. OS at 5 years was 75% in BRCA2 patients versus 61% in BRCA1 patients; this was not statistically significant. A non-significant trend toward improved OS was observed in BRCA2 patients with advanced-stage disease (hazard ratio = 0.59; 95% confidence interval 0.32-1.08). Age and grade differed significantly between BRCA1 and BRCA2 carriers in our study population. Whereas no overall differences in EFS or OS were observed, there was a trend toward improved OS in BRCA2 carriers with advanced-stage disease. This may reflect important differences between BRCA genotypes and should be validated in larger studies., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To assess the impact of a multimodal interdisciplinary course on genetic cancer risk assessment and research collaboration for community-based clinicians. Clinicians are increasingly requested to conduct genetic cancer risk assessment, but many are inadequately prepared to provide these services., Methods: A prospective analysis of 131 participants (48 physicians, 41 advanced-practice nurses, and 42 genetic counselors) from community settings across the United States. The course was delivered in three phases: distance didactic learning, face-to-face training, and 12 months of web-based professional development activities to support integration of skills into practice. Cancer genetics knowledge, skills, professional self-efficacy, and practice changes were measured at baseline, immediate, and 14 months postcourse., Results: Knowledge, skills, and self-efficacy scores were significantly different between practice disciplines; however, postscores increased significantly overall and for each discipline (P < 0.001). Fourteen-month practice outcomes reflect significant increases in provision of genetic cancer risk assessment services (P = 0.018), dissemination of cancer prevention information (P = 0.005) and high-risk screening recommendations (P = 0.004) to patients, patient enrollment in research (P = 0.013), and educational outreach about genetic cancer risk assessment (P = 0.003)., Conclusions: Results support the efficacy of the multimodal course as a tool to develop a genetically literate workforce. Sustained alumni participation in web-based professional development activities has evolved into a distance-mediated community of practice in clinical cancer genetics, modeling the lifelong learning goals envisioned by leading continuing medical education stakeholders.

Objective: Health literacy and numeracy are necessary to understand health information and to make informed medical decisions. This study explored the relationships among health literacy, numeracy, and ability to accurately interpret graphical representations of breast cancer risk., Methods: Participants (N=120) were recruited from the Facing Our Risk of Cancer Empowered (FORCE) membership. Health literacy and numeracy were assessed. Participants interpreted graphs depicting breast cancer risk, made hypothetical treatment decisions, and rated preference of graphs., Results: Most participants were Caucasian (98%) and had completed at least one year of college (93%). Fifty-two percent had breast cancer, 86% had a family history of breast cancer, and 57% had a deleterious BRCA gene mutation. Mean health literacy score was 65/66; mean numeracy score was 4/6; and mean graphicacy score was 9/12. Education and numeracy were significantly associated with accurate graph interpretation (r=0.42, p<0.001 and r=0.65, p<0.001, respectively). However, after adjusting for numeracy in multivariate linear regression, education added little to the prediction of graphicacy (r(2)=0.41 versus 0.42, respectively)., Conclusion: In our highly health-literate population, numeracy was predictive of graphicacy., Practice Implications: Effective risk communication strategies should consider the impact of numeracy on graphicacy and patient understanding., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Olaparib is a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. We aimed to assess the efficacy and safety of olaparib for treatment of advanced ovarian cancer in patients with BRCA1 or BRCA2 mutations., Methods: In this international, multicentre, phase 2 study, we enrolled two sequential cohorts of women (aged >or=18 years) with confirmed genetic BRCA1 or BRCA2 mutations, and recurrent, measurable disease. The study was undertaken in 12 centres in Australia, Germany, Spain, Sweden, and the USA. The first cohort (n=33) was given continuous oral olaparib at the maximum tolerated dose of 400 mg twice daily, and the second cohort (n=24) was given continuous oral olaparib at 100 mg twice daily. The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494442., Findings: Patients had been given a median of three (range 1-16) previous chemotherapy regimens. ORR was 11 (33%) of 33 patients (95% CI 20-51) in the cohort assigned to olaparib 400 mg twice daily, and three (13%) of 24 (4-31) in the cohort assigned to 100 mg twice daily. In patients given olaparib 400 mg twice daily, the most frequent causally related adverse events were nausea (grade 1 or 2, 14 [42%]; grade 3 or 4, two [6%]), fatigue (grade 1 or 2, ten [30%]; grade 3 or 4, one [3%]), and anaemia (grade 1 or two, five [15%]; grade 3 or 4, one [3%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, seven [29%]; grade 3 or 4, two [8%]) and fatigue (grade 1 or 2, nine [38%]; none grade 3 or 4)., Interpretation: Findings from this phase 2 study provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA-mutated advanced ovarian cancer., Funding: AstraZeneca., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer., Methods: Women (aged >or=18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234., Findings: Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%])., Interpretation: The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations., Funding: AstraZeneca., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Post-breast cancer treatment-related angiosarcomas were first observed in lymphedematous extremities after mastectomy and are now being reported with increasing frequency after lumpectomy and radiation. A case history is presented of a BRCA2 carrier who had a postmastectomy chest wall angiosarcoma but had neither therapeutic radiation nor clinically evident lymphedema. The absence of established risk factors led to speculation that the BRCA2 germline mutation could be a causative factor in the development of this patient's angiosarcoma. A literature review supported this concept.

Purpose: To describe nongenetics clinicians' perceptions and knowledge of cancer genetics and laws prohibiting genetic discrimination, attitudes toward the use of cancer genetic testing, and referral practices., Methods: Invitations to participate were sent to a random stratified sample of California Medical Association members and to all members of California Association of Nurse Practitioners and California Latino Medical Association. Responders in active practice were eligible and completed a 47-item survey., Results: There were 1181 qualified participants (62% physicians). Although 96% viewed genetic testing as beneficial for their patients, 75% believed fear of genetic discrimination would cause patients to decline testing. More than 60% were not aware of federal or California laws prohibiting health insurance discrimination--concern about genetic discrimination was selected as a reason for nonreferral by 11%. A positive attitude toward genetic testing was the strongest predictor of referral (odds ratio: 3.55 [95% confidence interval: 2.24-5.63], P < 0.001) in stepwise logistic regression analyses. The higher the belief in genetic discrimination, the less likely a participant was to refer (odds ratio: 0.72 [95% confidence interval: 0.518-0.991], P < 0.05), whereas more knowledge of genetic discrimination law was associated with comfort recommending (odds ratio: 1.18 [95% confidence interval: 1.11-1.25], P < 0.001) and actual referral (odds ratio: 3.55 [95% confidence interval: 2.24-5.63], P < 0.001)., Conclusion: Concerns about genetic discrimination and knowledge deficits may be barriers to cancer genetics referrals. Clinician education may help promote access to cancer screening and prevention.

Purpose: The impact of genetic cancer risk assessment on communication of cancer risk information within families is not fully known. We compared women's selection of family members for cancer risk communication and perceived barriers to this communication before genetic cancer risk assessment and 6 months afterward., Methods: Mailed surveys were used to collect prospective data from consenting women undergoing genetic cancer risk assessment because of a personal and/or family history of breast or ovarian cancers. Analysis included descriptive statistics, chi-square and McNemar tests, and paired t tests., Results: A total of 122 women met the study criteria. Although risk communications increased with first-degree relatives (84%-90% for females; 53%-62% for males) and decreased with non-first-degree relatives (21%-9%) before and after genetic cancer risk assessment, the degree of change was nonsignificant. The most commonly cited communication barrier was loss of contact (30%). Demographics, personal or family cancer history, and BRCA status did not significantly influence findings., Conclusions: There was a high degree of cancer risk communications with female first-degree relatives, but less so with male first-degree relatives, both before and after genetic cancer risk assessment. For the majority of women, interpersonal barriers did not preclude risk discussions. Further research is needed to identify how best to facilitate risk communication.

Purpose: Genetic cancer risk assessment is an emerging interdisciplinary practice that requires knowledge of genetics and oncology and specialized patient and family counseling skills. There is a growing need for cancer risk assessment practitioners, but most clinicians have inadequate cross-disciplinary training. An interdisciplinary course was developed to promote practitioner-level competency in cancer risk assessment to community-based clinicians. METHODS Participants were competitively selected from a pool of board-certified/eligible genetic counseling, masters-trained advanced practice nursing and physician applicants. Preference was given to clinicians with strong institutional backing practicing in underserved regions. The Continuing Medical Education/Continuing Education Unit-accredited course included didactic lectures, workshops, counseling practicum, and case conferences. Pre- and postcourse knowledge tests measured cancer genetics knowledge. Six month and one-year postcourse practice outcome surveys measured the impact of the program on professional self-efficacy and continued professional development., Results/conclusions: Forty clinicians completed the course (23 genetic counselors, 14 nurses, and three physicians). There was a significant overall increase of 22.6% in postcourse knowledge scores (P < 0.001). Thirty-five (88%) completed prescribed practice development activities. Of 29 respondents to 1-year postcourse survey, 76% reported increased professional self-efficacy; 66% reported increase in number of patients seen, and virtually all indicated interest in additional training. Outcomes demonstrate the value and efficacy of interdisciplinary training in genetic cancer risk assessment targeted to motivated community-based clinicians. Courses such as this can help address the need for competent cancer risk assessment services in communities outside the academic health center.

Molecular genetic alterations of chromosome 11p15.5 are a common finding in human cancer. We previously reported the characterization of two cosmids representing a 55-kilobase (kb) region of DNA surrounding the protooncogene HRAS1. A cluster of genes was identified adjacent to this locus, and one of these genes, HRC1, was divergently transcribed 30 kb upstream from HRAS1. A recent report placed the gene for placental ribonuclease inhibitor (RNH, ribonuclease-angiogenin inhibitor) within 90 kb of HRAS1 by pulsed-field gel electrophoresis (PFGE) mapping. We used recombinant P1 bacteriophage clones for physical mapping to determine the position of RNH relative to the HRAS1 transcription unit and HRC1 on chromosome 11p15.5. PFGE and Southern analysis of genomic DNA suggested the order of the genes (HRC1-HRAS1-RNH). P1 clones confirmed this assignment, and placed RNH within 30-50 kb of the 3' end of HRAS1. Furthermore, a single 80-kb P1 clone that bears all three genes was isolated and clarified the Not I restriction map for the HRAS1-RNH interval. Their close physical association was predicted by simple screening of an arrayed P1 library; the clone containing all three genes was selected from multiple positive signals obtained for each HRC1 and RNH because it mapped to the same library-well address.

The vitamin K metabolism of three patients with factitious purpura due to brodifacoum ingestion was studied. These patients, who presented with bleeding disorders due to deficiency of the vitamin K-dependent blood clotting proteins, were refractory to vitamin K1 at standard doses and required fresh frozen plasma to control bleeding until large doses of vitamin K1 were used. Metabolic studies demonstrated a blockade in vitamin K utilization, consistent with the presence of a vitamin K antagonist, but the patients denied use of anticoagulants. Warfarin assays were negative. We show that the factitious purpura in each patient was due to the surreptitious ingestion of brodifacoum, a potent second generation long-acting vitamin K antagonist used as a rodenticide. The coagulopathies responded to long-term therapy with large doses of vitamin K1. The serum elimination half-time for brodifacoum ranged from 16 to 36 days in these patients. The anticoagulant effect is of long duration, requiring chronic vitamin K treatment. With increasing availability of new rodenticides, factitious purpura due to surreptitious ingestion of these potent vitamin K antagonists is emerging as a new problem, previously associated with warfarin, with important implications for diagnosis and treatment.