Lisa Kessler

Mitotic recombination as evidence of alternative pathogenesis of gastrointestinal stromal tumours in neurofibromatosis type 1

Background: Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder resulting in the growth of a variety of tumours, and is inherited in an autosomal dominant pattern. Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that commonly harbour oncogenic mutations in KIT or PDGFRA and are thought to arise from the interstitial cells of Cajal (ICC; the pacemaker cells of the gut). Aim: To characterise two patients with NF1 and GISTs. Methods: Two patients were genotyped for germline mutations in NF1. GISTs from both patients were genotyped for somatic mutations in KIT and PDGFRA. Loss of heterozygosity (LOH) of NF1 in one GIST was assessed by genotyping seven microsatellite markers spanning 2.39 Mb of the NF1 locus in the tumour and in genomic DNA. The known germline mutation in NF1 was confirmed in GIST DNA by sequencing. The copy number of the mutated NF1 allele was determined by multiplex ligand-dependent probe amplification. Results: GISTs from both patients were of wild type for mutations in KIT and PDGFRA. In the GIST with adequate DNA, all seven markers were informative and showed LOH at the NF1 locus; sequencing of NF1 from that GIST showed no wild-type sequence, suggesting that it was lost in the tumour. Multiplex ligand-dependent probe amplification analysis showed that two copies of all NF1 exons were present. Conclusions: This is the first evidence of mitotic recombination resulting in a reduction to homozygosity of a germline NF1 mutation in an NF1-associated GIST. We hypothesise that the LOH of NF1 and lack of KIT and PDGFRA mutations are evidence of an alternative pathogenesis in NF1-associated GISTs.

Low rates of acceptance of BRCA1 and BRCA2 test results among African American women at increased risk for hereditary breast-ovarian cancer

Purpose: This study evaluated rates of BRCA1 and BRCA2 (BRCA1/2) test result acceptance among African American women and identified determinants of test result acceptance.Methods: Acceptance of BRCA1/2 test results was evaluated among 157 African American women at high and moderate risk for having a BRCA1/2 mutation who were offered genetic testing as part of a clinical genetic counseling research program.Results: Twenty-two percent of women received BRCA1/2 test results. Test result acceptance differed between women with ≥10% prior probability of having a BRCA1/2 mutation (34%) and those who had a 5% prior probability (8%). Among women with ≥10% prior probability, test result acceptors were most likely to be married (OR = 5.29, 95% CI = 1.82, 15.38, P = 0.002) and be less certain about their risk of developing cancer (OR = 3.18, 95% CI = 1.04, 9.80, P = 0.04).Conclusion: These results demonstrate that acceptance of BRCA1/2 test results may be limited among African American women. Being married and having less certainty about ones cancer risk may motivate acceptance of BRCA1/2 test results among African American women. It may be important to emphasize the possibility that BRCA1/2 test results may not clarify cancer risks during pre-test counseling with African American women to ensure informed decision-making about testing.

Attitudes about genetic testing and genetic testing intentions in African American women at increased risk for hereditary breast cancer

Purpose: To evaluate attitudes about the benefits, limitations, and risks of genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations and explore testing intentions in African American women at increased risk for hereditary breast cancer.Methods: Attitudes and intentions were evaluated by telephone in African American women (n = 74) at moderate and high risk for having a BRCA1/2 mutation.Results: Attitudes about the benefits of genetic testing were endorsed at a higher rate relative to limitations and risks; however, only 30% of respondents indicated that they would definitely have testing. In regression analysis, women most likely to be considering testing were those with fatalistic beliefs about cancer and those who believed they had a BRCA1/2 mutation. Women who had two or more affected relatives were also most likely to be considering testing. Women who had a personal history of cancer and those who believed they were at high risk for developing breast cancer were most likely to report greater limitations and risks. Pros scores were higher among women older than age 50 and those who were unemployed.Conclusion: Although African American women at moderate and high risk for BRCA1/2 mutations report favorable attitudes about genetic testing, interest in testing may be limited. Women affected with cancer and those who believe they are at a higher risk for developing breast cancer may be most concerned about the negative consequences of testing. Increased attention may need to be given to beliefs about genetic testing and testing motivations during genetic counseling with African American women.

Genetic testing for inherited breast cancer risk in African Americans.

As genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations is increasingly integrated into the clinical management of high-risk women, it will be important to understand barriers and motivations for genetic counseling among women from underserved minority groups to ensure equitable access to these services. Therefore, the purpose of this review was to synthesize literature on knowledge and attitudes about genetic counseling and testing for inherited breast cancer risk in African Americans. We also review studies that evaluated genetic testing intentions in this population. We conducted a search of the PubMed database to identify studies related to BRCA1/2 testing in African Americans that were published between 1995 and 2003. Overall, studies have evaluated ethnic differences in knowledge and attitudes about genetic testing or have compared African American and Caucasian women in terms of genetic testing intentions. These studies have shown that knowledge about breast cancer genetics and exposure to information about the availability of testing is low among African Americans, whereas expectations about the benefits of genetic testing are endorsed highly. However, much less is known about the psychological and behavioral impact of genetic testing for BRCA1/2 mutations in African Americans. Additional research is needed to understand barriers and motivations for participating in genetic testing for inherited cancer risk in African Americans. The lack of studies on psychological functioning, cancer surveillance, and preventive behaviors following testing is a significant void; however, for these studies to be conducted, greater access to genetic counseling and testing in African Americans will be needed.

Recruiting African American Women to Participate in Hereditary Breast Cancer Research

PURPOSEnThis study evaluated the process of recruiting African American women to participate in genetic counseling research for BRCA1 and BRCA2 (BRCA1/2) mutations with respect to referral, study enrollment, and participation in genetic counseling.nnnPATIENTS AND METHODSnAfrican American women (n = 783) were referred for study enrollment.nnnRESULTSnOf 783 referrals, 164 (21%) women were eligible for enrollment. Eligible women were most likely to be referred from oncology clinics (44%) and were least likely to be referred from general medical practices (11%; chi(2) = 96.80; P = .0001). Overall, 62% of eligible women enrolled onto the study and 50% of enrollees completed genetic counseling. Women with a stronger family history of cancer (odds ratio [OR] = 3.18; 95% CI, 1.36 to 7.44; P = .01) and those referred from oncology clinics and community oncology resources (OR = 2.97; 95% CI, 1.34 to 6.58; P = .01) were most likely to enroll onto the study. Referral from oncology clinics was associated significantly with participation in genetic counseling (OR = 5.46; 95% CI, 1.44 to 20.60; P = .01).nnnCONCLUSIONnDespite receiving a large number of referrals, only a small subset of women were eligible for enrollment. Oncology settings were the most effective at identifying eligible African American women and general medical practices were the least effective. Factors associated with enrollment included having a stronger family history of cancer and being referred from oncology clinics and community oncology resources. Referral from oncology clinics was the only factor associated significantly with participation in genetic counseling. Education about hereditary breast cancer may be needed among primary care providers to enhance appropriate referral of African American women to genetic counseling for BRCA1/2 mutations.

Knowledge About Genetics Among African Americans

Although knowledge about genetic concepts is important for individuals to be active participants in medical technologies that use genetic science, limited information is available on knowledge about basic genetic concepts and terminology in African Americans. The purpose of this study was to evaluate knowledge about general genetic concepts and medical genetics terminology among African Americans and to identify factors having independent associations with knowledge. Participants were 109 adult African Americans enrolled in a study on attitudes about race, genetics, and smoking. The majority of respondents were knowledgeable about general genetic concepts, but were less knowledgeable about medical genetics terminology. Education was the only factor independently associated with knowledge about sporadic disorders in multivariate logistic regression analysis. Respondents with at least some college education were most likely to be knowledgeable about sporadic disorders (OR=2.70, 95% CI=1.10, 6.67, p=.03). The results of this study suggest that genetics education targeted to African Americans may need to focus on increasing understanding about technical concepts related to genetics.

Psychological functioning in African American women at an increased risk of hereditary breast and ovarian cancer

Despite attention to psychological issues during genetic counselling and testing for hereditary breast and ovarian cancer risk, limited information is available on cancer‐specific distress among African American women being targeted for participation in counselling and testing. Therefore, the purpose of this study is to examine cancer‐specific distress in African American women at an increased risk of hereditary breast and ovarian cancer and to identify factors having significant associations with distress in this population. Respondents were 141 African American women identified for participation in genetic counselling and testing for BRCA1/2 mutations. Overall, respondents reported moderate levels of cancer‐specific distress. Younger age (coefficientu2003=u20036.0, pu2003=u20030.001), being unemployed (coefficientu2003=u2003−5.0, pu2003=u20030.01), and having a personal history of cancer (coefficientu2003=u20035.0, pu2003=u20030.02) had significant associations with intrusion. Younger age was also associated significantly with greater avoidance (ru2003=u20036.0, pu2003=u20030.02). These results suggest that African American women aged 50 and younger, those who are unemployed and women with a personal history of breast or ovarian cancer may be the most vulnerable to experiencing elevated levels of distress during genetic counselling and testing. Greater attention to psychological issues, including concerns about cancer and cancer risks, may be needed during genetic counselling and testing for BRCA1/2 mutations with these women.

Low Rates of African American Participation in Genetic Counseling and Testing for BRCA1/2 Mutations: Racial Disparities or Just a Difference?

Low rates of genetic counseling among African American women have generated concerns about disparities; however, to the extent that women’s decisions to accept or decline counseling are consistent with their values, then lower participation may reflect preferences and not disparities. We evaluated the extent to which women were satisfied with their decision about participating in genetic counseling for BRCA1/2 mutations and identified variables that were associated significantly with satisfaction. Prospective study of decision satisfaction with 135 African American women who had a minimum 5% prior probability of having a BRCA1/2 mutation. Decision satisfaction was evaluated one month after women were offered participation in genetic counseling using a structured questionnaire. Women were satisfied with their participation decision; more than 80% reported that their decision was consistent with their family values. However, women who declined pre-test counseling had significantly lower satisfaction scores. Our findings highlight the importance ensuring that racial differences that are due to preferences and values are not misclassified as disparities in order to identify and address the root causes of disparate treatment.

Early Onset Breast Cancer in a Registry-based Sample of African-American Women: BRCA Mutation Prevalence, and Other Personal and System-level Clinical Characteristics

Young Black women are disproportionately afflicted with breast cancer, a proportion of which may be due to BRCA1 and BRCA2 (BRCA) gene mutations. In a sample of Black women with early onset breast cancer, we evaluated BRCA mutations and explored personal and system‐level clinical characteristics. Black women diagnosed with invasive breast cancer (age ≤50) were recruited through the state cancer registry. Participants completed a questionnaire, genetic counseling and BRCA testing. Of the 48 women who consented to study participation, 46 provided a usable biologic specimen for BRCA testing. The overall prevalence of BRCA mutations and variants of uncertain significance (VUS) in participants was 6.5% and 34.8%, respectively. Of these, only 14 were referred for genetic counseling prior to study enrollment. Overall, those participants who chose to undergo bilateral mastectomy had a higher number of relatives with breast and ovarian cancer (p = 0.024) and a higher household income (p = 0.009). BRCA mutation prevalence and the high prevalence of VUS in participants are consistent with prior studies. Furthermore, clinical factors such as family history and financial means may influence type of surgery recommended and chosen, at both the provider and patient level, respectively. Finally, the limited number of patients referred for genetic counseling prior to surgical treatment for breast cancer may represent a missed clinical opportunity to inform surgical decisions.

Effect of Genetic Counseling and Testing for BRCA1 and BRCA2 Mutations in African American Women: A Randomized Trial

Background: Limited empirical data are available on the effects of genetic counseling and testing among African American women. Objective: To evaluate the effects of genetic counseling and testing in African American women based on different levels of exposure: (a) women who were randomized to culturally tailored (CTGC) and standard genetic counseling (SGC) to women who declined randomization (non-randomized group), (b) participants and non-participants in genetic counseling, and (c) BRCA1 and BRCA2 (BRCA1/2) test result acceptors and decliners. Design: Randomized trial of genetic counseling conducted from February 2003 to November 2006. Measures: We evaluated changes in perceived risk of developing breast cancer and cancer worry. Results: Women randomized to CTGC and SGC did not differ in terms of changes in risk perception and cancer worry compared to decliners. However, counseling participants had a significantly greater likelihood of reporting reductions in perceived risk compared to non-participants (p = 0.03). Test result acceptors also had a significantly greater likelihood of reporting decreases in cancer worry (p = 0.03). However, having a cancer history (p = 0.03) and a BRCA1/2 prior probability (p = 0.04) were associated with increases in cancer worry. Conclusions: Although CTGC did not lead to significant improvements in perceived risk or psychological functioning, African American women may benefit from genetic counseling and testing. Continued efforts should be made to increase access to genetic counseling and testing among African American women at increased risk for hereditary disease. But, follow-up support may be needed for women who have a personal history of cancer and those with a greater prior probability of having a BRCA1/2 mutation.