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ABSTRACT: INTRODUCTION: Thousands of individuals have undergone mutational analysis of BRCA1 and BRCA2. The Ohio State University Clinical Cancer Genetics program has identified 466 individuals from 289 families with a mutation in BRCA1 or BRCA2. Excluding Ashkenazi Jewish founder mutations, we observed nine deleterious BRCA mutations five or more times in ostensibly unrelated families and another thirteen mutations in 3-4 families. HYPOTHESIS: We hypothesized that some of the rarer recurrent mutations observed in our population were due to different branches of the same family being tested independently without knowledge of previous testing of relatives. METHODS: We examined 90 pedigrees for individuals with the same mutations that were seen 3 or more times for shared reported family medical history or surnames. RESULTS: Familial links were made in 4 instances out of a total of 22 shared mutations despite the fact that individuals were not aware that another family member had been tested. CONCLUSION: As more individuals undergo BRCA testing, we propose that this phenomenon will become more common. Being unaware of previous testing in a family not only affects the risk assessment but also likely increases the costs associated with the genetic testing and subsequent cancer screening in many cases.
Clinical Genetics 05/2013; · 3.13 Impact Factor
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Christophe Rosty,
Michael D Walsh,
Rhiannon J Walters,
Mark Clendenning,
Sally-Ann Pearson,
Mark A Jenkins,
Aung Ko Win,
John L Hopper, Kevin Sweet,
Wendy L Frankel, [......],
Jack Goldblatt,
Kathy Tucker,
Sian Greening,
Michael R Gattas,
Sonja Woodall,
Julie Arnold,
Neal I Walker,
Susan Parry,
Joanne P Young,
Daniel D Buchanan
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ABSTRACT: Serrated polyposis (SP) is a clinically defined syndrome characterized by the occurrence of multiple serrated polyps in the large intestine. Individuals with SP and their relatives are at increased risk of colorectal carcinoma (CRC). We aimed to determine the pathologic and molecular profiles of CRCs in individuals fulfilling World Health Organization criteria for SP. A total of 45 CRCs were obtained from 38 individuals with SP (27 female and 11 male patients; median age at CRC diagnosis, 58.5 y) attending genetics clinics. Tumor samples were pathologically reviewed, screened for somatic BRAF and KRAS mutations, and analyzed immunohistochemically for mismatch repair protein (MMR) expression. Tumors were spread throughout the large intestine, with 64% located in the proximal colon. Mutations in BRAF and KRAS and immunohistochemical evidence of MMR deficiency were found in 46%, 5%, and 38%, respectively. Nearly half of CRCs were BRAF/KRAS wild type, and these were associated with distal location (63%) and MMR proficiency (84%). Overexpression of p53 and/or evidence of β-catenin activation were identified in 13 CRCs. Ten patients (26%) had synchronous or metachronous CRCs. In conclusion, the majority of CRCs arising in individuals with SP do not harbor molecular hallmarks of serrated pathway CRCs but show a diverse range of molecular profiles. The high proportion of multiple CRCs suggests that individuals with SP would benefit from frequent colonoscopic surveillance and from a consideration of a more extensive colectomy at the time of CRC diagnosis.
The American journal of surgical pathology 12/2012; · 4.06 Impact Factor
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ABSTRACT: Serrated polyposis syndrome (SPS) is poorly defined and patients have an increased but unspecified risk for colorectal carcinoma through the serrated pathway. Despite this association SPS remains relatively obscure and is therefore likely underrecognized. We determined the frequency of SPS among patients with any serrated polyps (SPs) over a 6-month "index" period, and in doing so we assessed the ability of surgical pathologists to improve SPS detection. Particular attention was given to the index procedure to assess the potential predictive value of the findings resulting from a single colonoscopy. A total of 929 patients with at least 1 SP were identified, 17 of whom (1.8%) were determined to meet World Health Organization criteria for SPS. Nine patients met the first criterion (≥ 5 proximal SPs, 2 of which are > 10 mm); 4 met the third criterion (> 20 SPs of any size distributed throughout the colon); and 4 met both criteria. Although no specific SP size or number at the index procedure was clearly superior in its ability to predict SPS, > 50% of cases would be detected if a cutoff of ≥ 3 SPs or a single SP ≥ 15 mm at the index procedure is used. In summary, SPS is rare but more likely underdiagnosed. Additional studies to address the underlying genetic basis for SPS are ongoing in order to shed further light on this syndrome. Surgical pathologists are in a unique position to assist in this endeavor by identifying those patients who either meet or seem to be at high risk of meeting World Health Organization criteria.
The American journal of surgical pathology 08/2012; 36(8):1178-85. · 4.06 Impact Factor
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Hereditary Cancer in Clinical Practice 04/2012; 9:1-2. · 1.68 Impact Factor
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Aung Ko Win,
Rhiannon J Walters,
Daniel D Buchanan,
Mark A Jenkins, Kevin Sweet,
Wendy L Frankel,
Albert de la Chapelle,
Diane M McKeone,
Michael D Walsh,
Mark Clendenning, [......],
Sian Greening,
Steve Gallinger,
Melyssa Aronson,
Renee Perrier,
Michael O Woods,
Jane S Green,
Neal Walker,
Christophe Rosty,
Susan Parry,
Joanne P Young
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ABSTRACT: Serrated polyposis (hyperplastic polyposis) is characterized by multiple polyps with serrated architecture in the colorectum. Although patients with serrated polyposis are known to be at increased risk of colorectal cancer (CRC) and possibly extracolonic cancers, cancer risk for their relatives has not been widely explored. The aim of this study was to estimate the risks of CRC and extracolonic cancers for relatives of patients with serrated polyposis.
A cohort of the 1,639 first- and second-degree relatives of 100 index patients with serrated polyposis recruited regardless of a family history of polyps or cancer from genetic clinics in Australia, New Zealand, Canada, and the USA, were retrospectively analyzed to estimate the country-, age-, and sex-specific standardized incidence ratios (SIRs) for relatives compared with the general population.
A total of 102 CRCs were observed in first- and second-relatives (SIR 2.25, 95% confidence interval (CI) 1.75-2.93; P<0.001), with 54 in first-degree relatives (SIR 5.16, 95% CI 3.70-7.30; P<0.001) and 48 in second-degree relatives (SIR 1.38, 95% CI 1.01-1.91; P=0.04). Six pancreatic cancers were observed in first-degree relatives (SIR 3.64, 95% CI 1.70-9.21; P=0.003). There was no statistical evidence of increased risk for cancer of the stomach, brain, breast, or prostate.
Our finding that relatives of serrated polyposis patients are at significantly increased risk of colorectal and pancreatic cancer adds to the accumulating evidence that serrated polyposis has an inherited component.
The American Journal of Gastroenterology 04/2012; 107(5):770-8. · 7.28 Impact Factor
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Christophe Rosty,
Daniel D Buchanan,
Michael D Walsh,
Sally-Ann Pearson,
Erika Pavluk,
Rhiannon J Walters,
Mark Clendenning,
Kevin J Spring,
Mark A Jenkins,
Aung K Win, [......],
Wendy L Frankel,
Melyssa Aronson,
Steve Gallinger,
Jack Goldblatt,
Sonja Woodall,
Julie Arnold,
Neal I Walker,
Jeremy R Jass,
Susan Parry,
Joanne P Young
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ABSTRACT: Serrated polyposis syndrome (SPS), also known as hyperplastic polyposis, is a syndrome of unknown genetic basis defined by the occurrence of multiple serrated polyps in the large intestine and associated with an increased risk of colorectal cancer (CRC). There are a variety of SPS presentations, which may encompass a continuum of phenotypes modified by environmental and genetic factors. To explore the phenotype of SPS, we recorded the histologic and molecular characteristics of multiple colorectal polyps in patients with SPS recruited between 2000 and 2010 from genetics clinics in Australia, New Zealand, Canada, and the United States. Three specialist gastrointestinal pathologists reviewed the polyps, which they classified into conventional adenomas or serrated polyps, with various subtypes, according to the current World Health Organization criteria. Mutations in BRAF and KRAS and mismatch repair protein expression were determined in a subset of polyps. A total of 100 patients were selected for the study, of whom 58 were female and 42 were male. The total polyp count per patient ranged from 6 to 150 (median 30). The vast majority of patients (89%) had polyposis affecting the entire large intestine. From this cohort, 406 polyps were reviewed. Most of the polyps (83%) were serrated polyps: microvesicular hyperplastic polyps (HP) (n=156), goblet cell HP (n=25), sessile serrated adenoma/polyps (SSA/P) (n=110), SSA/P with cytologic dysplasia (n=28), and traditional serrated adenomas (n=18). A further 69 polyps were conventional adenomas. BRAF mutation was mainly detected in SSA/P with dysplasia (95%), SSA/P (85%), microvesicular HP (76%), and traditional serrated adenoma (54%), whereas KRAS mutation was present mainly in goblet cell HP (50%) and in tubulovillous adenoma (45%). Four of 6 SSA/Ps with high-grade dysplasia showed loss of MLH1/PMS2 expression. CRC was diagnosed in 39 patients who were more often found to have a conventional adenoma compared with patients without CRC (P=0.003). Patients with SPS referred to genetics clinics had a pancolonic disease with a high polyp burden and a high rate of BRAF mutation. The occurrence of CRC was associated with the presence of conventional adenoma.
The American journal of surgical pathology 04/2012; 36(6):876-82. · 4.06 Impact Factor
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Nasim Mavaddat,
Daniel Barrowdale,
Irene L Andrulis,
Susan M Domchek,
Diana Eccles,
Heli Nevanlinna,
Susan J Ramus,
Amanda Spurdle,
Mark Robson,
Mark Sherman, [......],
Kunle Odunsi,
Lara Sucheston,
Simon A Gayther,
Kate Nathanson,
Jenny Gross,
Christine Walsh,
Beth Karlan,
Georgia Chenevix-Trench,
Douglas F Easton,
Antonis C Antoniou
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ABSTRACT: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.
We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.
There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%). CONCLUSIONS/IMPACT: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis.
Cancer Epidemiology Biomarkers & Prevention 12/2011; 21(1):134-47. · 4.12 Impact Factor
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Jan Lubinski,
Tomasz Huzarski,
Tomasz Byrski,
Henry T Lynch,
Cezary Cybulski,
Parviz Ghadirian,
Malgorzata Stawicka,
William D Foulkes,
Ewa Kilar,
Charmaine Kim-Sing,
Susan L Neuhausen,
Susan Armel,
Dawna Gilchrist, Kevin Sweet,
Jacek Gronwald,
Andrea Eisen,
Bohdan Gorski,
Ping Sun,
Steven A Narod
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ABSTRACT: Women with a BRCA1 mutation face a high lifetime risk of breast cancer. It is unknown to what extent environmental factors modify the inherent genetic risk. If women from different countries, but with similar mutations, experience different levels of cancer risk, nongenetic risk modifiers are likely to be present. Study subjects were a cohort of 1477 women with a BRCA1 mutation, from Canada (n = 358), the United States (n = 256) and Poland (n = 863). The women were followed for a mean of 4.3 years and 130 incident cases of breast cancer were recorded. Annual cancer incidence rates were calculated, and based on these, penetrance curves were constructed for women from North America and Poland. In a Cox proportional hazards model, residence in Poland, versus North America, was associated with an adjusted hazard ratio of 0.54 (95% CI 0.34-0.86; p = 0.01). The risk of breast cancer to age 70 was estimated to be 49% for women from Poland and 72% for women from North America. Among women with BRCA1 mutations, the risk of breast cancer in women who reside in Poland is less than that of women who reside in North America. The reasons for the difference are unknown, but this observation suggests that environmental factors or genetic modifiers are important in determining risk.
International Journal of Cancer 08/2011; 131(1):229-34. · 5.44 Impact Factor
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Jessica Dennis,
Parviz Ghadirian,
Julian Little,
Jan Lubinski,
Jacek Gronwald,
Charmaine Kim-Sing,
William Foulkes,
Pal Moller,
Henry T Lynch,
Susan L Neuhausen,
Susan Domchek,
Susan Armel,
Claudine Isaacs,
Nadine Tung, Kevin Sweet,
Peter Ainsworth,
Ping Sun,
Daniel Krewski,
Steven Narod
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ABSTRACT: Alcohol consumption increases the risk of breast cancer among women in the general population, but its effect on women who carry a BRCA gene mutation is unclear. We conducted a case-control study of 1925 matched pairs of predominantly premenopausal women who carry a BRCA1 or a BRCA2 mutation. Information on current alcohol consumption was obtained from a questionnaire administered during the course of genetic counselling or at the time of enrollment. A modest inverse association between breast cancer and reported current alcohol consumption was observed among women with a BRCA1 mutation (OR = 0.82, 95% CI 0.70-0.96), but not among women with a BRCA2 mutation (OR = 1.00; 95% CI 0.71-1.41). Compared to non-drinkers, exclusive consumption of wine was associated with a significant reduction in the risk of breast cancer among BRCA1 carriers (p-trend = 0.01). Alcohol consumption does not appear to increase breast cancer risk in women carrying a BRCA gene mutation.
Breast (Edinburgh, Scotland) 12/2010; 19(6):479-83. · 2.09 Impact Factor
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Kelly Metcalfe,
Jan Lubinski,
Henry T Lynch,
Parviz Ghadirian,
William D Foulkes,
Charmaine Kim-Sing,
Susan Neuhausen,
Nadine Tung,
Barry Rosen,
Jacek Gronwald,
Peter Ainsworth, Kevin Sweet,
Andrea Eisen,
Ping Sun,
Steven A Narod
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ABSTRACT: Women who carry a deleterious mutation in BRCA1 or BRCA2 have high lifetime risks of breast and ovarian cancers. However, the influence of a family history of these cancers on these risks in women with BRCA mutations is unclear. We calculated cancer incidence rates for a multinational cohort comprising 3011 women with BRCA1 or BRCA2 mutations who were followed up for a mean of 3.9 years, during which time 243 incident breast or ovarian cancers were recorded. The 10-year cumulative risks of breast cancer were 18.1% (95% confidence interval [CI] = 13.3% to 22.8%) for women with a BRCA1 mutation and 15.2% (95% CI = 9.1% to 21.2%) for women with a BRCA2 mutation. Among women with a BRCA1 mutation, the risk of breast cancer increased by 1.2-fold for each first-degree relative with breast cancer before age 50 years (hazard ratio [HR] = 1.21; 95% confidence interval [CI] = 0.94 to 1.57) and the risk of ovarian cancer increased by 1.6 fold for each first- or second-degree relative with ovarian cancer (HR = 1.61; 95% CI = 1.21 to 2.14). Among women with a BRCA2 mutation, the risk of breast cancer increased by 1.7-fold for each first-degree relative younger than 50 years with breast cancer (HR = 1.67; 95% CI = 1.04 to 2.07).
CancerSpectrum Knowledge Environment 12/2010; 102(24):1874-8. · 14.07 Impact Factor
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Daniel D Buchanan, Kevin Sweet,
Musa Drini,
Mark A Jenkins,
Aung Ko Win,
Michael Gattas,
Michael D Walsh,
Mark Clendenning,
Diane McKeone,
Rhiannon Walters, [......],
Sian Greening,
Steven Gallinger,
Jane Green,
Michael O Woods,
Renee Spaetgens,
Albert de la Chapelle,
Finlay Macrae,
Neal I Walker,
Jeremy R Jass,
Joanne P Young
International Journal of Colorectal Disease 10/2010; · 2.38 Impact Factor
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Daniel D Buchanan, Kevin Sweet,
Musa Drini,
Mark A Jenkins,
Aung Ko Win,
Michael Gattas,
Michael D Walsh,
Mark Clendenning,
Diane McKeone,
Rhiannon Walters, [......],
Sian Greening,
Steven Gallinger,
Jane Green,
Michael O Woods,
Renee Spaetgens,
Albert de la Chapelle,
Finlay Macrae,
Neal I Walker,
Jeremy R Jass,
Joanne P Young
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ABSTRACT: Hyperplastic polyposis is a colonic polyposis condition of unknown aetiology. The purpose of this study was to examine the spectrum of phenotypic variation in patients with multiple serrated polyps as a basis for gene discovery.
One hundred and twenty-six patients with multiple (> or = 5) serrated polyps were recruited to the study. Polyp counts were extracted from histology and colonoscopy reports. Ethnicity was self-reported. Family history of cancer data were derived from pedigrees. Ascertainment status was classified as either index case or identified by screening.
The average reported polyp count was 39. Patients with highest polyp numbers were more likely to be male (P = 0.02). Colorectal cancer (CRC) was identified in 49 of 119 patients (41%) and 28% of these patients had multiple CRC. Young onset patients had higher polyp numbers (P = 0.03) and were more likely to have their CRC in the distal colon (P = 0.02). CRC was significantly associated with the presence of adenomas (P = 0.03). Patients were divided into moderate polyposis (5-79 serrated polyps) and dense polyposis (80 or more) categories. The dense polyposis category was associated with a lack of family history for CRC (P = 0.034) and male gender (P = 0.014), independent of ascertainment status and recruitment site.
Multiple serrated polyps were associated with an increased personal risk of CRC. A subset of patients with the highest polyp numbers was more likely to be male and to have no family history of CRC. This result suggests heterogeneous modes of inheritance and has implications for studies investigating the genetic basis of multiple serrated polyps.
International Journal of Colorectal Disease 03/2010; 25(6):703-12. · 2.38 Impact Factor
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Daniel D Buchanan, Kevin Sweet,
Musa Drini,
Mark A Jenkins,
Aung Ko Win,
Dallas R English,
Michael D Walsh,
Mark Clendenning,
Diane M McKeone,
Rhiannon J Walters, [......],
John A Baron,
John D Potter,
Robert Haile,
Wendy Frankel,
Albert de la Chapelle,
Finlay Macrae,
Christophe Rosty,
Neal I Walker,
Susan Parry,
Joanne P Young
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ABSTRACT: Patients with multiple serrated polyps are at an increased risk for developing colorectal cancer (CRC). Recent reports have linked cigarette smoking with the subset of CRC that develops from serrated polyps. The aim of this work therefore was to investigate the association between smoking and the risk of CRC in high-risk genetics clinic patients presenting with multiple serrated polyps.
We identified 151 Caucasian individuals with multiple serrated polyps including at least 5 outside the rectum, and classified patients into non-smokers, current or former smokers at the time of initial diagnosis of polyposis. Cases were individuals with multiple serrated polyps who presented with CRC. Controls were individuals with multiple serrated polyps and no CRC. Multivariate logistic regression was performed to estimate associations between smoking and CRC with adjustment for age at first presentation, sex and co-existing traditional adenomas, a feature that has been consistently linked with CRC risk in patients with multiple serrated polyps. CRC was present in 56 (37%) individuals at presentation. Patients with at least one adenoma were 4 times more likely to present with CRC compared with patients without adenomas (OR = 4.09; 95%CI 1.27 to 13.14; P = 0.02). For females, the odds of CRC decreased by 90% in current smokers as compared to never smokers (OR = 0.10; 95%CI 0.02 to 0.47; P = 0.004) after adjusting for age and adenomas. For males, there was no relationship between current smoking and CRC. There was no statistical evidence of an association between former smoking and CRC for both sexes.
A decreased odds for CRC was identified in females with multiple serrated polyps who currently smoke, independent of age and the presence of a traditional adenoma. Investigations into the biological basis for these observations could lead to non-smoking-related therapies being developed to decrease the risk of CRC and colectomy in these patients.
PLoS ONE 01/2010; 5(7):e11636. · 4.09 Impact Factor
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ABSTRACT: The majority of pathogenic mutations in BRCA1 result in a truncated protein. Although most missense changes in BRCA1 are of unknown functional significance, a handful of deleterious missense mutations have been identified. The majority of these occur in splice sites or highly conserved protein domains. Previously, we developed a predictive model, VUS Predict, to classify BRCA variants of uncertain significance as neutral or deleterious. It uses evolutionary prediction algorithms together with clinical information from cancer pathology reports and BRCA genetic testing results. Because of the higher probability that missense changes occurring in conserved BRCA1 domains are of pathogenic significance, we identified all individuals in our cohort who had been tested for BRCA1 and BRCA2 mutations who had missense changes in the BRCA1 ring finger domain and sought to classify those changes. We applied VUS Predict to three previously uncharacterized variants and four missense changes known to be deleterious. Two variants, L22S and T37K, were predicted to be deleterious and one variant, K45Q, was predicted to be neutral by VUS Predict. The mutations C39R, C44Y, C44S, and C61G were confirmed as deleterious.
Breast Cancer Research and Treatment 07/2009; 119(3):737-43. · 4.43 Impact Factor
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ABSTRACT: Mutations in tumor suppressor genes BRCA1 and BRCA2 confer an increased lifetime risk of breast and ovarian cancer. Loss of heterozygosity (LOH) of the wildtype allele has been observed in approximately 80% of tumors from BRCA1 carriers and 70% of tumors from BRCA2 carriers and accounts for the majority of the "second-hits" occurring in BRCA-related tumors. Few sporadic tumors have been reported to have mutations in BRCA. Some sporadic tumors do show LOH of BRCA1 and BRCA2. BRCA1 promoter methylation has also been observed in sporadic ovarian and breast tumors; however, BRCA2 promoter methylation has not been reported in sporadic tumors. The relationship between BRCA LOH and BRCA promoter methylation has not been well characterized in tumors from BRCA germline mutation carriers. The goal of this study was to determine if BRCA1 and BRCA2 promoter hypermethylation serves as a "second-hit" in tumors from mutation carriers that do not show LOH. We studied 38 tumors from BRCA1 carriers and 23 tumors from BRCA2 carriers for LOH. To determine if BRCA1 and BRCA2 promoter hypermethylation serves as a "second-hit" in tumors with germline mutations, we tested 15 tumors lacking LOH and nine tumors with LOH for BRCA1 or BRCA2 promoter methylation. We identified seven BRCA1 tumors and nine BRCA2 tumors lacking LOH. Of these, only one tumor with a BRCA2 mutation showed promoter methylation. These data indicate that promoter methylation is a not a frequent "second-hit" in tumors from BRCA1 or BRCA2 carriers.
Familial Cancer 05/2009; 8(4):339-46. · 1.30 Impact Factor
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ABSTRACT: Family history of cancer is an important risk factor for the disease, and communicating with family and physicians about family history is critical to cancer risk assessment. This study examined cancer risk communication with family and physicians.
A telephone interview was administered to randomly selected participants (n=217) from 5 urban, lower-income communities in 2006 and 2007. A large proportion of the population were minorities and of lower socio-economic status (47% African American, 43% incomes <$25,000). Most (76%) believed family history was important, and approximately half talked to their family (50%) or their physician (49%) about their cancer risk.
Respondents were equally likely as family members to initiate discussions about cancer risk, but respondents were more likely to initiate discussions with physicians. Logistic regression models were fit to talk to family, talk to physician, and perceived risk. In multivariable analysis, higher income and greater worry were associated with talking to family about risk, and higher income was associated with talking to physician about risk. Gender, family history and worry were associated with greater perceived risk.
Efforts to decrease income barriers to cancer risk communication are needed.
Preventive Medicine 01/2009; 48(4):392-6. · 3.22 Impact Factor
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ABSTRACT: Twenty percent of individuals with a strong family and/or personal history of breast and ovarian cancer carry a deleterious mutation in BRCA1 or BRCA2. Identification of mutations in these genes is extremely beneficial for patients pursuing risk reduction strategies. Approximately 7% of individuals who have genetic testing of BRCA1 and BRCA2 carry a variant of uncertain significance (VUS), making clinical management less certain. The majority of identified VUS occur only in one to two individuals; these variants are not able to be classified using current classification models with segregation analysis components.
To develop a clinically applicable method that can predict the pathogenicity of VUS that does not require familial information or segregation analysis, we identified characteristics of breast or ovarian tumors that distinguished sporadic tumors from tumors with BRCA1 or BRCA2 mutations. Study participants included individuals with known deleterious mutations in BRCA1 or BRCA2 and individuals with classified or unclassified BRCA variants.
We applied the models to 57 tumors with 43 different deleterious BRCA mutations and 57 tumors with 54 unique classified and unclassified BRCA variants. Of the 33 previously unclassified VUS studied, we found evidence of neutrality for 21.
Our models showed 98% sensitivity and 76% specificity for predicting classified DNA changes. We classified 64% of unknown variants as neutral. Classification of VUS as neutral will have immediate benefit for those individuals and their family members. These models are adaptable for the clinic and will be useful for individuals with limited available family history.
Journal of Clinical Oncology 10/2008; 26(33):5393-400. · 18.37 Impact Factor
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ABSTRACT: This paper discusses the lessons learned by our collaborative, transdisciplinary team while developing a pilot/demonstration educational health campaign geared toward underserved communities in the Columbus, Ohio metropolitan area. The objective of the current study was to determine the feasibility of a campaign to raise awareness of the association between family history and cancer risk and to inform individuals of the availability of Jameslink, an online familial cancer risk assessment tool. The research team included members of The Ohio State University Primary Care Research Institute, which includes a unique combination of expertise in Genetics, Behavioral Science, Social and Health Psychology, Communication, Medicine, and Methodology. The experience of the team in developing university and community partnerships, identifying stakeholders and formulating campaign messages is described. Groups who aided in this process as well as the perspectives they brought to the project are discussed. The lessons learned may be helpful to those developing similar community health projects.
Community Genetics 02/2008; 11(5):304-10. · 1.32 Impact Factor
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ABSTRACT: Although breast cancer is relatively common, only about 5% of cases are due to inheritance of highly penetrant cancer susceptibility genes. The majority of these are caused by mutations in the BRCA1 and BRCA2 genes, which are also associated with an increased risk of ovarian cancer. Increased surveillance, chemoprevention, and prophylactic surgeries are standard options for the effective medical management of mutation carriers. However, optimal management of female carriers who choose to undergo prophylactic surgeries is still poorly understood.
The authors provide an overview of the current literature regarding medical management options for women carriers of BRCA1 and BRCA2 gene mutations and the implications for those individuals who have chosen to undergo prophylactic surgeries.
BRCA mutation carriers who opt for prophylactic surgeries are still at risk for development of malignancy, and appropriate monitoring is warranted.
There are limited data on the appropriate medical management for BRCA mutation carriers after prophylactic surgeries. However, a management plan can be extrapolated from the general management recommendations for surveillance and other risk-reducing strategies in BRCA-positive individuals.
Cancer control: journal of the Moffitt Cancer Center 11/2007; 14(4):330-7.
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Kevin Sweet,
Joseph Willis,
Xiao-Ping Zhou,
Carol Gallione,
Takeshi Sawada,
Pia Alhopuro,
Sok Kean Khoo,
Attila Patocs,
Cossette Martin,
Scott Bridgeman,
John Heinz,
Robert Pilarski,
Rainer Lehtonen,
Thomas W Prior,
Thierry Frebourg,
Bin Tean Teh,
Douglas A Marchuk,
Lauri A Aaltonen,
Charis Eng
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ABSTRACT: Significant proportions of patients with hamartomatous polyposis or with hyperplastic/mixed polyposis remain without specific clinical and molecular diagnosis or present atypically. Assigning a syndromic diagnosis is important because it guides management, especially surveillance and prophylactic surgery.
To systematically classify patients with unexplained hamartomatous or hyperplastic/mixed polyposis by extensive molecular analysis in the context of central rereview of histopathology results.
Prospective, referral-based study of 49 unrelated patients from outside institutions (n = 28) and at a comprehensive cancer center (n = 21), conducted from May 2, 2002, until December 15, 2004. Germline analysis of PTEN, BMPR1A, STK11 (sequence, deletion), SMAD4, and ENG (sequence), specific exon screening of BRAF, MYH, and BHD, and rereview of polyp histology results were performed.
Molecular, clinical, and histopathological findings in patients with unexplained polyposis.
Of the 49 patients, 11 (22%) had germline mutations. Of 14 patients with juvenile polyposis, 2 with early-onset disease had mutations in ENG, encoding endoglin, previously only associated with hereditary hemorrhagic telangiectasia; 1 had hemizygous deletion encompassing PTEN and BMPR1A; and 1 had an SMAD4 mutation. One individual previously classified with Peutz-Jeghers syndrome had a PTEN deletion. Among 9 individuals with an unknown hamartomatous polyposis, 4 had mutations in STK11 (1), BMPR1A (2), and SMAD4 (1). Of the 23 patients with hyperplastic/mixed polyposis, 2 had PTEN mutations. Substantial discrepancies in histopathology results were seen.
Systematic molecular classification of 49 patients with unexplained hamartomatous or hyperplastic polyposis uncovered a potential novel susceptibility gene, ENG, for juvenile polyposis. Importantly, given the substantial proportion of patients found to have germline mutations, more extensive analysis of the known susceptibility genes is indicated. Rereview of histology results by a dedicated gastrointestinal pathologist should be considered routinely, as organ-specific surveillance rests on defining syndromic diagnosis.
JAMA The Journal of the American Medical Association 12/2005; 294(19):2465-73. · 30.03 Impact Factor
