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Supplementary Table 2 from Screening for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) among Endometrial Cancer Patients

Endometrial cancer is the most common cancer in women with Lynch syndrome. The identification of individuals with Lynch syndrome is desirable because they can benefit from increased cancer surveillance. The purpose of this study was to determine the feasibility and desirability of molecular screening for Lynch syndrome in all endometrial cancer patients. Unselected endometrial cancer patients (N = 543) were studied. All tumors underwent microsatellite instability (MSI) testing. Patients with MSI-positive tumors underwent testing for germ line mutations in MLH1, MSH2, MSH6, and PMS2. Of 543 tumors studied, 118 (21.7%) were MSI positive (98 of 118 MSI high and 20 of 118 MSI low). All 118 patients with MSI-positive tumors had mutation testing, and nine of them had deleterious germ line mutations (one MLH1, three MSH2, and five MSH6). In addition, one case with an MSI-negative tumor had abnormal MSH6 immunohistochemical staining and was subsequently found to have a mutation in MSH6. Immunohistochemical staining was consistent with the mutation result in all seven truncating mutation–positive cases but was not consistent in two of the three missense mutation cases. We conclude that in central Ohio, at least 1.8% (95% confidence interval, 0.9-3.5%) of newly diagnosed endometrial cancer patients had Lynch syndrome. Seven of the 10 Lynch syndrome patients did not meet any published criteria for hereditary nonpolyposis colorectal cancer, and six of them were diagnosed at age >50. Studying all endometrial cancer patients for Lynch syndrome using a combination of MSI and immunohistochemistry for molecular prescreening followed by gene sequencing and deletion analysis is feasible and may be desirable. (Cancer Res 2006; 66(15): 7810-7)

Consensus guidelines for hereditary breast and ovarian cancer include management recommendations for pathogenic/likely pathogenic (P/LP) variants in

To assess the utilization of genetics on the United States Medical Licensing Examination (USMLE®). A team of clinical genetics educators performed an analysis of the representation of genetics content on a robust sample of recent Step 1, Step 2 Clinical Knowledge (CK), and Step 3 examination forms. The content of each question was mapped to curriculum recommendations from the peer reviewed Association of Professors of Human and Medical Genetics white paper, Medical School Core Curriculum in Genetics, and the USMLE Content Outline. The committee identified 13.4%, 10.4%, and 4.4% of Steps 1, 2 and 3 respectively, as having genetics content. The genetics content of the exams became less pertinent to the questions from Step 1 to 3, with decreasing genetics content by exam and increasing percentages of questions identified as having genetics content in the distractors only. The current distribution of genetics in USMLE licensing examinations reflects traditional curricular approaches with genetics as a basic science course in the early years of medical school and de-emphasizes clinical relevance of the field. These observations support the notion that further integration is required to move genetics into the clinical curriculum of medical schools and the clinical content of USMLE Step exams.

Background While most known causes of infertility relate to the health of the woman and/or her partner, questions have been raised regarding the possible contributions of transgenerational or epigenetic factors. Objective The goal of this hypothesis-generating work was to examine whether Generation 1's (G1's) age at the delivery of G2 (Generation 2) was associated with G2's fertility in later life. Methods We conducted a retrospective cohort study of women (G2s) recruited online in 2016. A questionnaire queried G2s regarding demographics and fertility. The primary exposure was G1's age at G2's birth. Outcome measures included the following: 12-month infertility, time to pregnancy, and childlessness. The adjusted relative risk (RR) of G2 infertility and childlessness by G1 age at G2's birth was estimated through a modified Poisson regression approach. The fecundity odds ratio (FOR) for the association between G1's age at G2 birth and time to pregnancy for G2 was estimated by discrete-time survival models, with complementary log-log link. Results A total of 2,854 women enrolled. We found no association between G1 age at G2's birth and G2 infertility. Being born to a G1 aged 15-19 years was associated with a longer time to pregnancy for G2 (FOR 0.84, 95% confidence interval 0.72, 0.99), relative to being born to a G1 aged 20-24 years. We observed the suggestion of a possible increased risk of childlessness among G2s born to older G1s, but the estimate was imprecise. Conclusions While being born to a G1 who was 15-19 years old was associated with an increase in G2 time to pregnancy, we found no association between G1 age at G2's birth and infertility and only the suggestion of a modest association with childlessness. These data suggest a possible subtle effect of G1 age at G2's birth on G2 fertility, which warrants further study.

Consensus guidelines for hereditary breast and ovarian cancer include management recommendations for pathogenic/likely pathogenic (P/LP) variants in ATM, CHEK2, PALB2, and other DNA damage repair (DDR) genes beyond BRCA1 or BRCA2. We report on clinical management decisions across three academic medical centers resulting from P/LP findings in DDR genes in breast/ovarian cancer patients. Among 2184 patients, 156 (7.1%) carried a P/LP variant in a DDR gene. Clinical follow-up information was available for 101/156 (64.7%) patients. Genetic test result-based management recommendations were made for 57.8% (n = 59) of patients and for 64.7% (n = 66) of patients’ family members. Most recommendations were made for moderate-to-high risk genes and were consistent with guidelines. Sixty-six percent of patients (n = 39/59) implemented recommendations. This study suggests that P/LP variants in DDR genes beyond BRCA1 and BRCA2 can change clinical management recommendations for patients and their family members, facilitate identification of new at-risk carriers, and impact treatment decisions. Additional efforts are needed to improve the implementation rates of genetic-testing-based management recommendations for patients and their family members.

Constitutional SMARCB1 mutations at 22q11.23 have been found in ~50% of familial and

Background: The Cognitive Behavior Survey (CBS) assesses learner behavior in healthcare-related fields. Purpose: The study aims were to evaluate the factorial validity of the CBS, which purports to measure three dimensions of learner behavior—conceptualization, reflection, and memorization—and propose and test an alternative model including its time invariance. Methods: The CBS was administered to 3 cohorts of medical students upon matriculation and at the end of their 1st and 2nd year. Results: Confirmatory factor analysis (CFA) did not support the original CBS model. Exploratory factor analysis (EFA) with an independent sample provided a new model. Retesting the EFA model using CFA with the original sample yielded a model with improved fit and time invariance. Conclusions: This study provides evidence for the original CBS 3-factor structure but requires alternative scoring for a time-invariant model.

e18705Background: Germline testing guidelines are centered on BRCA1 and BRCA2 despite clear medical management recommendations in several other high and moderate penetrance genes. Clinician utiliza...

Background The clinical utility of germline genetic testing for BRCA1 and BRCA2 has long been established. However, management recommendations for pathogenic variants in other genes, typically included in multigene panels, have only recently been included in consensus guidelines for HBOC. The clinician actions implemented for findings in these genes, and patient follow-up, are not yet well studied. We report interim results from a multi-site study of clinical actions undertaken in patients presenting with HBOC and carrying a pathogenic germline mutation in cancer risk genes other than BRCA1/2. Methods We retrospectively examined a cohort of patients with a personal history of HBOC who had been referred for hereditary cancer multigene testing from three major academic medical centers. For patients with pathogenic findings in a non-BRCA1/2 cancer risk gene, ordering clinicians completed a short case report form describing the clinical actions taken in response to the genetic test result, and patient follow-up. Some patients were lost to follow-up and answers of “unknown” were permitted. Genes with positive findings included CHEK2, PALB2, ATM, MUTYH, RAD51C, TP53, MSH6, RAD50, APC, BARD1, BRIP1, MSH2, NF1, NBN, PMS2, and PTEN. Case report forms were available for 77 patients as of our cut off date, and these data were de-identified and summarized for this interim report. Additional cases continue to accrue in this ongoing study. Results In 57% (44/77) of cases, clinicians reported that counseling and/or clinical management recommendations were changed in response to the genetic test findings. Management changes included modification of imaging surveillance (38%), considered or recommended surgical prophylaxis (12%), modified surgical plan for an existing malignancy (5%), and for one patient each: inclusion in a research trial for PARP inhibitors, modification of colonoscopy schedule, and screening for cancers other than existing malignancy. Clinicians indicated that genetic test results changed management in 48% of patients, did not change management in 29%, and had unknown impact for 23%. Clinicians also reported that counseling and/or management for the patients' family members was changed in 67% (52/77) of cases, including family variant testing. 27% (21/77) of the patient families had cascade genetic testing, and one or more new carriers were identified in 47% (10) of the tested families. In 58% of cases, the impact of management recommendations on family members was unknown as of the case report date. Conclusions Pathogenic variants in non-BRCA genes are present in about 3-11% of patients with a history of HBOC. This study suggests that genetic test results in cancer genes beyond BRCA1/2 changed clinical management for a majority of patients and their family members, led to identification of new carriers, and directly impacted treatment decisions. In almost half of these patients, genetic test results impacted their health outcome, including those reported to be disease free after undergoing interventional or prophylactic surgery informed by their genetic variant. More research is needed to improve the implementation of genetic testing based management recommendations for patients and their family members. Citation Format: Esplin ED, Michalski S, Yang S, Hampel H, Jeter J, Sweet K, Pilarski R, Pearlman R, Shane K, Brock P, Westman J, Chittenden A, Stopfer J, Schneider K, Sacca R, Stickevers S, Kipnis L, Koeller D, Gaonkar S, Sotelo J, Vaccari E, Cochrane S, Champine M, Espinel W, Lincoln SE, Nussbaum RL. Clinical utility of finding pathogenic mutations beyond BRCA1/2 in breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-03-01.

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.

This article examines the impact of providing personalized familial cancer risk assessments with the Jameslink Cancer Risk Assessment Tool. Users of the Jameslink (N = 166) at eight community health fairs completed a survey including demographic, psychosocial and behavioral variables to better understand responses to the Jameslink. No differences were found between whites and those of other races for variables of interest, indicating suitability of the Jameslink for diverse populations. Those with higher Jameslink-assessed risk had higher perceived risk of cancer. Approximately half (53.8%) reported that they would speak to their physician about their Jameslink-assessed risk. A regression found Jameslink-assessed risk, cancer worry, and perceived risk of cancer predicted intentions to speak to a physician about their risk. In addition, open-ended data provided suggestions to improve the Jameslink. Changes in content and format were suggested; however most were happy with the program and encouraged its promotion. The lack of findings for differences as a function of race bolsters the use of computerized Cancer Risk Assessment Tools in diverse communities. The positive feedback of users and the close association between cancer risk assessment, perceived risk, and intention to speak to a physician are supportive of continued use and development of Cancer Risk Assessment Tools in the community to promote awareness of cancer risk.

Lynch syndrome is the predisposition to visceral malignancies that are associated with deleterious germline mutations in DNA mismatch repair genes, including MLH1, MSH2, MSH6, and PMS2. Muir-Torre syndrome is a variant of Lynch syndrome that includes a predisposition to certain skin tumors. We determined the frequency of Muir-Torre syndrome among 50 Lynch syndrome families that were ascertained from a population-based series of cancer patients who were newly diagnosed with colorectal or endometrial carcinoma. Histories of Muir-Torre syndrome-associated skin tumors were documented during counseling of family members. Muir-Torre syndrome was observed in 14 (28%) of 50 families and in 14 (9.2%) of 152 individuals with Lynch syndrome. Four (44%) of nine families with MLH1 mutations had a member with Muir-Torre syndrome compared with 10 (42%) of 24 families with MSH2 mutations (P = .302). Families who carried the c.942+3A>T MSH2 gene mutation had a higher frequency of Muir-Torre syndrome than families who carried other mutations in the MSH2 gene (75% vs 25%; P = .026). Muir-Torre syndrome was not found in families with mutations in the MSH6 or PMS2 genes. Our results suggest that Muir-Torre syndrome is simply a variant of Lynch syndrome. Screening for Muir-Torre syndrome-associated skin lesions among patients with Lynch syndrome is recommended.

There are approximately 160,000 Amish in North America who live mostly in rural areas in Pennsylvania, Ohio, and other Midwestern states.1,2 Individuals living outside the Amish community are familiar with some characteristics of the Amish lifestyle, including their avoidance of telephones and electricity and their use of a horse and buggy for transportation. Typical jobs performed by the Amish include farming and woodworking; however, Amish men also work in manufacturing jobs. The lifestyle of the Amish is largely influenced by the Ordnung, which is a set of rules dictating what is permitted and what is forbidden in their culture.1,2 These rules vary among Amish church districts and are periodically reviewed and revised. The Holmes County Amish settlement, with approximately 24,000 members, is the largest in the world.1 This settlement is centered in Holmes County, Ohio, but Amish can also be found in the surrounding counties. Holmes County is 1 of the 29 Appalachian counties in Ohio and, according to the 2000 US Census, 89% of the households in the county are in rural areas.3 Lower cancer incidence rates have been reported among Holmes County Amish adults compared to non-Amish adults in Ohio.4 In this cancer incidence study, men and women from 92 households randomly selected from the Holmes County Amish Directory were interviewed and reported on cancer occurrences in their extended families. The estimated age-adjusted cancer incidence rate for all cancers was 55% of the age-adjusted adult rate in Ohio. A reduction was also observed for tobacco-related cancer incidence, which was 37% of the age-adjusted rate for Ohio adults. This latter finding suggested a low prevalence of tobacco use in this group.4 Tobacco use is widely discouraged by leaders in many Amish church districts.2 However, there is a period of time in the life of an Amish person where some behaviors are more tolerated. Over 80% of youth are baptized into the church as adults and many of them make this decision following a period of rumspringa (“running around”), which occurs between the completion of school (after the 8th grade) and baptism, usually occurring during the early 20s in the life of an Amish person.1 During this time, Amish interact to a greater extent with the non-Amish world and their social norms are unlike those followed to that point.5 According to Reiling,5 alcohol use is somewhat common during this period. Depression is also more prevalent during this period and it is likely attributed to the fact that youth are engaging in behaviors that are not part of the Amish culture. In the general population, alcohol use and depression among youth are related to tobacco use.6 Thus, if the Amish develop an addiction to nicotine during rumspringa, it is not clear if the strong adult Amish cultural influence will change the behavior. There have been few studies that have examined tobacco use among the Amish. In 2003, a face-to-face version of the Behavioral Risk Factor Surveillance System (BRFSS) survey was conducted among Holmes County Amish adults and the estimated prevalence of tobacco use was low: 13% (95% confidence interval 7%-19%) among males and 0% among females.7 Biochemical verification of the self-reported behavior with a marker of nicotine exposure, such as cotinine, was not included in the BRFSS. In most non-diseased populations little is gained with biochemical verification, as there is generally good agreement between the self-report and a biological marker.8 However, in populations where tobacco use is stigmatized there may be a more marked difference between self-reported tobacco use and a true marker of tobacco exposure.8,9 No current estimates of biochemically verified tobacco use are available for the Amish, which is important from a public health perspective because it is not known if they could benefit from prevention and cessation programs. The objectives of this study were to estimate the self-reported and cotinine-verified prevalence of tobacco use among Amish males and females and to estimate the extent of tobacco use misclassification. It was hypothesized that Amish men and women would use tobacco at a significantly lower rate than the general population.

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.

There have been many papers on the diagnostic criteria for specific hereditary cancer susceptibility syndromes and the likelihood that an individual has a germline mutation in one of the various cancer susceptibility genes. To assist health care professionals in deciding when a cancer genetics consultation is appropriate, available reports were critically reviewed in order to develop a single set of risk assessment criteria.The criteria were based on a comprehensive review of publications describing diagnostic criteria for hereditary cancer syndromes and risk to first degree relatives of cancer patients. Priority was given to diagnostic criteria from consensus statements (for example, those from the National Comprehensive Cancer Network). Expert opinion from study personnel was then used to adopt a single set of criteria from other publications whenever guidelines differed.Based on family history, a set of criteria was developed to identify patients at risk for a hereditary cancer susceptibility syndrome, patients with moderate risk who might benefit from increased cancer surveillance, and patients who are at average risk. The criteria were applied to 4360 individuals who provided their cancer family history between July 1999 and April 2002, using a touch screen computer system in the lobby of a comprehensive cancer centre. They categorised an acceptable number of users into each risk level: 14.9% high risk, 13.7% moderate risk, and 59.6% average risk; 11.8% provided insufficient information for risk assessment.These criteria should improve ease of referral and promote consistency across centres when evaluating patients for referral to cancer genetics specialists.

PURPOSE: Obtainment of family history and accurate assessment is essential for the identification of families at risk for hereditary cancer. Our study compared the extent to which the family cancer history in the physician medical record reflected that entered by patients directly into a touch-screen family history computer program. PATIENTS AND METHODS: The study cohort consisted of 362 patients seen at a comprehensive cancer center ambulatory clinic over a 1-year period who voluntarily used the computer program and were a mixture of new and return patients. The computer entry was assessed by genetics staff and then compared with the medical record for corroboration of family history information and appropriate physician risk assessment. RESULTS: Family history information from the medical record was available for comparison to the computer entry in 69%. It was most often completed on new patients only and not routinely updated. Of the 362 computer entries, 101 were assigned to a high-risk category. Evidence in the records confirmed 69 high-risk individuals. Documentation of physician risk assessment (ie, notation of significant family cancer history or hereditary risk) was found in only 14 of the high-risk charts. Only seven high-risk individuals (6.9%) had evidence of referral for genetic consultation. CONCLUSION: This study demonstrates the need to collect family history information on all new and established patients in order to perform adequate cancer risk assessment. The lack of identification of patients at highest risk seems to be directly correlated with insufficient data collection, risk assessment, and documentation by medical staff.

OBJECTIVE—A computer based touchscreen family cancer history questionnaire was developed and implemented to facilitate the provision of cancer risk assessments for the ambulatory and outpatient populations of a free standing cancer hospital. METHODS—A questionnaire consisting of a series of branched point decision making screens was developed which enables the participant to enter demographic data, personal cancer history, and cancer histories for first and second degree relatives. A freestanding touchscreen computer kiosk system was used to place the questionnaire in public areas of the cancer hospital and clinic. Genetic professionals analysed the data received, using published criteria, and provided a basic cancer risk assessment and surveillance recommendations within 10 business days. A survey was completed by a small random group of users (n=59) three to six months after receipt of their risk assessment. RESULTS—After 11 months, 1440 people had entered information and received a written communication. Only 2% of completed questionnaires contained insufficient information to provide a basic risk assessment. Of the small group of participants surveyed, almost all (95%) felt "very comfortable" using the system, 93% remembered receiving the risk assessment letter when queried three to six months later, 42% felt their perceptions about cancer risk had changed, and 20% had made changes in their or their family's cancer surveillance practices. CONCLUSION—The touchscreen computer family history questionnaire allows easy collection of family history information, provision of risk assessments to a broad population, and promotes increased awareness of familial risk and appropriate surveillance. Keywords: genetic counselling; risk assessment; computers; medical informatics

Microcephalic osteodysplastic primordial dwarfism type I (MOPD I) is a rare autosomal recessive developmental disorder characterized by extreme intrauterine growth retardation, severe microcephaly, central nervous system abnormalities, dysmorphic facial features, skin abnormalities, skeletal changes, limb deformations, and early death. Recently, mutations in the RNU4ATAC gene, which encodes U4atac, a small nuclear RNA that is a crucial component of the minor spliceosome, were found to cause MOPD I. MOPD I is the first disease known to be associated with a defect in small nuclear RNAs. We describe here the clinical and molecular data for 17 cases of MOPD I, including 15 previously unreported cases, all carrying biallelic mutations in the RNU4ATAC gene.

Lynch syndrome is the most common cause of inherited colorectal cancer, accounting for approximately 3% of all colorectal cancer cases in the United States. In 2009, an evidence-based review process conducted by the independent Evaluation of Genomic Applications in Practice and Prevention Working Group resulted in a recommendation to offer genetic testing for Lynch syndrome to all individuals with newly diagnosed colorectal cancer, with the intent of reducing morbidity and mortality in family members. To explore issues surrounding implementation of this recommendation, the Centers for Disease Control and Prevention convened a multidisciplinary working group meeting in September 2010. This article reviews background information regarding screening for Lynch syndrome and summarizes existing clinical paradigms, potential implementation strategies, and conclusions which emerged from the meeting. It was recognized that widespread implementation will present substantial challenges, and additional data from pilot studies will be needed. However, evidence of feasibility and population health benefits and the advantages of considering a public health approach were acknowledged. Lynch syndrome can potentially serve as a model to facilitate the development and implementation of population-level programs for evidence-based genomic medicine applications involving follow-up testing of at-risk relatives. Such endeavors will require multilevel and multidisciplinary approaches building on collaborative public health and clinical partnerships.

The Amish, a unique community living in Ohio Appalachia, have lower cancer incidence rates than non-Amish living in Ohio Appalachia. The purpose of this study was to examine cancer screening rates among Amish compared to non-Amish adults living in Ohio Appalachia and a national sample of adults of the same race and ethnicity in an effort to explain cancer patterns.Face-to-face interviews focusing on perception of risk, cancer screening behaviors, and screening barriers were conducted among Amish (n = 134) and non-Amish (n = 154) adults living in Ohio Appalachia. Cancer screening rates were calculated and then compared to a national sample of adults.More Ohio Appalachia non-Amish males (35.9% vs 14.5%; P= .022) and females (33.3% vs 12.5%; P= .008) reported that they would probably develop cancer in the future compared to Amish males and females. Amish adults had significantly lower prostate (13.5% vs 63.1% vs 44.6%; P.001), colorectal (males: 10.3% vs 40.0% vs 37.2%, females: 8.6% vs 31.6% vs 42.9%; P.001), cervical (48.0% vs 84.0% vs 80.0%; P.001), and female breast (24.8% vs 53.7% vs 56.9%; P.05) cancer screening rates compared to Ohio Appalachia non-Amish participants and a national sample of adults, respectively. Barriers to cancer screening were similar among the 2 Ohio groups; however, Amish males reported that prostate cancer screening was not necessary more often than did Ohio Appalachia non-Amish males (78.6% vs 16.7%; P= .003).Lower rates of cancer screening were documented among the Amish and may be a contributing factor to the reduced cancer incidence rates reported among this population.

Pancreatitis is a rare occurrence in patients with cystic fibrosis (CF) affecting 1.2% of all patients, but it can be the first presenting sign in approximately 15% of adults with pancreatic sufficiency and a milder CF phenotype. We report a case of a woman with recurrent pancreatitis who has one cystic fibrosis-causing mutation (G551D) and the first known description of a pathologic duplication of exon 19 of the CF transmembrane conductance regulator (CFTR). A 30-year-old white woman with 30 attacks of pancreatitis over a 5-year period starting at age 25 presented to the genetics department. She was found to have a mutation in the SPINK1 gene, IVS3+184T>A, and one cystic fibrosis-causing mutation (G551D) prompting full gene sequencing of the CFTR, revealing an additional duplication of exon 19. Sweat chloride testing was elevated at 97 and 106 mmol/L. Despite normal growth parameters and lung function, it is important to be aware of recurrent pancreatitis as a presenting sign of CF. Comprehensive CF gene analysis is necessary to detect a second CF-causing mutation that may put patients at risk for more severe symptoms of pancreatitis. There is a significant difference in the prevalence of heterozygote mutations between available testing methods.

Small nuclear RNAs (snRNAs) are essential factors in messenger RNA splicing. By means of homozygosity mapping and deep sequencing, we show that a gene encoding U4atac snRNA, a component of the minor U12-dependent spliceosome, is mutated in individuals with microcephalic osteodysplastic primordial dwarfism type I (MOPD I), a severe developmental disorder characterized by extreme intrauterine growth retardation and multiple organ abnormalities. Functional assays showed that mutations (30G>A, 51G>A, 55G>A, and 111G>A) associated with MOPD I cause defective U12-dependent splicing. Endogenous U12-dependent but not U2-dependent introns were found to be poorly spliced in MOPD I patient fibroblast cells. The introduction of wild-type U4atac snRNA into MOPD I cells enhanced U12-dependent splicing. These results illustrate the critical role of minor intron splicing in human development.

The Amish have not been previously studied for cancer incidence, yet they have the potential to help in the understanding of its environmental and genetic contributions. The purpose of this study was to estimate the incidence of cancer among the largest Amish population.Adults from randomly selected households were interviewed and a detailed cancer family history was taken. Using both the household interview data and a search of the Ohio cancer registry data, a total of 191 cancer cases were identified between the years 1996 and 2003.The age-adjusted cancer incidence rate for all cancers among the Amish adults was 60% of the age-adjusted adult rate in Ohio (389.5/10(5) vs. 646.9/10(5); p0.0001). The incidence rate for tobacco-related cancers in the Amish was 37% of the rate for Ohio adults (p0.0001). The incidence rate for non-tobacco-related cancers in the Amish was 72% of the age-adjusted adult rate in Ohio (p = 0.0001).Cancer incidence is low in the Ohio Amish. These data strongly support reduction of cancer incidence by tobacco abstinence but cannot be explained solely on this basis. Understanding these contributions may help to identify additional important factors to target to reduce cancer among the non-Amish.

Purpose Identifying individuals with Lynch syndrome (LS) is highly beneficial. However, it is unclear whether microsatellite instability (MSI) or immunohistochemistry (IHC) should be used as the screening test and whether screening should target all patients with colorectal cancer (CRC) or those in high-risk subgroups. Patients and Methods MSI testing and IHC for the four mismatch repair proteins was performed on 500 tumors from unselected patients with CRC. If either MSI or IHC was abnormal, complete mutation analysis for the mismatch repair genes was performed. Results Among the 500 patients, 18 patients (3.6%) had LS. All 18 patients detected with LS (100%) had MSI-high tumors; 17 (94%) of 18 patients with LS were correctly predicted by IHC. Of the 18 probands, only eight patients (44%) were diagnosed at age younger than 50 years, and only 13 patients (72%) met the revised Bethesda guidelines. When these results were added to data on 1,066 previously studied patients, the entire study cohort (N = 1,566) showed an overall prevalence of 44 of 1,566 patients (2.8%; 95% CI, 2.1% to 3.8%) for LS. For each proband, on average, three additional family members carried MMR mutations. Conclusion One of every 35 patients with CRC has LS, and each has at least three relatives with LS; all of whom can benefit from increased cancer surveillance. For screening, IHC is almost equally sensitive as MSI, but IHC is more readily available and helps to direct gene testing. Limiting tumor analysis to patients who fulfill Bethesda criteria would fail to identify 28% (or one in four) cases of LS.

It has been estimated that approximately 2% of the general population has a family history that is indicative of hereditary breast/ovarian cancer. We aim to further document the proportions of women identified by several protocols as having a positive family history of breast/ovarian cancer, as a prelude to offering genetic counseling and BRCA1/2 mutation testing. This is a critical component of the evidence base needed when considering implementation of family history screening in primary care. We apply six separate family history screening protocols for breast/ovarian cancer to four cohorts of women, 21 to 55 years of age, for whom self-reported personal, and first and second degree family histories of breast/ovarian cancer have been obtained. We analyzed family history for 3,073 women in the four cohorts. The screen positive rates among the protocols vary widely both within and among the cohorts. In Cohort 4, the screen positive rate ranges between 6.9% to 20.8%, depending on the protocol. Applying one of the protocols to the four cohorts yields screen positive rates between 5.0% and 16.7%. The proportion of women that is screen positive on all six protocols (or three, if Ashkenazi Jewish) ranges from 1.9% to 4.0%. Used alone, none of the recommended family history protocols yields an acceptable screen positive rate. A more acceptable 2% to 4% screen positive rate can be expected when all six protocols agree.

Endometrial cancer is the most common cancer in women with Lynch syndrome. The identification of individuals with Lynch syndrome is desirable because they can benefit from increased cancer surveillance. The purpose of this study was to determine the feasibility and desirability of molecular screening for Lynch syndrome in all endometrial cancer patients. Unselected endometrial cancer patients (N = 543) were studied. All tumors underwent microsatellite instability (MSI) testing. Patients with MSI-positive tumors underwent testing for germ line mutations in MLH1, MSH2, MSH6, and PMS2. Of 543 tumors studied, 118 (21.7%) were MSI positive (98 of 118 MSI high and 20 of 118 MSI low). All 118 patients with MSI-positive tumors had mutation testing, and nine of them had deleterious germ line mutations (one MLH1, three MSH2, and five MSH6). In addition, one case with an MSI-negative tumor had abnormal MSH6 immunohistochemical staining and was subsequently found to have a mutation in MSH6. Immunohistochemical staining was consistent with the mutation result in all seven truncating mutation–positive cases but was not consistent in two of the three missense mutation cases. We conclude that in central Ohio, at least 1.8% (95% confidence interval, 0.9-3.5%) of newly diagnosed endometrial cancer patients had Lynch syndrome. Seven of the 10 Lynch syndrome patients did not meet any published criteria for hereditary nonpolyposis colorectal cancer, and six of them were diagnosed at age >50. Studying all endometrial cancer patients for Lynch syndrome using a combination of MSI and immunohistochemistry for molecular prescreening followed by gene sequencing and deletion analysis is feasible and may be desirable. (Cancer Res 2006; 66(15): 7810-7)

We describe two children with Williams syndrome and infantile spasms. The diagnosis of Williams syndrome was confirmed by documentation of a deletion of the elastin gene/Williams syndrome region at 7q11.23. The diagnosis of infantile spasms was confirmed through the presence of interictal hypsarrhythmia. This represents one of the first reports of infantile spasms in the Williams syndrome.

Germ-line mutations in the mismatch-repair genes MLH1, MSH2, MSH6, and PMS2 lead to the development of the Lynch syndrome (hereditary nonpolyposis colorectal cancer), conferring a strong susceptibility to cancer. We assessed the frequency of such mutations in patients with colorectal cancer and examined strategies for molecular screening to identify patients with the syndrome.Patients with a new diagnosis of colorectal adenocarcinoma at the major hospitals in metropolitan Columbus, Ohio, were eligible for the study. Genotyping of the tumor for microsatellite instability was the primary screening method. Among patients whose screening results were positive for microsatellite instability, we searched for germ-line mutations in the MLH1, MSH2, MSH6, and PMS2 genes with the use of immunohistochemical staining for mismatch-repair proteins, genomic sequencing, and deletion studies. Family members of carriers of the mutations were counseled, and those found to be at risk were offered mutation testing.Of 1066 patients enrolled in the study, 208 (19.5 percent) had microsatellite instability, and 23 of these patients had a mutation causing the Lynch syndrome (2.2 percent). Among the 23 probands with the Lynch syndrome, 10 were more than 50 years of age and 5 did not meet the Amsterdam criteria or the Bethesda guidelines for the diagnosis of hereditary nonpolyposis colorectal cancer (including the use of age and family history to identify patients at high risk for the Lynch syndrome). Genotyping for microsatellite instability alone and immunohistochemical analysis alone each failed to identify two probands. In the families of 21 of the probands, 117 persons at risk were tested, and of these, 52 had Lynch syndrome mutations and 65 did not.Routine molecular screening of patients with colorectal adenocarcinoma for the Lynch syndrome identified mutations in patients and their family members that otherwise would not have been detected. These data suggest that the effectiveness of screening with immunohistochemical analysis of the mismatch-repair proteins would be similar to that of the more complex strategy of genotyping for microsatellite instability.

The purpose of this study was to determine whether four types of professionalism deficiencies in medical students identified during a first-year course on doctor-patient relationships might predict poor performance in third-year clerkships.Preceptors identified students who had deficiencies in interviewing patients: extreme shyness, poor process skills, paternalism, or a negative attitude toward interviewing. Deficient students were matched by academic ability to a control group. Performance on third-year clerkships was compared.Students with paternalistic behavior or negative attitudes had significantly lower third-year grades.Professionalism deficiencies that result in the inability of the student to establish patient rapport are detectable early and predict problems in future clinical performance.

Background: The PARP inhibitors are being developed in combination with chemotherapy or radiation with the hope of inhibiting base excision repair. Homozygous deficiency of BRCA genes has been identified as a potential predictor of response to PARPi. These genes are part of the FA repair pathway, comprised of ∼20 genes, which collaborate to activate FANCD2 by ubiquitinating the protein following DNA damage. The activated protein is subsequently transported to subnuclear foci, which are the sites of DNA repair. We developed a test, which can be performed in paraffin embedded cancer tissues to identify FA deficient pts based on functionality, rather than individual gene assessment; a triple antibody immunofluorescence screening (FANCD2/DAPI/Ki-67)(FATSI) for foci formation in the nucleus of proliferating cancer cells. Methods: Consenting pts with advanced solid malignancies had their archived tumor tissue screened for FANCD2 foci formation by FATSI, and if absent, offered participation in a two arms dose escalation trial with the PARPi veliparib, as monotherapy or in combination with MMC. Results: 428 patients have consented. Of 390 patients with available/interpretable results, 106 (27%) had absent foci. All major solid tumors were represented. Thirty-eight pts (13 with colon, 9 breast, 5 NSCLC, 2 SCLC, 2 ovarian cancer, 1 each with anal, small bowel, cholangio, ampullary, thymoma, prostate, bladder cancer) have received veliparib, 22 as monotherapy in escalating dose cohorts (starting at 50 mg PO BID continuously), and 16 following MMC 10 mg/m2 every 4 weeks (40mg/m2 cumulative cap) at 50 mg BID at increased duration cohorts (1, 2 and 3 weeks) every 4 weeks (100 and 200 mg BID for 3 weeks in subsequent cohorts). Maximum tolerated doses have not yet been reached for either arm of the study, although grades 2/3 thrombocytopenia and emesis have been noted in the combination arm at the higher doses. Current dose levels are: veliparib 200 mg BID as monotherapy and MMC/veliparib100 mg BID three weeks duration. Analysis for germ line mutations (BRCA1 and 2 sequencing and for the 5 most common BRCA1 large rearrangements) in peripheral blood cells among 38 pts showed 5 (3 breast, 1 ampullary, 1 ovarian carcinoma) BRCA abnormalities: 4 known deleterious mutations and 1 which favors polymorphisms. Two of the pts with deleterious mutations were unaware of a presence of a germline mutation prior to participation in the study. Three RECIST criteria responses occurred (1CR, 2 PR) (1 lung, 2 breast), all in the combination arm. Two breast cancer pts on monotherapy have prolonged stability (20 and 14 months). Family history in the pt with ampullary carcinoma (newly identified deleterious mutation) showed 4 cases of breast cancer. rH2AX (n=36) and PAR (n=10) analysis in PBMC suggests veliparib dose dependency (higher rH2AX induction, lower PAR level and slower recovery for higher doses) Conclusions: A substantial proportion of pts across several tumor histologies are FA functionally deficient. FATSI test can lead to their identification and detection of previously unknown germ line genetic abnormalities. Veliparib had few toxicities up to 200 mg BID and can be administered safely in combination with MMC. A dose dependency for its biological effect is suggested. Phase 2 studies at recommended doses should be performed to evaluate the clinical benefit potential of the approach used in this study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A99.

We describe two infants with Menkes disease who had serious gastrointestinal bleeding from solitary gastric polyps. Hemorrhage in one patient was acute and proved fatal. Histopathologic examinations showed submucosal vascular ectasia with mucosal hyperplasia, edema, and ulceration. Gastric polyps may represent an underappreciated clinical abnormality in Menkes disease.

Menkes steely hair disease (MSHD) is a rare disorder which typically results in severe mental retardation and death in early childhood. A 21-month-old boy with an atypical milder form was presented by Procopis et al. [1981]. A second child with the atypical form is presented here who has survived to age 9 years and is doing well clinically.

Moped injuries are an important cause of traffic-related injuries in children. An attempt was made to define the epidemiology as well as the nature and severity of injuries sustained in 88 moped-related accidents. Bicycle injuries among children (579) were used as a control. The patients with moped injuries were younger than expected (mean 12.8 years with a minimum legal driving age of 14 years in the study area). Among 26 hospital admissions due to moped accidents, there were 11 admissions to the intensive care unit, demonstrating the severe nature of the injuries. Fifty percent of the patients had orthopaedic injuries and 46% had neurologic injuries. These injuries resulted in an average length of hospitalization of 8.5 days (intensive care unit admissions lasted an average of 14.6 days). Recommendations are made to aid pediatricians in the counseling of patients and parents.

To the Editor.— In a previous report studying moped-related injuries in children,1 we urged pediatricians to support and promote legislation encouraging the legal, safe use of mopeds. Since the time of the initial study, the state of Ohio passed legislation requiring that moped drivers be aged 14 years or older, wear an approved safety helmet, carry no passengers, ride within 3 ft (0.9 m) of the right side of the road when possible, have a rearview mirror, and have turning signals on the moped.