Clinical Impact of Pathogenic Variants in DNA Damage Repair Genes beyond BRCA1 and BRCA2 in Breast and Ovarian Cancer Patients.

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.

Training the next generation of genomic medicine providers: trends in medical education and national assessment.

PURPOSE: To assess the utilization of genetics on the United States Medical Licensing Examination (USMLE®). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Maternal age at delivery and fertility of the next generation.

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.

Veliparib Alone or in Combination with Mitomycin C in Patients with Solid Tumors With Functional Deficiency in Homologous Recombination Repair.

BACKGROUND: BRCA germline mutations are being targeted for development of PARP inhibitors. BRCA genes collaborate with several others in the Fanconi Anemia (FA) pathway. We screened cancer patients' tumors for FA functional defects then aimed to establish the safety/feasibility of administering PARP inhibitors as monotherapy and combined with a DNA-breaking agent. METHODS: Patients underwent FA functional screening for the presence (or lack) of tumor FancD2 nuclear foci formation on their archival tumor material, utilizing a newly developed method (Fanconi Anemia triple-stain immunofluorescence [FATSI]), performed in a Clinical Laboratory Improvement Amendments-certified laboratory. FATSI-negative patients were selected for enrollment in a two-arm dose escalation trial of veliparib, or veliparib/mitomycin-C (MMC). RESULTS: One hundred eighty-five of 643 (28.7%) screened patients were FATSI-negative. Sixty-one received veliparib or veliparib/MMC through 14 dose levels. Moderate/severe toxicities included fatigue (DLT at veliparib 400mg BID), diarrhea, and thrombocytopenia. Recommended doses are 300mg BID veliparib and veliparib 200mg BID for 21 days following 10mg/m(2) MMC every 28 days. Six antitumor responses occurred, five in the combination arm (3 breast, 1 ovarian, 1 endometrial [uterine], and 1 non-small cell lung cancer). Two patients have received 36 and 60 cycles to date. BRCA germline analysis among 51 patients revealed five deleterious mutations while a targeted FA sequencing gene panel showed missense/nonsense mutations in 29 of 49 FATSI-negative tumor specimens. CONCLUSIONS: FATSI screening showed that a substantial number of patients' tumors have FA functional deficiency, which led to germline alterations in several patients' tumors. Veliparib alone or with MMC was safely administered to these patients and produced clinical benefit in some. However, a better understanding of resistance mechanisms in this setting is needed.

Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.

Constitutional SMARCB1 mutations at 22q11.23 have been found in ∼50% of familial and <10% of sporadic schwannomatosis cases. We sequenced highly conserved regions along 22q from eight individuals with schwannomatosis whose schwannomas involved somatic loss of one copy of 22q, encompassing SMARCB1 and NF2, with a different somatic mutation of the other NF2 allele in every schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples. LZTR1 germline mutations were identified in seven of the eight cases. LZTR1 sequencing in 12 further cases with the same molecular signature identified 9 additional germline mutations. Loss of heterozygosity with retention of an LZTR1 mutation was present in all 25 schwannomas studied. Mutations segregated with disease in all available affected first-degree relatives, although four asymptomatic parents also carried an LZTR1 mutation. Our findings identify LZTR1 as a gene predisposing to an autosomal dominant inherited disorder of multiple schwannomas in ∼80% of 22q-related schwannomatosis cases lacking mutation in SMARCB1.

The cognitive behavior survey: testing for factorial validity and time invariance across two years of medical school.

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.

Implementing screening for Lynch syndrome among patients with newly diagnosed colorectal cancer: summary of a public health/clinical collaborative meeting.

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.

Cancer screening practices among Amish and non-Amish adults living in Ohio Appalachia.

PURPOSE: 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. METHODS: 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. FINDINGS: 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). CONCLUSIONS: 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.

A novel exon duplication of the cystic fibrosis transmembrane conductance regulator in a patient presenting with adult-onset recurrent pancreatitis.

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.

Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I.

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.

Low cancer incidence rates in Ohio Amish.

BACKGROUND: 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. METHODS: 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. RESULTS: 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); p < 0.0001). The incidence rate for tobacco-related cancers in the Amish was 37% of the rate for Ohio adults (p < 0.0001). The incidence rate for non-tobacco-related cancers in the Amish was 72% of the age-adjusted adult rate in Ohio (p = 0.0001). CONCLUSION: 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.

Cancer risk and risk communication in urban, lower-income neighborhoods.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Efforts to decrease income barriers to cancer risk communication are needed.

Feasibility of screening for Lynch syndrome among patients with colorectal cancer.

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.

Lessons learned while developing a cancer family history campaign in the Columbus, Ohio metropolitan area.

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.

Promotion of cancer family history awareness: Jameslink Cancer Risk Assessment Tool at community health fairs.

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.

The frequency of Muir-Torre syndrome among Lynch syndrome families.

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.

Tobacco use among the Amish in Holmes County, Ohio.

PURPOSE: The objective of this study was to estimate tobacco use prevalence among the Amish in Holmes County, Ohio, using both self-report and a biochemical marker of nicotine exposure. METHODS: Amish adults (n=134) were interviewed as part of a lifestyle study. Self-reported tobacco use was measured using standardized questions, and cotinine was measured from a saliva sample. The prevalence of smoking, total tobacco use, and misclassification were estimated separately by gender, and then compared to 2 non-Amish groups. One group was selected from 2 counties contained within the Holmes County Amish settlement (n=154) and the other was representative of non-Hispanic whites in the United States (n=4,099). FINDINGS: No Amish women reported current tobacco use and only 2 reported former use. This was significantly different (P<.0001) from the patterns observed among non-Amish in the settlement counties (15.7%) and US white (23.3%) women. The prevalence of tobacco use among Amish men was 17.6% and this was significantly lower than estimates from non-Amish in the settlement counties (38.8%, P=.04) and US white (32.2%, P=.005) men. No Amish women and only 2 Amish men underreported tobacco use and misclassification was similar in the comparison groups. CONCLUSIONS: Tobacco use is significantly lower among adults in the largest Amish settlement in the world compared to their non-Amish neighbors in Appalachia Ohio and US whites. A strength of this study is that self report was verified with a marker of nicotine, a critical measure to include in any study conducted in a group that stigmatizes tobacco use.

Screen positive rates among six family history screening protocols for breast/ovarian cancer in four cohorts of women.

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.

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.