Comparison of the clinical prediction model PREMM(1,2,6) and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer.

BACKGROUND: Lynch syndrome is caused by germline mismatch repair (MMR) gene mutations. The PREMM(1,2,6) model predicts the likelihood of a MMR gene mutation based on personal and family cancer history. OBJECTIVE: To compare strategies using PREMM(1,2,6) and tumour testing (microsatellite instability (MSI) and/or immunohistochemistry (IHC) staining) to identify mutation carriers. DESIGN: Data from population-based or clinic-based patients with colorectal cancers enrolled through the Colon Cancer Family Registry were analysed. Evaluation included MSI, IHC and germline mutation analysis for MLH1, MSH2, MSH6 and PMS2. Personal and family cancer histories were used to calculate PREMM(1,2,6) predictions. Discriminative ability to identify carriers from non-carriers using the area under the receiver operating characteristic curve (AUC) was assessed. Predictions were based on logistic regression models for (1) cancer assessment using PREMM(1,2,6), (2) MSI, (3) IHC for loss of any MMR protein expression, (4) MSI+IHC, (5) PREMM(1,2,6)+MSI, (6) PREMM(1,2,6)+IHC, (7) PREMM(1,2,6)+IHC+MSI. RESULTS: Among 1651 subjects, 239 (14%) had mutations (90 MLH1, 125 MSH2, 24 MSH6). PREMM(1,2,6) discriminated well with AUC 0.90 (95% CI 0.88 to 0.92). MSI alone, IHC alone, or MSI+IHC each had lower AUCs: 0.77, 0.82 and 0.82, respectively. The added value of IHC+PREMM(1,2,6) was slightly greater than PREMM(1,2,6)+MSI (AUC 0.94 vs 0.93). Adding MSI to PREMM(1,2,6)+IHC did not improve discrimination. CONCLUSION: PREMM(1,2,6) and IHC showed excellent performance in distinguishing mutation carriers from non-carriers and performed best when combined. MSI may have a greater role in distinguishing Lynch syndrome from other familial colorectal cancer subtypes among cases with high PREMM(1,2,6) scores where genetic evaluation does not disclose a MMR mutation.

Intimate partner violence among women veterans: previous interpersonal violence as a risk factor.

Experiences of abuse during childhood or military service may increase women veterans' risk for intimate partner violence (IPV) victimization. This study examined the relative impact of 3 forms of interpersonal violence exposure (childhood physical abuse [CPA], childhood sexual abuse [CSA], and unwanted sexual experiences during military service) and demographic and military characteristics on past-year IPV among women veterans. Participants were 160 female veteran patients at Veterans Afffairs hospitals in New England who completed a paper-and-pencil mail survey that included validated assessments of past-year IPV and previous interpersonal violence exposures. Women who reported CSA were 3.06 times, 95% confidence interval (CI) [1.14, 8.23], more likely to report past-year IPV relative to women who did not experience CSA. Similarly, women who reported unwanted sexual experiences during military service were 2.33 times, 95% CI [1.02, 5.35], more likely to report past-year IPV compared to women who did not report such experiences. CPA was not associated with IPV risk. Having less education and having served in the Army (vs. other branches) were also associated with greater risk of experiencing IPV in the past year. Findings have implications for assisting at risk women veterans in reducing their risk for IPV through detection and intervention efforts.

The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history.

BACKGROUND & AIMS: We developed and validated a model to estimate the risks of mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6 based on personal and family history of cancer. METHODS: Data were analyzed from 4539 probands tested for mutations in MLH1, MSH2, and MSH6. A multivariable polytomous logistic regression model (PREMM(1,2,6)) was developed to predict the overall risk of MMR gene mutations and the risk of mutation in each of the 3 genes. The discriminative ability of the model was validated in 1827 population-based colorectal cancer (CRC) cases. RESULTS: Twelve percent of the original cohort carried pathogenic mutations (204 in MLH1, 250 in MSH2, and 71 in MSH6). The PREMM(1,2,6) model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals [CIs]): male sex (1.9; 1.5-2.4), a CRC (4.3; 3.3-5.6), multiple CRCs (13.7; 8.5-22), endometrial cancer (6.1; 4.6-8.2), and extracolonic cancers (3.3; 2.4-4.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.82-0.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.83-0.92) for MSH2, and 0.81 (95% CI, 0.69-0.93) for MSH6; in validation, they were 0.88 for the overall cohort (95% CI, 0.86-0.90) and the population-based cases (95% CI, 0.83-0.92). CONCLUSIONS: We developed the PREMM(1,2,6) model, which incorporates information on cancer history from probands and their relatives to estimate an individual's risk of mutations in the MMR genes MLH1, MSH2, and MSH6. This Web-based decision making tool can be used to assess risk of hereditary CRC and guide clinical management.

Performance of PREMM(1,2,6), MMRpredict, and MMRpro in detecting Lynch syndrome among endometrial cancer cases.

PURPOSE: Lynch syndrome accounts for 2-5% of endometrial cancer cases. Lynch syndrome prediction models have not been evaluated among endometrial cancer cases. METHODS: Area under the receiver operating curve (AUC), sensitivity and specificity of PREMM(1,2,6), MMRpredict, and MMRpro scores were assessed among 563 population-based and 129 clinic-based endometrial cancer cases. RESULTS: A total of 14 (3%) population-based and 80 (62%) clinic-based subjects had pathogenic mutations. PREMM(1,2,6), MMRpredict, and MMRpro were able to distinguish mutation carriers from noncarriers (AUC of 0.77, 0.76, and 0.77, respectively), among population-based cases. All three models had lower discrimination for the clinic-based cohort, with AUCs of 0.67, 0.64, and 0.54, respectively. Using a 5% cutoff, sensitivity and specificity were as follows: PREMM(1,2,6), 93% and 5% among population-based cases and 99% and 2% among clinic-based cases; MMRpredict, 71% and 64% for the population-based cohort and 91% and 0% for the clinic-based cohort; and MMRpro, 57% and 85% among population-based cases and 95% and 10% among clinic-based cases. CONCLUSION: Currently available prediction models have limited clinical utility in determining which patients with endometrial cancer should undergo genetic testing for Lynch syndrome. Immunohistochemical analysis and microsatellite instability testing may be the best currently available tools to screen for Lynch syndrome in endometrial cancer patients.

Impact of genetic testing on endometrial cancer risk-reducing practices in women at risk for Lynch syndrome.

OBJECTIVE: Due to the increased lifetime risk of endometrial cancer (EC), guidelines recommend that women with Lynch syndrome (LS) age ≥ 35 undergo annual EC surveillance or prophylactic hysterectomy (PH). The aim of this study was to examine the uptake of these risk-reducing strategies. METHODS: The study population included women meeting clinical criteria for genetic evaluation for LS. Data on cancer risk-reducing behaviors were collected from subjects enrolled in two distinct studies: (1) a multicenter cross-sectional study involving completion of a one-time questionnaire, or (2) a single-center longitudinal study in which subjects completed questionnaires before and after undergoing genetic testing. The main outcome was uptake of EC risk-reducing practices. RESULTS: In the cross-sectional cohort, 58/77 (75%) women at risk for LS-associated EC reported engaging in EC risk-reduction. Personal history of genetic testing was associated with uptake of EC surveillance or PH (OR 17.1; 95% CI 4.1-70.9). Prior to genetic testing for LS, 26/40 (65%) women in the longitudinal cohort reported engaging in EC risk-reduction. At one-year follow-up, 16/16 (100%) mismatch repair (MMR) gene mutation carriers were adherent to guidelines for EC risk-reduction, 9 (56%) of whom had undergone PH. By three-year follow-up, 11/16 (69%) MMR mutation carriers had undergone PH. Among women with negative or uninformative genetic test results, none underwent PH after testing. CONCLUSIONS: Genetic testing for LS is strongly associated with uptake of EC risk-reducing practices. Women found to have LS in this study underwent prophylactic gynecologic surgery at rates comparable to those published for BRCA1/2 mutation carriers.

Prevalence and predictors of appropriate colorectal cancer surveillance in Lynch syndrome.

OBJECTIVES: Lynch syndrome (LS) is a hereditary cancer syndrome that conveys a high risk of colorectal cancer (CRC). Guidelines recommend colonoscopy every 1 to 2 years. There is limited information about screening compliance in this high-risk group. METHODS: Data about cancer screening behaviors were obtained from subjects recruited through four US cancer genetics clinics. The main outcome was prevalence of appropriate CRC surveillance for LS. RESULTS: A total of 181 individuals had a family history that met the Amsterdam criteria for LS (n=154) and/or had an identified mutation in a mismatch repair (MMR) gene (n=105). Of these 181 individuals, 131 (73%) had appropriate LS surveillance with colonoscopies at least every 2 years for their age >25 years. Of those with inadequate surveillance, 26/49 (53%) had colonoscopies at 3- to 5-year intervals. There were no significant differences in health-care setting, perceived risk of CRC, or compliance with screening for other cancers. Rates of appropriate surveillance were higher among individuals who had been referred for genetic evaluation for LS compared with those who had not (109/136 (80%) vs. 23/45 (51%), respectively, P=0.0004). In multivariate analysis, personal history of CRC (odds ratio (OR) 2.81), having a first-degree relative with CRC at age <50 years (OR 2.61), and having undergone a genetic evaluation (OR 4.62) were associated with appropriate CRC surveillance for LS. CONCLUSIONS: The time between colonoscopic exams in patients with LS is often longer than recommended by current guidelines and may place them at risk for interval cancers. Recognizing clinical features of LS and providing genetic counseling, evaluation, and intensive surveillance may improve cancer prevention for those at the highest risk for CRC.

Phenotype comparison of MLH1 and MSH2 mutation carriers in a cohort of 1,914 individuals undergoing clinical genetic testing in the United States.

BACKGROUND AND AIMS: Lynch syndrome is caused by germ-line mismatch repair gene mutations. We examined the phenotypic differences between MLH1 and MSH2 gene mutation carriers and whether mutation type (point versus large rearrangement) affected phenotypic expression. METHODS: This is a cross-sectional prevalence study of 1,914 unrelated probands undergoing clinical genetic testing for MLH1 and MSH2 mutations at a commercial laboratory. RESULTS: Fifteen percent (285 of 1,914) of subjects had pathogenic mutations (112 MLH1, 173 MSH2). MLH1 carriers had a higher prevalence of colorectal cancer (79% versus 69%, P = 0.08) and younger mean age at diagnosis (42.2 versus 44.8 years, P = 0.03) than MSH2 carriers. Forty-one percent of female carriers had endometrial cancer and prevalence was similar in both groups. Other cancers were more frequent in MSH2 carriers (24% versus 9%, P = 0.001) and their families (P < 0.001). Multivariable analyses confirmed these associations. Of the 1,016 subjects who underwent Southern blot analysis, 42 had large rearrangements (7 MLH1, 35 MSH2). There were no phenotypic differences between carriers with large rearrangements and point mutations. CONCLUSIONS: In this large study of mismatch repair gene mutation carriers from the United States, MLH1 carriers had more colorectal cancer than MSH2 carriers whereas endometrial cancer prevalence was similar. Large genomic rearrangements were more frequent in the MSH2 gene. MSH2 carriers and their relatives have more extracolonic nonendometrial Lynch syndrome-associated cancers and may benefit from additional screening.

Sharing genetic test results in Lynch syndrome: communication with close and distant relatives.

BACKGROUND & AIMS: Clinical genetic testing can help direct cancer screening for members of Lynch syndrome families; however, there is limited information about family communication of genetic test results. METHODS: A total of 174 probands who had genetic testing for Lynch syndrome were enrolled through 4 US cancer genetics clinics. Subjects were asked whether they had disclosed their genetic test results to first-, second-, and third-degree relatives. Univariate and multivariate analyses were used to identify clinical and demographic factors associated with informing immediate and extended family of genetic test results. RESULTS: One hundred seventy-one of 174 probands (98%; 95% confidence interval, 95%-100%) reported that they had disclosed their genetic test result to a first-degree relative. Communication of test results to other relatives occurred significantly less often, with only 109 of 162 (67%; 95% confidence interval, 59%-74%) subjects with second- or third-degree relatives sharing their results. Individuals with a pathogenic mutation were significantly more likely to inform distant relatives than were subjects with a negative or indeterminate test result (odds ratio, 2.49; 95% confidence interval, 1.14-5.40). Probands' age, sex, and cancer status did not influence communication of genetic test results. Lack of closeness and concerns that relatives would worry or not understand the implications of test results were the primary reasons for not sharing genetic test results. CONCLUSIONS: Most individuals who undergo genetic testing for Lynch syndrome share their test results with first-degree family members; however, these results reach more distant relatives significantly less often. Interventions to improve communication of genetic test results to members of the extended family are necessary to provide optimal cancer prevention care to at-risk families.

Comparison of Prediction Models for Lynch Syndrome Among Individuals With Colorectal Cancer.

BACKGROUND: Recent guidelines recommend the Lynch Syndrome prediction models MMRPredict, MMRPro, and PREMM1,2,6 for the identification of MMR gene mutation carriers. We compared the predictive performance and clinical usefulness of these prediction models to identify mutation carriers. METHODS: Pedigree data from CRC patients in 11 North American, European, and Australian cohorts (6 clinic- and 5 population-based sites) were used to calculate predicted probabilities of pathogenic MLH1, MSH2, or MSH6 gene mutations by each model and gene-specific predictions by MMRPro and PREMM1,2,6. We examined discrimination with area under the receiver operating characteristic curve (AUC), calibration with observed to expected (O/E) ratio, and clinical usefulness using decision curve analysis to select patients for further evaluation. All statistical tests were two-sided. RESULTS: Mutations were detected in 539 of 2304 (23%) individuals from the clinic-based cohorts (237 MLH1, 251 MSH2, 51 MSH6) and 150 of 3451 (4.4%) individuals from the population-based cohorts (47 MLH1, 71 MSH2, 32 MSH6). Discrimination was similar for clinic- and population-based cohorts: AUCs of 0.76 vs 0.77 for MMRPredict, 0.82 vs 0.85 for MMRPro, and 0.85 vs 0.88 for PREMM1,2,6. For clinic- and population-based cohorts, O/E deviated from 1 for MMRPredict (0.38 and 0.31, respectively) and MMRPro (0.62 and 0.36) but were more satisfactory for PREMM1,2,6 (1.0 and 0.70). MMRPro or PREMM1,2,6 predictions were clinically useful at thresholds of 5% or greater and in particular at greater than 15%. CONCLUSIONS: MMRPro and PREMM1,2,6 can well be used to select CRC patients from genetics clinics or population-based settings for tumor and/or germline testing at a 5% or higher risk. If no MMR deficiency is detected and risk exceeds 15%, we suggest considering additional genetic etiologies for the cause of cancer in the family.

Sexual intimate partner violence as a form of MST: An initial investigation.

Military sexual trauma (MST) is known to impact women's health, but little is known about the occurrence of MST perpetrated by a past or current intimate partner. This study identified the occurrence of intimate partner violence (IPV)-related MST in a sample of female veterans. We also examined the associations between MST history (no MST history, IPV-related MST, and MST by a nonintimate partner) and mental and physical health symptoms. Participants were 369 female veteran patients of Department of Veteran Affairs (VA) facilities in the New England region of the United States who completed a larger 2012 mail survey that included validated assessments of MST, posttraumatic stress disorder (PTSD Checklist) and depressive symptoms (CES-D), and general physical and mental health functioning (Short Form-36). Approximately half (49%) of the women in this sample reported a history of MST, of which 27 (15%) were categorized as IPV-related MST. Few differences in health measures were observed among women with IPV-related MST compared with women who experienced MST by a nonintimate partner or women with no MST history. However, women who experienced IPV-related MST had similarly severe health symptoms as women who reported MST by a nonintimate partner and more severe PTSD symptoms than women without a history of MST. Some women veterans have experienced MST at the hands of an intimate partner and face health impacts. This topic warrants additional attention in clinical and research efforts.

Impact of Childhood Abuse on Physical and Mental Health Status and Health Care Utilization Among Female Veterans.

OBJECTIVE: To determine whether childhood abuse predicts health symptoms and health care use among female veterans. METHODS: Participants were 369 female patients at Veterans Affairs hospitals in New England who completed a mail survey. Multiple regression analyses were conducted to determine the differential impact of childhood physical abuse and childhood sexual abuse on health symptoms and health care use, while accounting for age, race, military branch, and military sexual trauma (MST). RESULTS: In our sample, 109 (29%) female veterans reported experiencing childhood abuse. After adjusting for age, race, military branch, childhood sexual abuse, and MST, childhood physical abuse was predictive of poorer physical health, and greater depressive and post-traumatic stress disorder symptoms. No significant association was found between childhood sexual abuse and poor physical or mental health status. After adjusting for other factors, childhood physical abuse was associated with more frequent use of medical health care. Childhood sexual abuse was not a predictor for health care use. CONCLUSIONS: Childhood physical abuse remains an important contributor to physical health and mental health, even after adjusting for the more proximate experience of MST. Screening for adverse childhood experiences may facilitate access to appropriate physical and mental health treatment among female veterans.

Germline TP53 Mutations in Patients With Early-Onset Colorectal Cancer in the Colon Cancer Family Registry.

IMPORTANCE: Li-Fraumeni syndrome, usually characterized by germline TP53 mutations, is associated with markedly elevated lifetime risks of multiple cancers, and has been linked to an increased risk of early-onset colorectal cancer. OBJECTIVE: To examine the frequency of germline TP53 alterations in patients with early-onset colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter cross-sectional cohort study of individuals recruited to the Colon Cancer Family Registry (CCFR) from 1998 through 2007 (genetic testing data updated as of January 2015). Both population-based and clinic-based patients in the United States, Canada, Australia, and New Zealand were recruited to the CCFR. Demographic information, clinical history, and family history data were obtained at enrollment. Biospecimens were collected from consenting probands and families, including microsatellite instability and DNA mismatch repair immunohistochemistry results. A total of a 510 individuals diagnosed as having colorectal cancer at age 40 years or younger and lacking a known hereditary cancer syndrome were identified from the CCFR as being potentially eligible. Fifty-three participants were excluded owing to subsequent identification of germline mutations in DNA mismatch repair genes (n = 47) or biallelic MUTYH mutations (n = 6). INTERVENTIONS: Germline sequencing of the TP53 gene was performed. Identified TP53 alterations were assessed for pathogenicity using literature and international mutation database searches and in silico prediction models. MAIN OUTCOMES AND MEASURES: Frequency of nonsynonymous germline TP53 alterations. RESULTS: Among 457 eligible participants (314, population-based; 143, clinic-based; median age at diagnosis, 36 years [range, 15-40 years]), 6 (1.3%; 95% CI, 0.5%-2.8%) carried germline missense TP53 alterations, none of whom met clinical criteria for Li-Fraumeni syndrome. Four of the identified TP53 alterations have been previously described in the literature in probands with clinical features of Li-Fraumeni syndrome, and 2 were novel alterations. CONCLUSIONS AND RELEVANCE: In a large cohort of patients with early-onset colorectal cancer, germline TP53 mutations were detected at a frequency comparable with the published prevalence of germline APC mutations in colorectal cancer. With the increasing use of multigene next-generation sequencing panels in hereditary cancer risk assessment, clinicians will be faced with the challenge of interpreting the biologic and clinical significance of germline TP53 mutations in families whose phenotypes are atypical for Li-Fraumeni syndrome.

Attitudes toward childbearing and prenatal testing in individuals undergoing genetic testing for Lynch syndrome.

To examine attitudes toward childbearing and prenatal genetic testing among individuals at risk for Lynch syndrome (LS), the most common type of hereditary colorectal cancer. Individuals undergoing clinical genetic testing for mismatch repair (MMR) gene mutations completed written questionnaires before and after testing. 161 of 192 (84%) eligible individuals participated in the study. Mean age was 46 years (range 20-75), 71% were female, 53% had a personal diagnosis of cancer, and 68% had children. Eighty percent worried about their children's risk for developing cancer; however only 9% reported their decision to have children was affected by their family history of cancer. When asked whether providing prenatal testing to carriers of MMR gene mutations was ethical, 66% (86/130) of respondents agreed/strongly agreed, 25% (32) were neutral and 9% (12) disagreed/strongly disagreed. Of 48 individuals planning to have children in the future, 57% (27) intended to have children regardless of their genetic test result. If found to carry a MMR gene mutation that confirmed LS, 42% (20) would consider prenatal testing for a future pregnancy and 20% (7/35) of women would consider having children earlier in order to have prophylactic surgery to reduce their risk for gynecologic cancers. Individuals undergoing genetic testing for LS may utilize test results to make reproductive decisions. Clinicians should be prepared to discuss options of reproductive genetic technologies during counseling of LS patients of childbearing age.

Colorectal cancer risk perception on the basis of genetic test results in individuals at risk for Lynch syndrome.

PURPOSE: Lynch syndrome is associated with inherited germline mutations in mismatch repair (MMR) genes. Genetic testing in high-risk individuals may yield indeterminate results if no mutation is found or if a mutation of unclear pathogenic significance is observed. There are limited data regarding how well patients with Lynch syndrome understand the clinical implications of genetic test results. This study examines colorectal cancer (CRC) risk perception in individuals tested for MMR mutations and identifies the factors associated with an appropriate interpretation of their cancer risk. PATIENTS AND METHODS: A total of 159 individuals who met the Revised Bethesda Guidelines and had previously undergone genetic testing completed a questionnaire eliciting demographic data, cancer history, genetic test results, and an estimate of their CRC risk. Associations between clinical factors, genetic test results, and CRC risk perception were explored using multivariable analyses. RESULTS: Of the 100 individuals with a pathogenic mutation (true positive), 90 (90%) correctly estimated their CRC risk as "high" or "very high" compared with other individuals their age. However, only 23 (62%) of 37 individuals with an indeterminate genetic test result correctly estimated their risk. Individuals with a history of Lynch syndrome-associated cancer (odds ratio [OR], 0.1; 95% CI, 0.1 to 0.6) or indeterminate genetic test results (OR, 0.2; 95% CI, 0.1 to 0.6) were significantly less likely to estimate their CRC risk as increased. CONCLUSION: Patients at risk for Lynch syndrome with an indeterminate genetic test result may be falsely reassured. It is important that health care providers continue to discuss the implications of uninformative results on lifetime cancer risk.