Rowena Mercado

The PREMM1,2,6 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 individuals 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.

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. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2044–51)

Comparison of the clinical prediction model PREMM1,2,6 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 PREMM1,2,6 model predicts the likelihood of a MMR gene mutation based on personal and family cancer history. Objective To compare strategies using PREMM1,2,6 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 PREMM1,2,6 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 PREMM1,2,6, (2) MSI, (3) IHC for loss of any MMR protein expression, (4) MSI+IHC, (5) PREMM1,2,6+MSI, (6) PREMM1,2,6+IHC, (7) PREMM1,2,6+IHC+MSI. Results Among 1651 subjects, 239 (14%) had mutations (90 MLH1, 125 MSH2, 24 MSH6). PREMM1,2,6 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+PREMM1,2,6 was slightly greater than PREMM1,2,6+MSI (AUC 0.94 vs 0.93). Adding MSI to PREMM1,2,6+IHC did not improve discrimination. Conclusion PREMM1,2,6 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 PREMM1,2,6 scores where genetic evaluation does not disclose a MMR mutation.

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 PREMM1,2,6, 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. PREMM1,2,6, 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: PREMM1,2,6, 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.Genet Med advance online publication 8 March 2012

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.

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

Military sexual trauma (MST) is known to impact womens 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.

Impact of genetic testing on risk-reducing behavior in women at risk for hereditary gynecologic cancer syndromes

Background Women with hereditary breast and ovarian cancer (HBOC) have an estimated 15-65% lifetime risk of ovarian cancer; similarly, women with Lynch syndrome have a 40-60% lifetime risk of endometrial cancer and a 10-12% lifetime risk of ovarian cancer. The aim of this study was to investigate the impact of genetic testing on risk-reducing behavior for gynecologic malignancies in women being tested for HBOC and Lynch syndrome.

Factors associated with genetic testing distress in patients tested for Lynch Syndrome or Hereditary Breast and Ovarian Cancer Syndrome

Methods 140 individuals undergoing genetic testing for LS and 133 undergoing genetic testing for HBOS at the DanaFarber Cancer Institute were enrolled in a longitudinal questionnaire study. We assessed levels of genetic testing distress, anxiety and depression using The Multidimensional Impact of Cancer Risk Assessment (MICRA) and the Hospital Anxiety and Depression Scale (HADS). Multivariable regression analysis was used to identify factors associated with psychological distress in the LS and HBOS cohorts. One year follow-up data is based on 96 LS and 94 HBOS tested individuals that completed the one year questionnaire.

Impact of mismatch repair (MMR) genetic test result on perceived cancer risk and cancer screening

Background Information recall after genetic testing has been examined extensively in patients at risk for Hereditary Breast Ovarian Cancer. We examined perceived cancer risk, screening practices, and genetic testing-specific distress in individuals undergoing genetic testing for Lynch syndrome.