Margery Rosenblatt

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.

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.

Sebaceous neoplasms in Lynch syndrome.

Background Sebaceous neoplasms of the skin (SN) are described in the Muir Torre variant of Lynch syndrome (LS). Guidelines recommend evaluating individuals diagnosed with sebaceous adenomas or sebaceous carcinomas for LS with immunohistochemistry (IHC) for mismatch repair (MMR) proteins and/or microsatellite instability analysis (MSI). The assumption has been that SNs with defective MMR are related to LS. Purpose To describe outcomes of genetic testing for LS among individuals with SN. Results 24 individuals with a personal history of SN underwent a genetic evaluation for Lynch syndrome (LS) at DanaFarber Cancer Institute. 10 had family histories which met Amsterdam criteria, 8 had a personal history of another LS-associated malignancy, 23 had family history of one or more LS-associated cancers, and 1 had no other personal or family history of cancer. 11/24 (46%) probands had pathogenic MMR gene mutations (2 MLH1 and 9 MSH2) and each of these either met Amsterdam criteria or had a personal history of another LS-related cancer. Of 13 probands without identifiable MMR mutations, 6 had SNs with normal IHC and 7 had abnormal IHC (3 absent MSH2 and MSH6, 2 absent MLH1 and PMS2, 1a bsent MLH1 only and 1 absent MSH2 only). One of the probands whose SN showed absence of MSH2 and MSH6 had a family history which met Amsterdam criteria (PREMM score=33%) and the rest had PREMM model scores <5%. Conclusions Although prior reports suggest that MSI/IHC can be useful in screening patients with SNs for LS, we found many of these tumors demonstrate features of abnormal MMR even when family history is not suggestive of LS and genetic testing did not reveal MMR mutation. Further study is needed to determine whether other somatic mechanisms may produce the MMR deficient phenotypes seen in many SNs.

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.