Publications by authors named "Kristen M Shannon"

28 Publications

  • Page 1 of 1

ATM Variants in Breast Cancer: Implications for Breast Radiotherapy Treatment Recommendations.

Int J Radiat Oncol Biol Phys 2021 Feb 2. Epub 2021 Feb 2.

Department of Radiation Oncology, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114. Electronic address:

Purpose: Advances in germline genetic testing have led to a surge in identification of ATM variant carriers among breast cancer patients, raising numerous questions regarding use of breast radiotherapy (RT) in this population.

Methods: A literature search utilizing PubMed identified articles assessing association(s) between germline ATM variant status and risk of toxicity following breast RT. An expert panel of breast radiation oncologists, genetic counselors and basic scientists convened to review the association between ATM variants and radiation-induced toxicity or secondary malignancy risk and determine any impact on breast RT recommendations.

Results: Carriers of pathogenic variants in ATM have a 2-4-fold increased risk for developing breast cancer. ATM variants do not consistently increase risk of toxicities following RT, except possibly among patients with the single nucleotide variant, c5557G>A (rs1801516) in whom a small increased risk for the development of both acute and late radiation effects has been identified. In most breast cancer patients with ATM variants, the excess 5-year absolute risk of developing a secondary contralateral breast cancer (CBC) following radiation is extremely low. The exception is in women younger than 45 years old with deleterious rare ATM missense variants, who may be at higher risk for developing a radiation-induced CBC over time.

Conclusions: Adjuvant radiation is safe for most breast cancer patients who harbor ATM variants. The possible exceptions are patients with the variant c5557G>A (rs1801516) and patients younger than 45 years old with certain rare deleterious ATM variants who may be at higher risk for developing CBC. These latter patients should be counseled regarding this potential risk, and every effort should be made to minimize contralateral breast dose. However, the inconsistency of published data limits precise recommendations, magnifying the need for further prospective study and the development of a centralized database cataloging RT outcomes and genetic status.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.045DOI Listing
February 2021

Transition to telephone genetic counseling services during the COVID-19 pandemic.

J Genet Couns 2020 Dec 4. Epub 2020 Dec 4.

Center for Cancer Risk Assessment, Massachusetts General Hospital Cancer Center, Boston, MA, USA.

The COVID-19 pandemic has significantly disrupted the delivery of healthcare services, including oncology. To ensure continuity of cancer genetic counseling at a large academic medical center while also promoting the safety of patients and staff, our team transitioned to fully remote telephone genetic counseling and testing services within 48 hr. We compare differences in the six weeks following the shift to telephone genetic counseling (post-COVID) to the six weeks preceding the pandemic (pre-COVID). We maintained 99% of our total visit capacity and saw a decrease in patient no-show rate from 9.5% to 7.3%. Of all patients who received telephone genetic counseling, fewer consented to genetic testing as compared to patients seen in-person prior to the pandemic (79% pre-COVID v. 72% post-COVID; p = .012). Four weeks after this cohort was closed for analysis, 96 out of 303 samples (32%) had not been received by the genetic testing laboratory, despite at least one reminder phone call to the patient. In 13 reported instances, a second sample was required (quality not sufficient, lost or mislabeled sample), thus delaying test results. We conclude that a rapid transition to remote genetic counseling and testing allowed uninterrupted access to cancer genetics services during to the COVID-19 pandemic. Patient compliance with sample return and higher rates of sample failure emerge as potential barriers to timely genetic testing under this service delivery model.
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http://dx.doi.org/10.1002/jgc4.1365DOI Listing
December 2020

regulates the action of nitrogen-containing bisphosphonates on bone.

Sci Transl Med 2020 05;12(544)

Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital and Harvard School of Dental Medicine, Boston, MA 02114, USA.

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase, resulting in defects in protein prenylation. Yet, it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, Loss of function results in selective resistance to N-BP-mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. is required for alendronate inhibition of osteoclast function, and -deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Last, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. is one of three genes that contain rare nonsynonymous coding variants in patients with ONJ or an AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people.
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http://dx.doi.org/10.1126/scitranslmed.aav9166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882121PMC
May 2020

Case 7-2020: A 52-Year-Old Man with a Mass in the Left Breast.

N Engl J Med 2020 Feb;382(9):856-864

From the Departments of Medicine (S.J.I., K.M.S.), Radiology (C.D.L.), and Pathology (K.M.B.), Massachusetts General Hospital, and the Departments of Medicine (S.J.I.), Radiology (C.D.L.), and Pathology (K.M.B.), Harvard Medical School - both in Boston.

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http://dx.doi.org/10.1056/NEJMcpc1913470DOI Listing
February 2020

Gastric cancer in Lynch syndrome is associated with underlying immune gastritis.

J Med Genet 2019 12 4;56(12):844-845. Epub 2019 May 4.

Gastroenterology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States

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http://dx.doi.org/10.1136/jmedgenet-2018-105757DOI Listing
December 2019

Finding a Balance: Reconciling the Needs of the Institution, Patient, and Genetic Counselor for Optimal Resource Utilization.

J Genet Couns 2018 Jun 19. Epub 2018 Jun 19.

Center for Cancer Risk Assessment, Mass General Cancer Center, Massachusetts General Hospital, 55 Fruit St. - YAW 10B, Boston, MA, 02114, USA.

The current practice of cancer genetic counseling is undergoing widespread change and scrutiny. While there are clinical resources for genetic counselors (GCs) regarding the delivery of cancer genetic services, there is limited literature regarding effective management of a genetic counseling clinical program. We have developed administrative tools to manage a large team of GCs at a single academic medical center over a period of increasing demand for genetics services, with the initial aim of decreasing wait time for urgent genetic counseling visits. Here, we describe the three main elements of the clinical operations: Balancing patient volume between GCs, scheduling tracks for both routine and urgent appointments, and a team of triaging GCs to ensure appropriate patient referrals. For each of these elements, we describe how they have been modified over time and present data to support the utility of these strategies. The preliminary evidence offered here suggests that these tools allow for an equitable distribution of patient volume between team members, as well as the timely and accurate scheduling of urgent patients. As a result of the experiences presented here, other genetic counseling programs grappling with similar issues should be aware that it is possible to shift clinical operations to serve certain patient populations in a more timely fashion while keeping both providers and GC staff satisfied.
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http://dx.doi.org/10.1007/s10897-018-0270-4DOI Listing
June 2018

Universal screening of both endometrial and colon cancers increases the detection of Lynch syndrome.

Cancer 2018 08 11;124(15):3145-3153. Epub 2018 May 11.

Gastroenterology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Background: Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC) and endometrial cancer (EC). Screening of all CRCs for LS is currently recommended, but screening of ECs is inconsistent. The objective of this study was to determine the added value of screening both CRC and EC tumors in the same population.

Methods: A prospective, immunohistochemistry (IHC)-based screening program for all patients with newly diagnosed CRCs and ECs was initiated in 2011 and 2013, respectively, at 2 centers (primary and tertiary). Genetic testing was recommended for those who had tumors with absent mutS homolog 2 (MSH2), MSH6, or postmeiotoic segregation increased 2 (PMS2) expression and for those who had tumors with absent mutL homolog 1 (MLH1) expression and no v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation or MLH1 promoter methylation. Amsterdam II criteria, revised Bethesda criteria, and scores from prediction models for gene mutations (the PREMM and PREMM prediction models) were ascertained in patients with LS.

Results: In total, 1290 patients with CRC and 484 with EC were screened for LS, and genetic testing was recommended for 137 patients (10.6%) and 32 patients (6.6%), respectively (P = .01). LS was identified in 16 patients (1.2%) with CRC and in 8 patients (1.7%) with EC. Among patients for whom genetic testing was recommended, the LS diagnosis rate was higher among those with EC (25.0% vs 11.7%, P = .052). The Amsterdam II criteria, revised Bethesda criteria, and both PREMM calculators would have missed 62.5%, 50.0%, and 12.5% of the identified patients with LS, respectively.

Conclusions: Expanding a universal screening program for LS to include patients who had EC identified 50% more patients with LS, and many of these patients would have been missed by risk assessment tools (including PREMM ). Universal screening programs for LS should include both CRC and EC. Cancer 2018. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31534DOI Listing
August 2018

A Rapid Systematic Review of Outcomes Studies in Genetic Counseling.

J Genet Couns 2017 Jun 6;26(3):361-378. Epub 2017 Feb 6.

Department of Genetics, Cell Biology, and Development, University of Minnesota - Twin Cities, Minneapolis, MN, USA.

As healthcare reimbursement is increasingly tied to value-of-service, it is critical for the genetic counselor (GC) profession to demonstrate the value added by GCs through outcomes research. We conducted a rapid systematic literature review to identify outcomes of genetic counseling. Web of Science (including PubMed) and CINAHL databases were systematically searched to identify articles meeting the following criteria: 1) measures were assessed before and after genetic counseling (pre-post design) or comparisons were made between a GC group vs. a non-GC group (comparative cohort design); 2) genetic counseling outcomes could be assessed independently of genetic testing outcomes, and 3) genetic counseling was conducted by masters-level genetic counselors, or non-physician providers. Twenty-three papers met the inclusion criteria. The majority of studies were in the cancer genetic setting and the most commonly measured outcomes included knowledge, anxiety or distress, satisfaction, perceived risk, genetic testing (intentions or receipt), health behaviors, and decisional conflict. Results suggest that genetic counseling can lead to increased knowledge, perceived personal control, positive health behaviors, and improved risk perception accuracy as well as decreases in anxiety, cancer-related worry, and decisional conflict. However, further studies are needed to evaluate a wider array of outcomes in more diverse genetic counseling settings.
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http://dx.doi.org/10.1007/s10897-017-0067-xDOI Listing
June 2017

A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome.

Mod Pathol 2017 03 6;30(3):440-447. Epub 2017 Jan 6.

Department of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

To determine the correlation between BRAF genotype and MLH1 promoter methylation in a screening program for Lynch syndrome (LS), a universal screening program for LS was established in two medical centers. Tumors with abnormal MLH1 staining were evaluated for both BRAF V600E genotype and MLH1 promoter methylation. Tumors positive for both were considered sporadic, and genetic testing was recommended for all others. A total 1011 colorectal cancer cases were screened for Lynch syndrome, and 148 (14.6%) exhibited absent MLH1 immunostaining. Both BRAF and MLH1 methylation testing were completed in 126 cases. Concordant results (both positive or both negative) were obtained in 86 (68.3%) and 16 (12.7%) cases, respectively, with 81% concordance overall. The positive and negative predictive values for a BRAF mutation in predicting MLH1 promoter methylation were 98.9% and 41%, respectively, and the negative predictive value fell to 15% in patients ≥70 years old. Using BRAF genotyping as a sole test to evaluate cases with absent MLH1 staining would have increased referral rates for genetic testing by 2.3-fold compared with MLH1 methylation testing alone (31% vs 13.5%, respectively, P<0.01). However, a hybrid approach that reserves MLH1 methylation testing for BRAF wild-type cases only would significantly decrease the number of methylation assays performed and reduce the referral rate for genetic testing to 12.7%. A BRAF mutation has an excellent positive predictive value but poor negative predictive value in predicting MLH1 promoter methylation. A hybrid use of these tests may reduce the number of low-risk patients referred to genetic counseling and facilitate wider implementation of Lynch syndrome screening programs.
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http://dx.doi.org/10.1038/modpathol.2016.211DOI Listing
March 2017

Pathologic Findings in Prophylactic and Nonprophylactic Hysterectomy Specimens of Patients With Lynch Syndrome.

Am J Surg Pathol 2016 09;40(9):1177-91

Departments of *Pathology ∥Gynecology ¶Genetics †Cancer Epigenetics & Biology Group, Research Center, Portuguese Oncology Institute of Porto ‡Department of Pathology and Oncology, Medical Faculty **Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar ‡‡Cancer Signaling and Metabolism Group, Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP) & I3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal Departments of §Surgery ††Pathology, Centro Hospitalar São João, Porto, Portugal #Massachusetts General Hospital Cancer Center, Center for Cancer Risk Assessment §§James Homer Wright Pathology Laboratories, Massachusetts General Hospital ∥∥Department of Pathology, Harvard Medical School, Boston, MA.

Women with Lynch syndrome (LS) have a high risk of developing endometrial carcinoma (EC) and, less frequently, ovarian carcinoma. As EC not uncommonly is the first malignancy, prophylactic hysterectomy (PH) has been increasingly implemented. In this study, we report the clinicopathologic features of a series of 70 LS patients who underwent either PH (n=39) or nonprophylactic hysterectomy (NPH) (n=31) at 3 tertiary referral centers. Among the 39 patients with PH, 2 had endometrial tumors seen grossly, whereas 37 showed no macroscopic lesions. Total inclusion of the endometrium was performed in 24/39 (61.5%). Abnormal histologic findings were identified in 9/39 (23.1%) PHs: 3 endometrial endometrioid carcinomas (EECs), including the 2 macroscopic and 1 microscopic (0.6 cm), and 4 atypical and 6 nonatypical hyperplasias. NPH included those performed for endometrial and ovarian cancer treatment. Tumor sampling followed standard protocols. ECs comprised 26 EECs and 1 clear cell carcinoma, with a median size of 3.7 cm. Hyperplasia was observed in 10 (33.3%) as background in EC, in 4 showing atypia. Eight (29.6%) tumors were centered in the lower uterine segment (all EECs). EECs were predominantly well differentiated (53.8%) and FIGO stage I (77.8%). A papillary architecture was common (51.9%) and associated with microcystic elongated and fragmented foci in 4. Mucinous differentiation was observed in 25.9% of endometrial tumors, typically representing <10%. Most endometrial tumors (81.5%) showed tumor-infiltrating lymphocyte counts ≥42/10 high-power fields. Four tumors showed extensive necrosis. Eight patients had ovarian tumors (4 synchronous), including 2 endometrioid carcinomas, 2 clear cell carcinomas, 1 borderline clear cell adenofibroma, 1 Müllerian carcinoma of mixed cell types, 1 primitive neuroectodermal tumor, and 1 metastatic melanoma. Total inclusion of the endometrium should be done in all LS patients' surgical specimens without macroscopic lesions as some of these patients harbor preneoplastic or neoplastic conditions treatable at an early stage. The phenotype of LS-associated endometrial and ovarian tumors is variable and frequently includes features not commonly observed in sporadic cancers, but in our experience carcinomas were in general low grade and low stage.
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http://dx.doi.org/10.1097/PAS.0000000000000684DOI Listing
September 2016

Perceptions of Cancer Risk, Cause, and Needs in Participants from Low Socioeconomic Background at Risk for Hereditary Cancer.

Behav Med 2017 Oct-Dec;43(4):259-267. Epub 2016 Jan 25.

c Massachusetts General Hospital.

The purpose of this study was to describe perceptions of cancer risk, cause, and needs in participants from a low socioeconomic background at risk for hereditary cancer. We surveyed 307 individuals with the Cancer Awareness and Needs survey and received 128 responses (41.6% response rate). Family history, genetics, and tobacco use were selected most frequently as a cause of cancer; 36% (n = 46) selected fate and/or God's will. A total of 87.5% (n = 112) understood that having a close family member with breast cancer could increase personal risk; however responses were varied when asked if this was related to risk for other cancers. Most participants had undergone cancer screening, half reported undergoing breast magnetic resonance imaging, which was associated with personal (p < 0.01) and family cancer history (p = 0.03). An additional 76.6% (n = 98) felt informed about cancer screening and most received information from health care providers and family or friends. Ensuring that patients and clinicians are educated about hereditary cancer risk, detection, and prevention should be priorities for future research.
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http://dx.doi.org/10.1080/08964289.2016.1138925DOI Listing
February 2018

Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment.

JAMA Oncol 2015 Oct;1(7):943-51

Massachusetts General Hospital Cancer Center, Boston5Harvard Medical School, Boston, Massachusetts.

Importance: The practice of genetic testing for hereditary breast and/or ovarian cancer (HBOC) is rapidly evolving owing to the recent introduction of multigene panels. While these tests may identify 40% to 50% more individuals with hereditary cancer gene mutations than does testing for BRCA1/2 alone, whether finding such mutations will alter clinical management is unknown.

Objective: To define the potential clinical effect of multigene panel testing for HBOC in a clinically representative cohort.

Design, Setting, And Participants: Observational study of patients seen between 2001 and 2014 in 3 large academic medical centers. We prospectively enrolled 1046 individuals who were appropriate candidates for HBOC evaluation and who lacked BRCA1/2 mutations.

Interventions: We carried out multigene panel testing on all participants, then determined the clinical actionability, if any, of finding non-BRCA1/2 mutations in these and additional comparable individuals.

Main Outcomes And Measures: We evaluated the likelihood of (1) a posttest management change and (2) an indication for additional familial testing, considering gene-specific consensus management guidelines, gene-associated cancer risks, and personal and family history.

Results: Among 1046 study participants, 40 BRCA1/2-negative patients (3.8%; 95% CI, 2.8%-5.2%) harbored deleterious mutations, most commonly in moderate-risk breast and ovarian cancer genes (CHEK2, ATM, and PALB2) and Lynch syndrome genes. Among these and an additional 23 mutation-positive individuals enrolled from our clinics, most of the mutations (92%) were consistent with the spectrum of cancer(s) observed in the patient or family, suggesting that these results are clinically significant. Among all 63 mutation-positive patients, additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone would be considered for most (33 [52%] of 63; 95% CI, 40.3%-64.2%). Furthermore, additional familial testing would be considered for those with first-degree relatives (42 [72%] of 58; 95% CI, 59.8%-82.2%) based on potential management changes for mutation-positive relatives. This clinical effect was not restricted to a few of the tested genes because most identified genes could change clinical management for some patients.

Conclusions And Relevance: In a clinically representative cohort, multigene panel testing for HBOC risk assessment yielded findings likely to change clinical management for substantially more patients than does BRCA1/2 testing alone. Multigene testing in this setting is likely to alter near-term cancer risk assessment and management recommendations for mutation-affected individuals across a broad spectrum of cancer predisposition genes.
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http://dx.doi.org/10.1001/jamaoncol.2015.2690DOI Listing
October 2015

Response.

J Natl Cancer Inst 2014 Jun 4;106(6):dju131. Epub 2014 Jun 4.

Affiliations of authors: Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH (RP); Huntsman Cancer Institute, Salt Lake City, UT (RB, WK, LP); University of Utah School of Medicine, Salt Lake City, UT (RB, WK); Department of Dermatology, University of Utah, Salt Lake City, UT (LP); Massachusetts General Hospital Cancer Center, Center for Cancer Risk Assessment, Boston, MA (KMS); University of Washington Medical Center/Seattle Cancer Care Alliance, Seattle, WA (ES).

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http://dx.doi.org/10.1093/jnci/dju131DOI Listing
June 2014

Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria.

J Natl Cancer Inst 2013 Nov 17;105(21):1607-16. Epub 2013 Oct 17.

Affiliations of authors: Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH (RP); Huntsman Cancer Institute, Salt Lake City, UT (RB, WK, LP); University of Utah School of Medicine, Salt Lake City, UT (RB, WK); Department of Dermatology, University of Utah, Salt Lake City, UT (LP); Massachusetts General Hospital Cancer Center, Center for Cancer Risk Assessment, Boston, MA (KMS); University of Washington Medical Center/Seattle Cancer Care Alliance, Seattle, WA (ES).

Background: PTEN hamartoma tumor syndrome (PHTS) refers to a spectrum of disorders caused by mutations in the phosphatase and tensin homolog (PTEN) gene. Diagnostic criteria for Cowden syndrome, the principal PTEN-related disorder, were first established in 1996 before the identification of the PTEN gene and the ability to molecularly confirm a clinical diagnosis. These consortium criteria were based on clinical experience and case reports in the existing literature, with their inherent selection biases. Although it was initially reported that approximately 80% of patients with Cowden syndrome had an identifiable germline PTEN mutation, more recent work has shown these diagnostic criteria to be far less specific. In addition, increasing evidence has documented the association of a broader spectrum of clinical features with PTEN mutations. Our goal was to develop revised, evidence-based diagnostic criteria and to include features of the broader spectrum of PTEN-related clinical syndromes.

Methods: We performed a systematic search and review of the medical literature related to clinical features reported in individuals with a PTEN mutation and/or a related clinical diagnosis.

Results: We found no sufficient evidence to support inclusion of benign breast disease, uterine fibroids, or genitourinary malformations as diagnostic criteria. There was evidence to include autism spectrum disorders, colon cancer, esophageal glycogenic acanthosis, penile macules, renal cell carcinoma, testicular lipomatosis, and vascular anomalies.

Conclusions: We propose revised, evidence-based criteria covering the spectrum of PTEN-related clinical disorders. Additional research on clinical features associated with PTEN mutations is warranted.
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http://dx.doi.org/10.1093/jnci/djt277DOI Listing
November 2013

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

Gynecol Oncol 2012 Dec 29;127(3):544-51. Epub 2012 Aug 29.

Beth Israel Deaconess Medical Center, Boston, MA, USA.

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.
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http://dx.doi.org/10.1016/j.ygyno.2012.08.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496001PMC
December 2012

Which individuals undergoing BRACAnalysis need BART testing?

Cancer Genet 2011 Aug;204(8):416-22

Massachusetts General Hospital, Center for Cancer Risk Assessment, Boston, MA, USA.

Deleterious mutations in BRCA1 and BRCA2 include those identified by sequencing technology as well as large genomic rearrangements (LGR). The main testing laboratory in the United States, Myriad Genetics Laboratory (MGL), has defined criteria for inclusion of LGR testing (i.e., BRACAnalysis Rearrangement Test, or BART™) when BRCA1 and BRCA2 testing is ordered. We were interested in determining how many of our patients with LGR mutations in BRCA1 and BRCA2 fulfilled these MGL criteria. A retrospective chart review was performed on all individuals who underwent genetic testing at our institution since August 2006. Individuals who underwent LGR testing were classified as either having or not having a LGR in BRCA1 or BRCA2. Each individual's history was classified as meeting MGL defined LGR criteria, meeting criteria using third-degree relatives, or not meeting criteria. A total of 257 BART tests were ordered at our institution from August 2006 to August 2009. Five individuals (1.9%) had an LGR mutation. Two LGR were identified in patients who met MGL defined LGR criteria. One LGR was identified in a patient that met MGL defined LGR criteria only when using third-degree relatives. Two LGR were identified in individuals who did not meet MGL defined criteria. LGR are present in individuals who do not have a high pretest probability of carrying a mutation in BRCA1 or BRCA2. These data suggest that when BRCA1 and BRCA2 genetic testing is performed, testing should always include LGR testing so that the results are the most comprehensive and reliable.
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http://dx.doi.org/10.1016/j.cancergen.2011.07.005DOI Listing
August 2011

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

Am J Gastroenterol 2010 Aug 30;105(8):1851-60. Epub 2010 Mar 30.

Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

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.
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http://dx.doi.org/10.1038/ajg.2010.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091484PMC
August 2010

Prevalence and functional analysis of sequence variants in the ATR checkpoint mediator Claspin.

Mol Cancer Res 2009 Sep 8;7(9):1510-6. Epub 2009 Sep 8.

Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA.

Mutational inactivation of genes controlling the DNA-damage response contributes to cancer susceptibility within families and within the general population as well as to sporadic tumorigenesis. Claspin (CLSPN) encodes a recently recognized mediator protein essential for the ATR and CHK1-dependent checkpoint elicited by replicative stress or the presence of ssDNA. Here, we describe a study to determine whether mutational disruption of CLSPN contributes to cancer susceptibility and sporadic tumorigenesis. We resequenced CLSPN from the germline of selected cancer families with a history of breast cancer (n = 25) or a multicancer phenotype (n = 46) as well as from a panel of sporadic cancer cell lines (n = 52) derived from a variety of tumor types. Eight nonsynonymous variants, including a recurrent mutation, were identified from the germline of two cancer-prone individuals and five cancer cell lines of breast, ovarian, and hematopoietic origin. None of the variants was present within population controls. In contrast, mutations were rare within genes encoding the CLSPN-interacting protein ATR and its binding partner ATRIP. One variant of CLSPN, encoding the I783S missense mutation, was defective in its ability to mediate CHK1 phosphorylation following DNA damage and was unable to rescue sensitivity to replicative stress in CLSPN-depleted cells. Taken together, these observations raise the possibility that CLSPN may encode a component of the DNA-damage response pathway that is targeted by mutations in human cancers, suggesting the need for larger population-based studies to investigate whether CLSPN variants contribute to cancer susceptibility.
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http://dx.doi.org/10.1158/1541-7786.MCR-09-0033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994259PMC
September 2009

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

J Clin Oncol 2009 Aug 20;27(24):3981-6. Epub 2009 Jul 20.

Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

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.
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http://dx.doi.org/10.1200/JCO.2008.18.6940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734398PMC
August 2009

Professional challenges in cancer genetic testing: who is the patient?

Oncologist 2008 Mar;13(3):232-8

Massachusetts General Hospital Cancer Center/Center for Cancer Risk Assessment, Boston, MA 02114, USA.

In the genetic counseling setting, the health care provider can be challenged by opposing duties to members of the same family: protecting the privacy of the patient identified with a gene mutation and the ethical obligation to warn at-risk relatives. In a situation of nondisclosure between members of a family with a known disease-predisposing mutation, this type of dilemma can present in acute form for the provider who cares for different members of the family. This can hinder effective medical decision making. To minimize this effect, we recommend detailed pretest genetic counseling steps to empower the patient to communicate with their at-risk relatives their intent to pursue testing and willingness to share information. In addition, post-test counseling should reiterate the implications of a positive result for at-risk relatives and conclude with a written summary that patients can share with their family.
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http://dx.doi.org/10.1634/theoncologist.2007-0203DOI Listing
March 2008

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

Clin Gastroenterol Hepatol 2008 Mar 7;6(3):333-8. Epub 2008 Feb 7.

Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

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.
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http://dx.doi.org/10.1016/j.cgh.2007.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2536607PMC
March 2008

Should menopausal women at increased risk for breast cancer use tamoxifen, raloxifene, or hormone therapy?: a framework for personalized risk assessment and counseling.

J Cancer Educ 2007 ;22(1):10-4

Cancer Genetic Counseling, Yale Cancer Center, Yale School of Medicine,New Haven, CT 06520, USA.

Background: Menopausal women with a family history of breast cancer have several treatment options, including tamoxifen, raloxifene, and hormone therapy. This complex decision should be based on each woman's risk to develop breast cancer, menopausal symptoms, preferences, and risks for other conditions. Current models in use do not include pedigree analysis, personalized risk assessment, or genetic testing in this process.

Methods: We created a personalized risk assessment and genetic counseling intervention for healthy women with a first-degree relative with breast cancer. Participants were given a personalized risk assessment for breast cancer, heart disease, osteoporosis, and uterine cancer based on family history and personal health data. COUNSELING MODEL: The effectiveness of this novel genetic counseling intervention was demonstrated in a randomized trial and these results are published elsewhere. The framework for this counseling model, with case examples from the clinical trial, is outlined in this article.

Conclusions: As more menopausal therapies are developed, each with its own risks and benefits, it will become even more critical to have a personalized counseling model for use in this process. Clinicians and educators can utilize the framework presented here for counseling women with a family history of breast cancer.
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http://dx.doi.org/10.1007/BF03174368DOI Listing
September 2007

Prevalence of thyroid cancer in familial adenomatous polyposis syndrome and the role of screening ultrasound examinations.

Clin Gastroenterol Hepatol 2007 Mar 26;5(3):367-73. Epub 2007 Jan 26.

Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

Background & Aims: Thyroid carcinoma is an extraintestinal manifestation of familial adenomatous polyposis (FAP) syndrome, but the precise risk is unknown. The optimal approach for thyroid cancer screening has not been established. We sought to define the prevalence of thyroid cancer and the role of screening ultrasound in FAP patients.

Methods: We performed a retrospective chart review of 51 patients with a proven diagnosis of FAP at a single tertiary institution. Clinical records, genetic test results, ultrasound examinations, and histopathology were reviewed.

Results: Papillary thyroid cancer was diagnosed in 6 female patients (12%). The mean age of thyroid cancer diagnosis was 33 years, and mean tumor size was 12 mm. However, all patients had additional malignant foci that were small (1-9 mm), and none had suspicious features of malignancy on ultrasound. Of 28 patients who had at least one screening ultrasound, 22 (79%) had thyroid nodules, and 2 (7%) had papillary thyroid carcinoma. Of those with nodules, 68% had multinodular disease. A follow-up ultrasound in 12 patients after a mean of 15 months revealed no changes in either the number or size of nodules.

Conclusions: The 12% prevalence of thyroid cancer in this series of FAP patients is significantly higher than in previous reports. Among patients undergoing screening ultrasound, 7% had thyroid cancer. Nodular thyroid disease is very common in FAP. Because small nodules (<9 mm) might also be malignant, close follow-up with ultrasound and fine-needle aspiration might be warranted.
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http://dx.doi.org/10.1016/j.cgh.2006.10.019DOI Listing
March 2007

Healthy women with a family history of breast cancer: impact of a tailored genetic counseling intervention on risk perception, knowledge, and menopausal therapy decision making.

J Womens Health (Larchmt) 2006 Sep;15(7):843-56

Yale University School of Medicine, Yale Cancer Center, New Haven, Connecticut 06520, USA.

Background: Women with a family history of breast cancer have several menopausal therapy options, including tamoxifen, hormone therapy (HT), alternative medications, or no treatment. This complex decision should be based on each woman's risk to develop breast cancer, menopausal symptoms, preferences, and risks for other conditions. The authors determined the effects of a personalized risk assessment and genetic counseling intervention on knowledge, risk perception, and decision making in a group of healthy women who had a first-degree relative with breast cancer.

Methods: Forty-eight cancer-free menopausal women age > or =40 years who had at least one first-degree relative with breast cancer were randomized to a genetic counseling intervention or control. Intervention participants were given a personalized risk assessment for breast cancer, heart disease, osteoporosis, and uterine cancer based on family history and personal health data. Knowledge, risk perception, and medication usage were measured at baseline, 1 month, and 6 months.

Results: Knowledge was higher in the intervention group at both follow-up time points postintervention. Perceived risk for developing breast cancer was significantly lower and more accurate in the intervention group at 1 and 6 months postintervention than at baseline, as was perceived risk of developing heart disease. Although the counseling intervention did affect both knowledge and risk perception, overall, both groups were reluctant to take any form of menopausal therapy.

Conclusions: A personalized risk assessment and genetic counseling intervention improves patient knowledge and risk perception; however, it is unclear that the intervention influenced menopausal treatment decisions.
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http://dx.doi.org/10.1089/jwh.2006.15.843DOI Listing
September 2006

Correlation of polyp number and family history of colon cancer with germline MYH mutations.

Clin Gastroenterol Hepatol 2005 Oct;3(10):1022-8

Gastrointestinal Unit and Department of Medicine, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

Background & Aims: Affected individuals with biallelic MYH mutations are believed to display multiple adenomatous polyps without evidence of vertical transmission. Our goal was to determine the detection rate of germline MYH mutations in a high-risk gastrointestinal cancer clinic population by using polyp number as a selection criterion.

Methods: Patients were screened for the 2 most common MYH mutations: Y165C and G382D. The complete MYH coding region was sequenced in cases with a heterozygous mutation.

Results: Among 45 patients with more than 15 adenomatous polyps not diagnosed with familial adenomatous polyposis, 7 (15.6%) had biallelic MYH mutations. When 122 participants from a high-risk gastrointestinal cancer clinic who did not fulfill these criteria were tested, 2 additional patients with biallelic mutations were identified. Both had young-onset colorectal cancer (age, <50 y) with fewer than 15 polyps. Surprisingly, most of the 9 patients with biallelic MYH mutations reported family histories consistent with the hereditary nonpolyposis colorectal cancer syndrome (HNPCC), with 7 cases meeting at least 1 of the Bethesda criteria, 5 cases fulfilling 3 Bethesda criteria, and 2 cases fulfilling the Amsterdam II criteria.

Conclusions: Most individuals with MYH mutations exhibit multiple adenomatous polyps. However, 22% of cases were missed when this was the sole criterion for germline testing. A significant number reported a strong family history of cancer that was consistent with HNPCC. MYH testing thus can be considered for patients who meet clinical criteria for HNPCC in the absence of DNA mismatch repair gene mutations.
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http://dx.doi.org/10.1016/s1542-3565(05)00411-8DOI Listing
October 2005

Model-based predictions of BRCA1/2 mutation status in breast carcinoma patients treated at an academic medical center.

Cancer 2002 Jan;94(2):305-13

Division of Hematology/Oncology, Massachusetts General Hospital, Boston 02114, USA.

Background: Women with an existing breast carcinoma diagnosis who are found to carry a BRCA1/2 mutation have a substantial risk of developing both a contralateral breast carcinoma and ovarian carcinoma. In a newly diagnosed breast carcinoma patient, this genetic information may influence the management of her disease. To assess the volume of patients who may need genetic services at the time of diagnosis, the authors determined the proportion of women with newly diagnosed breast carcinoma at the study institution who would be eligible for genetic testing.

Methods: Fifty consecutive women with new breast carcinoma who were attending a multidisciplinary clinic were interviewed. Detailed, three-generation pedigrees were collected for each patient by a genetic counselor. Three commonly used probability models were used to calculate each woman's predicted risk of harboring a germline BRCA1/2 mutation.

Results: Eleven of 50 patients (22% [95% confidence interval, 12-36%]) were calculated to have a > or = 10% probability of carrying a BRCA1/2 mutation by at least one mathematic model and should have been offered genetic counseling that included the discussion of genetic testing. There were considerable discrepancies between probability calculations among the three mathematic models. One of the 11 patients who was eligible for genetic testing pursued genetic counseling within 12 months of diagnosis.

Conclusions: At a large academic medical center, a substantial proportion of unselected women attending a multidisciplinary clinic were found to have a > or = 10% risk of carrying a BRCA1/2 mutation. The actual number of patients eligible to receive BRCA1/2 genetic testing outweighs the number of patients seen for genetic counseling at the study institution. Finally, limited correlation was found between current predictive models.
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http://dx.doi.org/10.1002/cncr.10223DOI Listing
January 2002