Characterization of family history profiles in a large series of Lynch syndrome carriers.

414 Background: The identification of Lynch syndrome carriers is an unmet medical need. Large studies characterizing family history profiles of unaffected individuals diagnosed with Lynch syndrome in the absence of a known family mutation have not been reported. Methods: We queried our laboratory database for unaffected patients who underwent Lynch syndrome genetic testing between September 2010 and May 2013 and had a positive test result. All individuals underwent full sequence and large rearrangement analysis of MLH1 and MSH2, and full sequence analysis of MSH6. Some patients also underwent full sequence and large rearrangement analysis of PMS2 and large rearrangement analysis of MSH6 and EPCAM. Those being tested for a known mutation in the family and patients undergoing single gene testing were excluded. We assessed family history profiles in 200 unaffected patients with genetically confirmed Lynch syndrome. Results: Of the 200 patients, 162 female and 38 male Lynch syndrome carriers were identified. Mutations in MLH1 and MSH2 were the most common (30.0% and 32.5%) while mutations in MSH6, PMS2, and EPCAM accounted for 21.0%, 13.5%, and 3.0% of all deleterious mutations, respectively. Eighteen patients did not have a first or second degree relative with colorectal cancer. Only 37.8% (73/193) of individuals had a first- or second-degree relative meeting the Amsterdam II criteria and 76.8 % (149/194) of individuals had a first or second degree relative meeting the Revised Bethesda criteria. The average PREMM1,2,6 score was 10.0% with 43.5% (87/200) falling below 5%. In this large cohort, 15.5% (31/200) had neither a first or second degree relative who met the Amsterdam II or Revised Bethesda criteria nor a PREMM1,2,6 score of 5% or greater. Conclusions: In order to improve detection of Lynch syndrome in the population, it is important to consider genetic testing in unaffected individuals even in the absence of a known family mutation. Development of guidelines that include having a single affected relative and extra-colonic cancers is needed to support healthcare providers in identifying appropriate patients for testing.

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Familial colorectal cancer risk in half siblings and siblings: nationwide cohort study

BMJ ◽

10.1136/bmj.l803 ◽

2019 ◽

pp. l803 ◽

Cited By ~ 6

Author(s):

Yu Tian ◽

Elham Kharazmi ◽

Kristina Sundquist ◽

Jan Sundquist ◽

Hermann Brenner ◽

...

Keyword(s):

Colorectal Cancer ◽

Cohort Study ◽

Family History ◽

Cancer Risk ◽

Confidence Interval ◽

Cumulative Risk ◽

Degree Relative ◽

History Of ◽

Half Sibling ◽

Second Degree

AbstractObjectiveTo explore the risk of colorectal cancer in family members of patients with colorectal cancer, with an emphasis on subtypes of second degree relatives, especially half siblings, which were lacking in the literature.DesignAmbidirectional cohort study.SettingNationwide Swedish Family Cancer Data (record linkage).ParticipantsAll people residing in Sweden and born after 1931, with their biological parents, totalling >16 million individuals (follow-up: 1958-2015); of those with clear genealogy, 173 796 developed colorectal cancer.Main outcome measuresLifetime (0-79 years) cumulative risk and standardised incidence ratio of colorectal cancer among first degree relatives and second degree relatives.ResultsThe overall lifetime cumulative risk of colorectal cancer in siblings of patients was 7%, which represents a 1.7-fold (95% confidence interval 1.6 to 1.7; n=2089) increase over the risk in those without any family history of colorectal cancer. A similarly increased lifetime cumulative risk (6%) was found among half siblings (standardised incidence ratio 1.5, 95% confidence interval 1.3 to 1.8; n=140). The risk in people with colorectal cancer in both a parent and a half sibling (standardised incidence ratio 3.6, 2.4 to 5.0; n=32) was close to the risk in those with both an affected parent and an affected sibling (2.7, 2.4 to 3.0; n=396). Family history of colorectal cancer in only one second degree relative other than a half sibling (without any affected first degree relatives), such as a grandparent, uncle, or aunt, showed minor association with the risk of colorectal cancer.ConclusionFamily history of colorectal cancer in half siblings is similarly associated with colorectal cancer risk to that in siblings. The increase in risk of colorectal cancer among people with one affected second degree relative was negligible, except for half siblings, but the risk was substantially increased for a combination of family history in one affected second degree relative and an affected first degree relative (or even another second degree relative). These evidence based findings provide novel information to help to identify people at high risk with a family history of colorectal cancer that can potentially be used for risk adapted screening.

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Germline pathogenic variants in patients with pheochromocytoma.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.668 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 668-668

Author(s):

Shirley A Yao ◽

Elizabeth A Wiley ◽

Lisa R. Susswein ◽

Megan L. Marshall ◽

Natalie J. Carter ◽

...

Keyword(s):

Genetic Testing ◽

Family History ◽

Single Gene ◽

Molecular Data ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Testing ◽

History Of ◽

Testing Algorithms ◽

Cancer Panel

668 Background: Approximately 25% of pheochromocytomas (PCC) have a hereditary basis, and germline variants in the SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 genes have been associated with a predisposition to PCC and paraganglioma (PGL). Multi-gene hereditary cancer panel testing for PCC has become increasingly more common than single-gene testing algorithms. Identification of a pathogenic or likely pathogenic variant (PV/LPV) in one of these genes has important implications for surveillance in patients and their family members. Here we describe the spectrum of PV/LPV variants identified in individuals with PCC. Methods: We performed a retrospective review of clinical and molecular data for all individuals diagnosed with PCC who underwent panel testing through BioReference Laboratories that included at least SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 between January 2016 and February 2017. Results: Seventy-nine individuals underwent testing due to a personal (n = 76) or family (n = 3) history of PCC. The positive yield was 14% (11/79). The majority of PV/LPV were in SDHB (n = 4; 36%), followed by RET (n = 2, 18%), with the remaining variants being identified in SDHA (1), SDHC (1), VHL (1), TMEM127 (1), and MAX (1). Approximately half (6/11) of those with a PV/LPV had a non-syndromic presentation of a unilateral PCC with no reported family history of PCC or PGL. The average age at tumor diagnosis was lower for probands testing positive than those without PV/LPV (34y±14 vs 44y±16). Conclusions: Our data support previous recommendations that patients with apparently sporadic, non-syndromic PCC be considered for genetic testing. Panel testing is a useful tool for identifying individuals with hereditary PCC.

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Lynch Syndrome Identification in Endometrial Cancer Patients: Should Universal Screening be Used for all Histologies?

Current Women s Health Reviews ◽

10.2174/1573404817666210302153551 ◽

2021 ◽

Vol 17 ◽

Author(s):

Jessica E. Parker ◽

Caitlin Mauer ◽

Wenxin Zheng ◽

David S. Miller ◽

Jayanthi S. Lea

Keyword(s):

Endometrial Cancer ◽

Genetic Testing ◽

Family History ◽

Lynch Syndrome ◽

Cancer Patients ◽

Universal Screening ◽

Type I ◽

Type Ii ◽

Screening Approach ◽

Endometrial Cancers

Background: There is an increased proportion of non-endometrioid histologies in Lynch syndrome-associated compared to sporadic endometrial cancer, however screening recommendations do not differ between type I and type II cancers. Objective: Our objective was to examine the frequency of Lynch syndrome identified in type I and type II endometrial cancers and their associated characteristics. Methods: We reviewed patients with type I and type II endometrial cancer who were screened for Lynch Syndrome or referred for genetic testing according to an age and family-history based screening protocol. All patients were seen and treated at large academic institution affiliated with a county safety-net hospital. Clinical, pathologic, immunohistochemistry, and germline genetic testing results were obtained as well as choice of genetic screening approach, personal and family history, and compliance with testing. Results: 234 women with type I and 29 patients with type II endometrial cancer were identified. Lynch syndrome was diagnosed in a total of eight (3.4%) type I endometrial cancer patients, all identified after age-based tumor screening. In the type II endometrial cancer group, three (10.3%) patients had Lynch syndrome. One was referred for testing after abnormal immunohistochemistry screening under age 60. The other two were >60 years old and identified after abnormal immunohistochemistry screening performed by physician request. Conclusion: Age based screening may not diagnose Lynch Syndrome in women with type II endometrial cancers. Our findings underscore the need for a universal screening approach in patients with type II endometrial cancers, even in a low resource population.

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Impact of Changing Guidelines on Genetic Testing and Surveillance Recommendations in a Contemporary Cohort of Breast Cancer Survivors with Family History of Pancreatic Cancer

10.21203/rs.3.rs-396248/v1 ◽

2021 ◽

Author(s):

Annie Wang ◽

Jessica N. Everett ◽

Jennifer Chun ◽

Cindy Cen ◽

Diane M. Simeone ◽

...

Keyword(s):

Breast Cancer ◽

Pancreatic Cancer ◽

Genetic Testing ◽

Family History ◽

Cancer Survivors ◽

Breast Cancer Survivors ◽

Degree Relative ◽

Genetic Risk Assessment ◽

Changing Practice ◽

History Of

Abstract Background: Changing practice guidelines and recommendations have important implications for cancer survivors. This study investigated genetic testing patterns and outcomes and reported family history of pancreatic cancer (FHPC) in a large registry population of breast cancer (BC) patients. Methods: Variables including clinical and demographic characteristics, FHPC in a first or second-degree relative, and genetic testing outcomes were analyzed for BC patients diagnosed between 2010-2018 in the NYU Langone Health Breast Cancer Database. Results: Among 3334 BC patients, 232 (7%) had a positive FHPC. BC patients with FHPC were 1.68 times more likely to have undergone genetic testing (p<0.001), but 33% had testing for BRCA1/2 only and 44% had no genetic testing. Pathogenic germline variants (PGV) were identified in 15/129 (11.6%) BC patients with FHPC, and in 145/1315 (11.0%) BC patients without FHPC. Across both groups, updates in genetic testing criteria and recommendations could impact up to 80% of this cohort. Conclusions: Within a contemporary cohort of BC patients, 7% had a positive FHPC. The majority of these patients (56%) had no genetic testing, or incomplete testing by current standards, suggesting under-diagnosis of PC risk. This study supports recommendations for survivorship care that incorporate ongoing genetic risk assessment and counseling.

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Family History of Venous Thromboembolism (VTE) and the Risk of VTE Recurrence in Patients with a First Unprovoked VTE: A Multicenter Prospective Cohort Study

Blood ◽

10.1182/blood.v118.21.2299.2299 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2299-2299

Author(s):

Karine Gauthier ◽

Elham Sabri ◽

Susan R. Kahn ◽

Philip S Wells ◽

David Anderson ◽

...

Keyword(s):

Cohort Study ◽

Venous Thromboembolism ◽

Family History ◽

Conflicts Of Interest ◽

Anticoagulation Therapy ◽

Degree Relative ◽

National Cohort ◽

History Of ◽

Recurrent Vte ◽

Second Degree

Abstract Abstract 2299 Introduction: The duration of anticoagulation after unprovoked venous thromboembolism (VTE) has been characterized as the most important unanswered question in clinical thrombosis management. This has led to research to identify predictors of recurrent VTE to identify high-risk patients who might warrant indefinite anticoagulation. Many clinicians assume that a family history of VTE is a predictor of recurrent VTE. This study aims to assess the value of family history as a predictor for recurrent VTE. Methods: Prospective multi-center multi-national cohort study recruited patients with a first objectively proven unprovoked VTE who completed 5 to 7 months of anticoagulation therapy. A detailed family history of VTE was completed for every subject. The information recorded included the number of affected relatives, whether they were first or second degree relatives and if the VTE was unprovoked or secondary. Patients were then followed for recurrent VTE. Results: 664 subjects were enrolled between October 2001 and March 2006, 649 subjects were followed for a mean duration of 3.8 years (3.6–3.98 95% C.I.). The mean age of subjects in this cohort was 53 years (min-max 18–95) and 49% of subjects were females. A family history of VTE in at least 1 first-degree relative was recorded for 112 (17.3%) subjects. A total of 142 (21.9%) suspected VTE events were adjudicated as recurrences. The recurrence rate was 5.94% (4.89–7.15 95% C.I.) per patient-year for patients without any family history of VTE, and it was 4.82% (3.02–7.30 95% C.I.) per patient-year in patients with a family history of VTE in at least 1 first-degree relative. In secondary analyses, neither a family history of unprovoked VTE, multiple unprovoked VTE, in first-degree nor second-degree relatives was a predictor of recurrent VTE. A multivariate analysis was performed to adjust for known risk factors for VTE recurrence, but the adjusted hazard ratios were again not significantly different. Conclusion: A family history of VTE is not a predictor for recurrent VTE, and therefore should not be used to segregate unprovoked VTE patients in high- and low-risk categories. Disclosures: No relevant conflicts of interest to declare.

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Comparison of Lynch predictive models for identification of MLH1/MSH2 mutation carriers in a Spanish multicentre clinic- based cohort

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e22077 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e22077-e22077

Author(s):

I. Valenzuela ◽

J. Balmaña ◽

M. Rue ◽

I. Blanco ◽

A. Torres ◽

...

Keyword(s):

Genetic Testing ◽

Lynch Syndrome ◽

Predictive Models ◽

Carrier Status ◽

Operating Characteristics ◽

Comparative Performance ◽

Large Rearrangement ◽

Clinical Criteria ◽

Msh2 Mutation ◽

Mutation Carriers

e22077 Background: Different predictive models for Lynch syndrome have recently been developed and their comparative performance in a clinic-based cohort has not been assessed. We aimed to analyze the accuracy of the MMRpro, Barnetson, and PREMM1,2 models to predict MLH1/MSH2 mutation carrier status in 564 unrelated probands with clinical suspicion of hereditary colorectal cancer and compare it with Wijnen model and clinical criteria. Methods: Overall, 538 individuals (95%) underwent mismatch repair (MMR) deficiency screening before germline genetic testing (sequencing with or without large rearrangement analysis) and 26 (5%) performed direct genetic testing. Prediction scores for all individuals were calculated by each model. Sensitivity, specificity, positive predictive value (PPV), and the areas under the receiver operating characteristics curves (AUC) for all models were calculated and compared with the Revised Bethesda Guidelines (RBG). Results: 114 individuals (20%) were mutation carriers (63 MLH1, 51 MSH2). The AUC was 0.95 (95% CI: 0.93–0.97) for MMRpro, 0.87 (95% CI 0.83–0.91) for the Barnetson model, 0.87 (95% CI 0.83–0.91) for PREMM1,2, and 0.75 (95% CI 0.69–0.80) for the Wijnen model (p<0.001). Testing thresholds and specificity at 100% and 90% sensitivity for each model were: 0.001/17% and 0.33/89% for MMRpro, 0.01/9% and 0.07/59% for Barnetson, 0.05/5% and 0.11/58% for PREMM1,2. Sensitivity and specificity of RBG were 86% and 14%, respectively. Calibration was 0.92, 1.05, 0.50, and 1.25 for PREMM1,2,Barnetson, Wijnen, and MMRpro, respectively. Conclusions: In a population of individuals at risk of Lynch syndrome, the MMRpro model has the largest AUC, although the Barnetson and PREMM1,2 model also show adequate discrimination. Any of the models perform better than the RBG and provide quantitative risk estimation of finding a MLH1/MSH2 mutation useful in genetic counselling. No significant financial relationships to disclose.

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Risk of breast cancer among Japanese women with a positive family history.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.27_suppl.191 ◽

2011 ◽

Vol 29 (27_suppl) ◽

pp. 191-191

Author(s):

J. Suzuki ◽

T. Hojo ◽

K. Jimbo ◽

S. Asaga ◽

T. Kinoshita

Keyword(s):

Breast Cancer ◽

Family History ◽

Positive Family History ◽

Gene Mutations ◽

Contralateral Breast ◽

Brca1 And Brca2 ◽

Degree Relative ◽

Increased Risk ◽

Significant Difference ◽

Second Degree

191 Background: Most breast cancer cases are sporadic, rather than associated with inherited gene mutations, such as BRCA1 and BRCA2. However, women with a family history of breast cancer are at increased risk of developing breast cancer compared to those women without any family history, even if they lack these gene mutations. Methods: We analyzed 10892 patients including bilateral breast cancer cases (total of 11398 breast cancers) who underwent surgery at our hospital between 1962 and 2009. We excluded 295 cases whose family history data were not available. Clinical and pathological differences between following patient groups were tested; 9528 patients or 9955 cancers (88%) with negative family history (FH-), 896 patients or 951 cancers (8%) who had at least one first-degree relative with breast cancer (1FH+), 468 patients or 492 cancers (4%) who had second-degree relative with breast cancer (2FH+), and 1364 patients or 1443 cancers (12%) with family history regardless of first- or second-degree relative (FH+). Significance was established at a p-value of < 0.05. Results: Among the family members, sisters were more likely to have treated for breast cancer (38% in FH+ group), followed by mothers (27%), aunts (26%), grandmothers (7%), and daughters (2%). The incidence of developing contralateral breast cancer was significantly higher in 1FH+ group, compared to patients in FH- and 2FH+ groups. No other factors showed any significant difference, including the incidence of cancer in other organs, pathological characteristics, and age of onset, although BRCA1 and BRCA2 mutation may be associated with increased risk of developing breast cancer at younger age. Outcome studies with available data did not show any significant difference in overall survival between FH+ and FH- patients. Conclusions: A Japanese woman with a positive family history has a higher risk of developing breast cancer than women without any close relatives with breast cancer, similar to the results reported in Western countries where prevalence of breast cancer is higher. Regular checkup of contralateral breast is important for those patients whose first-degree relatives have also been diagnosed with breast cancer.

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Does a Family History of Male Breast Cancer Influence Risk Perception and Use of Genetic Testing?

The American Surgeon ◽

10.1177/000313481007600835 ◽

2010 ◽

Vol 76 (8) ◽

pp. 879-882

Author(s):

Suzanne C. Schiffman ◽

Anees B. Chagpar

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Risk Perception ◽

Family History ◽

Male Breast Cancer ◽

Population Based ◽

Female Breast Cancer ◽

Male Breast ◽

Degree Relative ◽

History Of

We sought to determine differences in risk perception and use of genetic testing in these individuals compared with those with a family history of female breast cancer (FHxFBC) in a population-based cohort. Data from the 2005 National Health Interview Survey were used to assess risk perception and use of genetic counseling in individuals with a family history of male breast cancer (FHxMBC) versus those with a FHxFBC. Of the 2429 individuals with a first-degree relative with breast cancer surveyed, 21 (0.7%) had a FHxMBC, whereas 2408 (99.3%) had a FHxFBC. Women who had a FHxMBC perceived themselves as being at higher risk for developing breast cancer than those with a FHxFBC (61.5 vs 46.5%, P = 0.011). Fewer individuals with a FHxMBC had heard about genetic testing than those with a FHxFBC (38.4 vs 50.8%, P = 0.322). Of these, none of the individuals with a FHxMBC discussed this with their physician (vs 13% of individuals with a FHxFBC, P = 0.004) and none underwent genetic testing (vs 3% of individuals with a FHxFBC, P = 0.009). Women with a FHxMBC perceive this as being associated with increased cancer risk, but few discuss this with their physicians. Physicians should be proactive in discussing risk with these patients.

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Risk of Breast Cancer in Women With a CHEK2 Mutation With and Without a Family History of Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2010.34.0778 ◽

2011 ◽

Vol 29 (28) ◽

pp. 3747-3752 ◽

Cited By ~ 124

Author(s):

Cezary Cybulski ◽

Dominika Wokołorczyk ◽

Anna Jakubowska ◽

Tomasz Huzarski ◽

Tomasz Byrski ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

Mutation Screening ◽

Positive Family History ◽

Baseline Risk ◽

Degree Relative ◽

Chek2 Mutation ◽

Truncating Mutation ◽

History Of ◽

Second Degree

Purpose To estimate the risk of breast cancer in a woman who has a CHEK2 mutation depending on her family history of breast cancer. Patients and Methods Seven thousand four hundred ninety-four BRCA1 mutation–negative patients with breast cancer and 4,346 control women were genotyped for four founder mutations in CHEK2 (del5395, IVS2+1G>A, 1100delC, and I157T). Results A truncating mutation (IVS2+1G>A, 1100delC, or del5395) was present in 227 patients (3.0%) and in 37 female controls (0.8%; odds ratio [OR], 3.6; 95% CI, 2.6 to 5.1). The OR was higher for women with a first- or second-degree relative with breast cancer (OR, 5.0; 95% CI, 3.3 to 7.6) than for women with no family history (OR, 3.3; 95% CI, 2.3 to 4.7). If both a first- and second-degree relative were affected with breast cancer, the OR was 7.3 (95% CI, 3.2 to 16.8). Assuming a baseline risk of 6%, we estimate the lifetime risks for carriers of CHEK2 truncating mutations to be 20% for a woman with no affected relative, 28% for a woman with one second-degree relative affected, 34% for a woman with one first-degree relative affected, and 44% for a woman with both a first- and second-degree relative affected. Conclusion CHEK2 mutation screening detects a clinically meaningful risk of breast cancer and should be considered in all women with a family history of breast cancer. Women with a truncating mutation in CHEK2 and a positive family history of breast cancer have a lifetime risk of breast cancer of greater than 25% and are candidates for magnetic resonance imaging screening and for tamoxifen chemoprevention.

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Women With Synchronous Primary Cancers of the Endometrium and Ovary: Do They Have Lynch Syndrome?

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.5915 ◽

2005 ◽

Vol 23 (36) ◽

pp. 9344-9350 ◽

Cited By ~ 66

Author(s):

Pamela T. Soliman ◽

Russell R. Broaddus ◽

Kathleen M. Schmeler ◽

Molly S. Daniels ◽

Delia Gonzalez ◽

...

Keyword(s):

Ovarian Cancer ◽

Family History ◽

Lynch Syndrome ◽

Germline Mutation ◽

Risk Groups ◽

Prior History ◽

Degree Relative ◽

Cancer Predisposition Syndrome ◽

Amsterdam Criteria ◽

Medium Risk

Purpose Lynch syndrome (hereditary nonpolyposis colorectal cancer; HNPCC) is an autosomal-dominant cancer predisposition syndrome that increases risk for multiple cancers, including colon, endometrial, and ovarian cancer. Revised Bethesda Criteria recommend that patients with two HNPCC-associated cancers undergo molecular evaluation to determine whether they have a mismatch repair (MMR) defect associated with HNPCC. The purpose of our study was to determine the likelihood of MMR defects (MSH2, MSH6, MLH1) in women with synchronous endometrial and ovarian cancer. Patients and Methods Between 1989 and 2004, 102 women with synchronous endometrial and ovarian cancers were identified; 59 patients had tumor blocks available for analysis. Patients were divided into risk groups based on family history: high (met Amsterdam criteria), medium (personal history or first-degree relative with an HNPCC-associated cancer), and low (all others). Protein expression for MSH2, MSH6, and MLH1 was evaluated by immunohistochemistry. Microsatellite instability and MLH1 promoter methylation analyses were performed on a subset of cases. Results Median age was 50 years. Two patients met Amsterdam criteria for HNPCC. Five additional patients, all medium-risk, had molecular findings consistent with a germline mutation of either MSH2 or MLH1. None of the low-risk patients had molecular results consistent with a germline mutation. Conclusion Overall, 7% of women in our cohort met either clinical or molecular criteria for Lynch syndrome. All of these women had a prior history or a first-degree relative with an HNPCC-associated cancer. Limiting genetic evaluation to women with synchronous endometrial and ovarian cancer who have a family history suggestive of HNPCC may appropriately identify women with Lynch syndrome.

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