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BACKGROUND & AIMS: Genetic testing uptake for cancer susceptibility in family members of patients with cancer is suboptimal. Among relatives of patients with pancreatic ductal adenocarcinoma (PDAC), The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated 2 online genetic education/testing delivery models and their impact on patient-reported psychological outcomes. METHODS: Eligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in 1 of 13 PDAC predisposition genes. Participants were randomized by family, between May 8, 2019, and June 1, 2021. Arm 1 participants underwent a remote interactive telemedicine session and online genetic education. Arm 2 participants were offered online genetic education only. All participants were offered germline testing. The primary outcome was genetic testing uptake, compared by permutation tests and mixed-effects logistic regression models. We hypothesized that Arm 1 participants would have a higher genetic testing uptake than Arm 2. Validated surveys were administered to assess patient-reported anxiety, depression, and cancer worry at baseline and 3 months postintervention. RESULTS: A total of 424 families were randomized, including 601 participants (n = 296 Arm 1; n = 305 Arm 2), 90% of whom completed genetic testing (Arm 1 [87%]; Arm 2 [93%], P = .014). Arm 1 participants were significantly less likely to complete genetic testing compared with Arm 2 participants (adjusted ratio [Arm1/Arm2] 0.90, 95% confidence interval 0.78-0.98). Among participants who completed patient-reported psychological outcomes questionnaires (Arm 1 [n = 194]; Arm 2 [n = 206]), the intervention did not affect mean anxiety, depression, or cancer worry scores. CONCLUSIONS: Remote genetic education and testing can be a successful and complementary option for delivering genetics care. (Clinicaltrials.gov, number NCT03762590).
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Carcinoma Ductal Pancreático , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Neoplasias Pancreáticas , Medición de Resultados Informados por el Paciente , Telemedicina , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/psicología , Neoplasias Pancreáticas/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/psicología , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/terapia , Predisposición Genética a la Enfermedad/psicología , Medición de Riesgo , Anciano , Ansiedad/psicología , Ansiedad/diagnóstico , Ansiedad/etiología , Adulto , Depresión/diagnóstico , Depresión/genética , Depresión/psicología , Asesoramiento Genético/psicología , Mutación de Línea Germinal , Familia/psicologíaRESUMEN
BACKGROUND: Little is known about patient-specific risk factors for skin neoplasia in individuals with Lynch syndrome (LS). OBJECTIVE: Identify clinical factors associated with development of skin neoplasms in LS. METHODS: Clinical data were systematically collected on a cohort of LS carriers (confirmed pathogenic germline variants in MLH1, MSH2, MSH6, PMS2, or EPCAM) age ≥18 undergoing clinical genetics care at Dana-Farber Cancer Institute from January 2000 to March 2020. Multivariable logistic regression was performed to evaluate clinical factors associated with skin neoplasia. RESULTS: Of 607 LS carriers, 9.2% had LS-associated skin neoplasia and 15.0% had non-LS-associated skin neoplasia; 58.2% (353/607) had documentation of prior dermatologic evaluation; 29.7% (38/128) with skin neoplasms lacked a history of visceral LS-associated malignancy. LS-associated skin neoplasms were significantly associated with male sex, age, race, MLH1 pathogenic germline variants, MSH2/EPCAM pathogenic germline variants, and personal history of non-LS skin neoplasms. Non-LS-associated skin neoplasms was significantly associated with age, number of first- and second-degree relatives with non-LS-associated skin neoplasms, and personal history of LS-associated skin neoplasms. LIMITATIONS: Single-institution observational study; demographic homogeneity. CONCLUSIONS: Skin neoplasms are common in individuals with LS. We identified clinical factors associated with LS- and non-LS-associated skin neoplasms. Regular dermatologic surveillance should be considered for all LS carriers.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Cutáneas , Humanos , Masculino , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Molécula de Adhesión Celular Epitelial/genética , Proteína 2 Homóloga a MutS/genética , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/genética , Mutación de Línea Germinal , Reparación de la Incompatibilidad de ADNRESUMEN
BACKGROUND: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management. METHODS: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. RESULTS: Fifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours. CONCLUSIONS: Next-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Inestabilidad de Microsatélites , Neoplasias Encefálicas , Neoplasias Colorrectales , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN/genética , Humanos , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Homólogo 1 de la Proteína MutL/genética , Mutación , Síndromes Neoplásicos HereditariosRESUMEN
BACKGROUND & AIMS: Lynch syndrome (LS) is associated with increased risks of various gastrointestinal, gynecologic, genitourinary, and other cancers. Many clinical practice guidelines recommend that LS carriers' screening strategies be devised based on their family history of various cancers, in addition to age-, sex-, and gene-specific considerations. The aim of this study was to examine the association between family history and other clinical factors with LS carriers' histories of various cancers. METHODS: Two cohorts of LS carriers were analyzed: a laboratory-based cohort of consecutively ascertained individuals undergoing germline LS testing and a clinic-based cohort of LS carriers undergoing clinical care at an academic medical center. Multivariable logistic regression was performed to assess clinical factors associated with LS carriers' histories of various cancers/neoplasms. Familial burden was defined as LS carriers' aggregate number of first-/second-degree relatives with a history of a given malignancy. RESULTS: Multivariable analysis of the laboratory-based cohort (3828 LS carriers) identified familial burden as being incrementally associated with LS carriers' personal history of endometrial (odds ratio [OR], 1.37 per affected first-/second-degree relative; 95% confidence interval [CI], 1.21-1.56), urinary tract (OR, 2.72; 95% CI, 2.02-3.67), small bowel (OR, 3.17; 95% CI, 1.65-6.12), gastric (OR, 1.93; 95% CI, 1.24-3.02), and pancreaticobiliary cancers (OR, 2.10; 95% CI, 1.21-3.65) and sebaceous neoplasms (OR, 7.39; 95% CI, 2.71-20.15). Multivariable analysis of the clinic-based cohort (607 LS carriers) confirmed a significant association of familial burden of endometrial and urinary tract cancers. CONCLUSIONS: Familial burden - in addition to age, sex, and specific LS gene - should be used to assess LS carriers' risks of specific cancers and guide decision-making about organ-specific surveillance.
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Biomarcadores de Tumor/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN , Mutación de Línea Germinal , Adulto , Factores de Edad , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Estudios Transversales , Femenino , Predisposición Genética a la Enfermedad , Herencia , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Medición de Riesgo , Factores de Riesgo , Factores SexualesRESUMEN
PURPOSE: This study aimed to evaluate the laboratory-related outcomes of participants who were offered genomic testing based on cancer family history risk assessment tools. METHODS: Patients from clinics that serve populations with access barriers, who are screened at risk for a hereditary cancer syndrome based on adapted family history collection tools (the Breast Cancer Genetics Referral Screening Tool and PREMM5), were offered exome-based panel testing for cancer risk and medically actionable secondary findings. We used descriptive statistics, electronic health record review, and inferential statistics to explore participant characteristics and results, consultations and actions related to pathogenic/likely pathogenic variants identified, and variables predicting category of findings, respectively. RESULTS: Of all the participants, 87% successfully returned a saliva kit. Overall, 5% had a pathogenic/likely pathogenic cancer risk variant and 1% had a secondary finding. Almost all (14/15, 93%) participants completed recommended consultations with nongenetics providers after an average of 17 months. The recommended actions (eg, breast magnetic resonance imaging) were completed by 17 of 25 participants. Participant personal history of cancer and PREMM5 score were each associated with the category of findings (history and colon cancer finding, Fisher's exact P = .02; history and breast cancer finding, Fisher's exact P = .01; PREMM5TM score; and colon cancer finding, Fisher's exact P < .001). CONCLUSION: This accessible model of hereditary cancer risk assessment and genetic testing yielded results that were often acted upon by patients and physicians.
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Neoplasias de la Mama , Neoplasias del Colon , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias del Colon/genética , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Humanos , Medición de RiesgoRESUMEN
PURPOSE: Models used to predict the probability of an individual having a pathogenic homozygous or heterozygous variant in a mismatch repair gene, such as MMRpro, are widely used. Recently, MMRpro was updated with new colorectal cancer penetrance estimates. The purpose of this study was to evaluate the predictive performance of MMRpro and other models for individuals with a family history of colorectal cancer. METHODS: We performed a validation study of 4 models, Leiden, MMRpredict, PREMM5, and MMRpro, using 784 members of clinic-based families from the United States. Predicted probabilities were compared with germline testing results and evaluated for discrimination, calibration, and predictive accuracy. We analyzed several strategies to combine models and improve predictive performance. RESULTS: MMRpro with additional tumor information (MMRpro+) and PREMM5 outperformed the other models in discrimination and predictive accuracy. MMRpro+ was the best calibrated with an observed to expected ratio of 0.98 (95% CI = 0.89-1.08). The combination models showed improvement over PREMM5 and performed similar to MMRpro+. CONCLUSION: MMRpro+ and PREMM5 performed well in predicting the probability of having a pathogenic homozygous or heterozygous variant in a mismatch repair gene. They serve as useful clinical decision tools for identifying individuals who would benefit greatly from screening and prevention strategies.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Reparación de la Incompatibilidad de ADN , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN/genética , Mutación de Línea Germinal/genética , Heterocigoto , Humanos , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Homólogo 1 de la Proteína MutL/genéticaRESUMEN
BACKGROUND: Risk assessment for hereditary cancer syndromes is recommended in primary care, but family history is rarely collected in enough detail to facilitate risk assessment and referral - a roadblock that disproportionately impacts individuals with healthcare access barriers. We sought to qualitatively assess a literacy-adapted, electronic patient-facing family history tool developed for use in diverse, underserved patient populations recruited in the Cancer Health Assessments Reaching Many (CHARM) Study. METHODS: Interview participants were recruited from a subpopulation of CHARM participants who experienced barriers to tool use in terms of spending a longer time to complete the tool, having incomplete attempts, and/or providing inaccurate family history in comparison to a genetic counselor-collected standard. We conducted semi-structured interviews with participants about barriers and facilitators to tool use and overall tool acceptability; interviews were recorded and professionally transcribed. Transcripts were coded based on a codebook developed using inductive techniques, and coded excerpts were reviewed to identify overarching themes related to barriers and facilitators to family history self-assessment and acceptability of the study tool. RESULTS: Interviewees endorsed the tool as easy to navigate and understand. However, they described barriers related to family history information, literacy and language, and certain tool functions. Participants offered concrete, easy-to-implement solutions to each barrier. Despite experience barriers to use of the tool, most participants indicated that electronic family history self-assessment was acceptable or preferable in comparison to clinician-collected family history. CONCLUSIONS: Even for participants who experienced barriers to tool use, family history self-assessment was considered an acceptable alternative to clinician-collected family history. Barriers experienced could be overcome with minor adaptations to the current family history tool. TRIAL REGISTRATION: This study is a sub-study of the Cancer Health Assessments Reaching Many (CHARM) trial, ClinicalTrials.gov, NCT03426878. Registered 8 February 2018.
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BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.
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Reparación de la Incompatibilidad de ADN/genética , Detección Precoz del Cáncer , Neoplasias de la Próstata/diagnóstico , Adulto , Anciano , Biomarcadores de Tumor/sangre , Proteínas de Unión al ADN/genética , Mutación de Línea Germinal , Heterocigoto , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Proteína 2 Homóloga a MutS/genética , Estudios Prospectivos , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/genéticaRESUMEN
BACKGROUND: COVID-19 pandemic-related disruptions to EUS-based pancreatic cancer surveillance in high-risk individuals remain uncertain. METHODS: Analysis of enrolled participants in the CAPS5 Study, a prospective multicenter study of pancreatic cancer surveillance in high-risk individuals. RESULTS: Amongst 693 enrolled high-risk individuals under active surveillance, 108 (16%) had an EUS scheduled during the COVID-19 pandemic-related shutdown (median length of 78 days) in the spring of 2020, with 97% of these procedures being canceled. Of these canceled surveillance EUSs, 83% were rescheduled in a median of 4.1 months, however 17% were not rescheduled after 6 months follow-up. Prior history of cancer was associated with increased likelihood of rescheduling. To date no pancreatic cancer has been diagnosed among those whose surveillance was delayed. CONCLUSIONS: COVID-19 delayed pancreatic cancer surveillance with no adverse outcomes in efficiently rescheduled individuals. However, 1 in 6 high-risk individuals had not rescheduled surveillance, indicating the need for vigilance to ensure timely surveillance rescheduling.
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BACKGROUND & AIMS: Lynch syndrome is the most common inherited cause of gastrointestinal cancer and increases risk for a variety of malignancies, including gastric cancer. We aimed to identify clinical factors associated with gastric cancer in carriers of germline variants causing Lynch syndrome. METHODS: We collected data from 52,758 consecutive individuals tested for genetic variants associated with Lynch syndrome from June 2006 through July 2013 at a commercial laboratory. We obtained clinical and demographic data, as well as information on personal and family histories of cancer (first- and second-degree relatives) from forms completed by ordering providers. We performed multivariate logistic regression to identify clinical factors associated with gastric cancer in carriers of mutations that cause Lynch syndrome (pathogenic mutations). RESULTS: After we excluded individuals with missing clinical data (n = 1664) or with multiple pathogenic mutations (n = 8), we analyzed data from 51,086 individuals. Of these, 3828 persons carried pathogenic mutations (1346 with mutations in MLH1, 1639 with mutations in MSH2, 670 with mutations in MSH6, 145 with mutations in PMS2, and 28 with mutations in EPCAM). Of the 3828 carriers of pathogenic mutations, 41 (1.1%) had a previous gastric cancer and 350 (9.1%) had 1 or more first- or second-degree relatives with gastric cancer. In multivariate analysis, male sex (odds ratio [OR], 2.82; 95% CI, 1.48-5.38), older age (OR, 2.07 per 10 years; 95% CI, 1.64-2.61), mutations in MLH1 (OR, 6.53; 95% CI, 1.50-28.42) or MSH2 (OR, 5.23 compared to mutations in MSH6, PMS2, or EPCAM; 95% CI, 1.21-22.71), and number of first-degree relatives with gastric cancer (OR, 2.52; 95% CI, 1.42-4.45), but not second-degree relatives (OR, 1.12; 95% CI, 0.40-3.18) were independently associated with gastric cancer among carriers of pathogenic mutations. CONCLUSIONS: In an analysis of data from almost 4000 carriers of Lynch syndrome-associated mutations, we found history of gastric cancer to be independently associated with male sex, older age, mutations in MLH1 or MSH2, and number of first-degree relatives with gastric cancer. These findings suggest that personalized, risk-stratified approaches to gastric cancer surveillance may be appropriate for individuals with Lynch syndrome-associated mutations.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Gástricas , Anciano , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Humanos , Masculino , Homólogo 1 de la Proteína MutL/genética , Proteína 2 Homóloga a MutS/genética , Mutación , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/genéticaRESUMEN
BACKGROUND & AIMS: African Americans (AAs) have the highest incidence of and mortality resulting from colorectal cancer (CRC) in the United States. Few data are available on genetic and nongenetic risk factors for CRC among AAs. Little is known about cancer risks and mutations in mismatch repair (MMR) genes in AAs with the most common inherited CRC condition, Lynch syndrome. We aimed to characterize phenotype, mutation spectrum, and risk of CRC in AAs with Lynch syndrome. METHODS: We performed a retrospective study of AAs with mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) using databases from 13 US referral centers. We analyzed data on personal and family histories of cancer. Modified segregation analysis conditioned on ascertainment criteria was used to estimate age- and sex-specific CRC cumulative risk, studying members of the mutation-carrying families. RESULTS: We identified 51 AA families with deleterious mutations that disrupt function of the MMR gene product: 31 in MLH1 (61%), 11 in MSH2 (21%), 3 in MSH6 (6%), and 6 in PMS2 (12%); 8 mutations were detected in more than 1 individual, and 11 have not been previously reported. In the 920 members of the 51 families with deleterious mutations, the cumulative risks of CRC at 80 years of age were estimated to be 36.2% (95% confidence interval [CI], 10.5%-83.9%) for men and 29.7% (95% CI, 8.31%-76.1%) for women. CRC risk was significantly higher among individuals with mutations in MLH1 or MSH2 (hazard ratio, 13.9; 95% CI, 3.44-56.5). CONCLUSIONS: We estimate the cumulative risk for CRC in AAs with MMR gene mutations to be similar to that of individuals of European descent with Lynch syndrome. Two-thirds of mutations were found in MLH1, some of which were found in multiple individuals and some that have not been previously reported. Differences in mutation spectrum are likely to reflect the genetic diversity of this population.
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Negro o Afroamericano/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Reparación de la Incompatibilidad de ADN/genética , Familia , Mutación , Proteínas Adaptadoras Transductoras de Señales/genética , Adenosina Trifosfatasas/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Estudios Retrospectivos , Factores de Riesgo , Factores SexualesRESUMEN
Survivors of childhood cancers are at increased risk of developing secondary gastrointestinal cancers, including colorectal cancer, later in life, possibly from exposure to abdominopelvic radiotherapy and/or alkylating chemotherapy. Profuse gastrointestinal polyposis is associated with rare, inherited colorectal cancer predisposition syndromes, most commonly caused by mutations in the adenomatous polyposis coli (APC) or mutY homolog (MUTYH) genes. We describe 5 patients who developed gastrointestinal polyposis many years after radiotherapy and chemotherapy for a childhood cancer. Genetic analysis of all 5 subjects did not identify pathogenic germline mutations in APC or MUTYH. Chemotherapy and/or radiotherapy therefore might cause gastrointestinal polyposis in some patients by undiscovered mechanisms.
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Antineoplásicos/efectos adversos , Poliposis Intestinal/inducido químicamente , Neoplasias/terapia , Radioterapia/efectos adversos , Proteína de la Poliposis Adenomatosa del Colon/genética , Adolescente , Adulto , Antineoplásicos/uso terapéutico , ADN Glicosilasas/genética , Femenino , Genotipo , Humanos , Lactante , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
INTRODUCTION: Colorectal cancer (CRC) screening utilization is low among low-income, uninsured, and minority populations that receive care in community health centers (CHCs). There is a need for evidence-based interventions to increase screening and follow-up care in these settings. METHODS: A multilevel, multi-component pragmatic cluster randomized controlled trial is being conducted at 8 CHCs in two metropolitan areas (Boston and Los Angeles), with two arms: (1) Mailed FIT outreach with text reminders, and (2) Mailed FIT-DNA with patient support. We also include an additional CHC in Rapid City (South Dakota) that follows a parallel protocol for FIT-DNA but is not randomized due to lack of a comparison group. Eligible individuals in participating clinics are primary care patients ages 45-75, at average-risk for CRC, and overdue for CRC screening. Participants with abnormal screening results are offered navigation for follow-up colonoscopy and CRC risk assessment. RESULTS: The primary outcome is the completion rate of CRC screening at 90 days. Secondary outcomes include the screening completion rate at 180 days and the rate of colonoscopy completion within 6 months among participants with an abnormal result. Additional goals are to enhance our understanding of facilitators and barriers to CRC risk assessment in CHC settings. CONCLUSIONS: This study assesses the effectiveness of two multilevel interventions to increase screening participation and follow-up after abnormal screening in under-resourced clinical settings, informing future efforts to address CRC disparities. TRIAL REGISTRATION: NCT05714644.
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Current algorithms for diagnosing Lynch syndrome (LS) include multistep molecular tumor tests to distinguish LS-associated from sporadic colorectal cancer (CRC), which add cost and complexity to the evaluation. We hypothesized that PREMM5, a clinical LS prediction tool, could be an alternative approach to screen for LS, thereby lessening the need for specialized molecular diagnostics. We reviewed a consecutively ascertained institutional cohort of 1058 CRC patients on whom pathologic and clinical data were available, including prior LS germline testing. Data from MMR-D/MSI-H CRC patients were reviewed and PREMM5 scores were calculated for each individual. Using a PREMM5 score cutoff ≥ 2.5% to characterize the need for germline testing, we determined the rate of pathogenic/likely pathogenic germline variants (PGVs) in LS genes in patients with PREMM5 scores ≥ 2.5% versus < 2.5%. Sensitivity and negative predictive values (NPV) of PREMM5 were calculated for all MMR-D/MSI-H CRC patients, and those with MLH1-deficient CRC. MMR IHC and/or MSI results were available on 572/1058 cases. We identified 74/572 (12.9%) cases as MMR-D/MSI-H, of which 28/74 (37.8%) harbored a LS PGV. 11/49 (22.4%) patients with MLH1-deficient CRC harbored a LS PGV. PREMM5 had 100% sensitivity (95% CI: 87.7-100 for any MMR-D/MSI-H; 95% CI: 71.5-100 for MLH1-deficient CRC) and 100% NPV (95% CI: 83.2-100 for any MMR-D/MSI-H; 95% CI: 82.4-100 for MLH1-deficient CRC) for identifying LS PGVs in these cohorts. PREMM5 accurately distinguishes LS- from non-LS-associated MMR-D/MSI-H CRC without additional somatic molecular testing. These findings are particularly relevant for limited-resource settings where advanced molecular diagnostics may be unavailable.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Colorrectales , Síndromes Neoplásicos Hereditarios , Humanos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Reparación de la Incompatibilidad de ADN/genética , Mutación de Línea Germinal , Inestabilidad de Microsatélites , Homólogo 1 de la Proteína MutL/genéticaRESUMEN
Lynch syndrome (LS) is a hereditary cancer susceptibility condition associated with varying cancer risks depending on which of the five causative genes harbors a pathogenic variant; however, lifestyle and medical interventions provide options to lower those risks. We developed MyLynch, a patient-facing clinical decision support (CDS) web application that applies genetically-guided personalized medicine (GPM) for individuals with LS. The tool was developed in R Shiny through a patient-focused iterative design process. The knowledge base used to estimate patient-specific risk leveraged a rigorously curated literature review. MyLynch informs LS patients of their personal cancer risks, educates patients on relevant interventions, and provides patients with adjusted risk estimates, depending on the interventions they choose to pursue. MyLynch can improve risk communication between patients and providers while also encouraging communication among relatives with the goal of increasing cascade testing. As genetic panel testing becomes more widely available, GPM will play an increasingly important role in patient care, and CDS tools offer patients and providers tailored information to inform decision-making. MyLynch provides personalized cancer risk estimates and interventions to lower these risks for patients with LS.
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PURPOSE: With the availability of multigene panel testing (MGPT) for hereditary cancer risk assessment, clinicians need to assess the likelihood of pathogenic germline variants (PGVs) across numerous genes in parallel. This study's aim was to develop and validate a clinical prediction model (PREMMplus) for MGPT risk assessment. MATERIALS AND METHODS: PREMMplus was developed in a single-institution cohort of 7,280 individuals who had undergone MGPT. Logistic regression models with Least Absolute Shrinkage and Selection Operator regularization were used to examine candidate predictors (age, sex, ethnicity, and personal/family history of 18 cancers/neoplasms) to estimate one's likelihood of carrying PGVs in 19 genes (broadly categorized by phenotypic overlap and/or relative penetrance: 11 category A [APC, BRCA1/2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53] and eight category B genes [ATM, BRIP1, CDKN2A, CHEK2, PALB2, PTEN, RAD51C, and RAD51D]). Model performance was validated in nonoverlapping data sets of 8,691 and 14,849 individuals with prior MGPT ascertained from clinic- and laboratory-based settings, respectively. RESULTS: PREMMplus (score ≥ 2.5%) had 93.9%, 91.7%, and 89.3% sensitivity and 98.3%, 97.5%, and 97.8% negative-predictive value (NPV) for identifying category A gene PGV carriers in the development and validation cohorts, respectively. PREMMplus assessment (score ≥ 2.5%) had 89.9%, 85.6%, and 84.2% sensitivity and 95.0%, 93.5%, and 93.5% NPV, respectively, for identifying category A/B gene PGV carriers. Decision curve analyses support MGPT for individuals predicted to have ≥ 2.5% probability of a PGV. CONCLUSION: PREMMplus accurately identifies individuals with PGVs in a diverse spectrum of cancer susceptibility genes with high sensitivity/NPV. Individuals with PREMMplus scores ≥ 2.5% should be considered for MGPT.
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Predisposición Genética a la Enfermedad , Neoplasias , Humanos , Modelos Estadísticos , Pronóstico , Neoplasias/genéticaRESUMEN
Lynch syndrome (LS) is the most common inherited cause of colorectal and endometrial cancers. Identifying individuals at risk for LS without personal cancer history requires detailed collection and assessment of family health history. However, barriers exist to family health history collection, especially in historically underserved populations. To improve LS risk assessment in historically underserved populations, we adapted the provider-facing PREdiction Model for gene Mutations (PREMM5™ model), a validated LS risk assessment model, into a patient-facing electronic application through an iterative development process involving expert and patient stakeholders. We report on preliminary findings based on the first 500 individuals exposed to the adapted application in a primary care population enriched for low-literacy and low-resource patients. Major adaptations to the PREMM5™ provider module included reduction in reading level, addition of interactive literacy aids, incorporation of family history assessment for both maternal and paternal sides of the family, and inclusion of questions about individual relatives or small groups of relatives to reduce cognitive burden. In the first 500 individuals, 90% completed the PREMM5™ independently; of those, 94% did so in 5 min or less (ranged from 0.2 to 48.8 min). The patient-facing application was able to accurately classify 84% of patients as having clinically significant or not clinically significant LS risk. Our preliminary results suggest that in this diverse study population, most participants were able to rapidly, accurately, and independently complete an interactive application collecting family health history assessment that accurately assessed for Lynch syndrome risk.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Endometriales , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Endometriales/genética , Femenino , Humanos , Inestabilidad de Microsatélites , Mutación , Medición de RiesgoRESUMEN
PURPOSE: National guidelines recommend genetic counseling and multigene germline testing (GC/MGT) for all patients with pancreatic ductal adenocarcinoma (PDAC). This study's aim was to assess real-world effectiveness of implementing systematic GC/MGT for all patients with PDAC at a high-volume academic institution. METHODS: An iterative process for systematizing GC/MGT was developed in which gastrointestinal oncology providers at the Dana-Farber Cancer Institute were recommended to refer all patients with PDAC for GC/MGT (clinician-directed referral). Workflows were subsequently changed such that patients with PDAC were automatically offered GC/MGT when scheduling their initial oncology consultation (automated referral). Clinical and germline data were collected on a consecutive cohort of patients with PDAC undergoing GC/MGT during a 25-month enrollment period (19-month clinician-directed referrals; 6-month automated referrals). RESULTS: One thousand two hundred fourteen patients with PDAC were seen for initial oncologic evaluation, 266 (21.9%) of whom underwent GC/MGT. Compared with baseline clinician-directed referrals, implementation of automated referrals led to a significant increase in patients with PDAC undergoing GC/MGT (16.5% v 38.0%, P < .001), including those undergoing multigene germline testing (MGT) ≤ 7 days of initial oncology evaluation (14.7% v 60.3%, P < .001), with preserved pathogenic variant detection rates (10.0% v 11.2%, P = 0.84). 16 of 28 (57.1%) pathogenic variant carriers had relatives who pursued cascade germline testing, and 13 of 26 (50.0%) carriers with incurable disease received targeted therapy based on MGT results. CONCLUSION: Implementation of systematic GC/MGT in patients with PDAC is feasible and leads to management changes for patients with PDAC and their families. GC/MGT workflows that bypass the need for clinician referral result in superior uptake and time to testing. Further investigation is needed to identify other barriers and facilitators of universal GC/MGT.
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Asesoramiento Genético , Neoplasias Pancreáticas , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Células Germinativas , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genéticaRESUMEN
Germline variants in the APC and MUTYH genes contribute to colorectal cancer (CRC) and adenoma risk, though may occur with varying frequencies in individuals of different ancestries. The aim of this study was to evaluate the prevalence of APC, monoallelic MUTYH and biallelic MUTYH germline variants in Ashkenazi Jewish (AJ) and Other Ancestry (OA) individuals with colorectal adenomas. We studied 7225 individuals with colorectal adenomas who had germline APC and MUTYH testing at a commercial laboratory. Cross-sectional medical history data were extracted from provider-completed test requisition forms. We performed bivariate analysis to compare the frequency of APC and MUTYH variants between AJ and OA, and examined APC p.I1307K and monoallelic MUTYH carrier phenotypes using logistic regression. Pathogenic APC variants occurred in 38/285 AJ (13%) and 1342/6940 OA (19%; P = 0.09); biallelic MUTYH variants in 2/285 (1%) AJ and 399/6940 (6%) OA (P < 0.0001); APC p.I1307K in 35/285 (12%) AJ and 29/6940 (1%) OA (P < 0.0001); and monoallelic MUTYH in 2/285 (1%) AJ and 133/6940 (2%) OA (P = 0.06). Monoallelic MUTYH variants were significantly associated with having a personal history of CRC, regardless of ancestry (OR 1.78; 95% CI 1.21-2.49; P < 0.01), but no significant association was found between APC p.I1307K variants and personal history of CRC (OR 1.38; 95% CI 0.79-2.44; P = 0.26). Ashkenazim with colorectal adenomas rarely have monoallelic or biallelic MUTYH variants, suggesting different genetic etiologies for polyposis in AJ compared to OA individuals. AJ ancestry assessment may be important in clinical evaluation for polyposis.
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Adenoma/genética , Neoplasias Colorrectales/genética , ADN Glicosilasas/genética , Genes APC , Mutación de Línea Germinal/genética , Judíos/genética , Adenoma/etnología , Estudios de Cohortes , Neoplasias Colorrectales/etnología , Femenino , Frecuencia de los Genes , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , FenotipoRESUMEN
IMPORTANCE: Pathogenic germline variants in the ATM gene have been associated with pancreatic cancer risk. Although genetic testing identifies these variants in approximately 1% to 3% of unselected patients with pancreatic cancer, the lifetime risk of pancreatic cancer among individuals with pathogenic ATM variants has not been well estimated. OBJECTIVE: To estimate age-specific penetrance of pancreatic cancer in individuals with a pathogenic variant in the ATM gene. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter cohort study of pancreatic cancer family registries in the US and Canada using pedigree data from 130 pancreatic cancer kindreds with a pathogenic germline ATM variant. Data analyses were performed from January 2020 to February 2021. MAIN OUTCOMES AND MEASURES: Observational age-specific risk of pancreatic cancer. Penetrance was estimated using modified segregation analysis. RESULTS: The study population of 130 families (123 [95%] White families) comprised 2227 family members (mean age [SD], 58 [22] years; 1096 [49%] women) with complete records (ie, including familial relationships, pancreatic cancer diagnosis, ATM status, proband status, and age), of which 155 individuals had positive results for an ATM pathogenic variant, 16 had a negative result, and the remainder did not have a test result. In these 130 families, 217 individuals had pancreatic cancer: 78 families had 1 such member; 34 families had 2 such members; and 18 families had 3 or more members with pancreatic cancer. The average (range) age at diagnosis was 64 (31-98) years. The cumulative risk of pancreatic cancer among individuals with a germline pathogenic ATM variant was estimated to be 1.1% (95% CI, 0.8%-1.3%) by age 50 years; 6.3% (95% CI, 3.9%-8.7%) by age 70 years; and 9.5% (95% CI, 5.0%-14.0%) by age 80 years. Overall, the relative risk of pancreatic cancer was 6.5 (95% CI, 4.5-9.5) in ATM variant carriers compared with noncarriers. CONCLUSIONS AND RELEVANCE: This multicenter cohort study found that individuals with a germline pathogenic ATM variant were at an increased lifetime risk of pancreatic cancer. These risk estimates can help guide decision-making when evaluating the risks and benefits of enhanced early detection surveillance.