Colonoscopy is expected to reduce colorectal cancer (CRC) incidence in Lynch syndrome (LS) by detecting and removing adenomas. The existence of gene-specific differences in adenoma detection has been proposed yet remains insufficiently explored. This study aims to elucidate gene-specific adenoma detection rates and their association with post-colonoscopy CRC (PCCRC), which stands as an important issue in LS surveillance.

In this multicenter study, we analyzed 1072 LS carriers without prior CRC undergoing surveillance colonoscopy, evaluating adenoma and advanced adenoma (AA) detection rates by gene. The primary outcome was to compare adenoma detection rates in individuals without prior CRC carrying pathogenic variants in MLH1/MSH2 vs MSH6/PMS2. Subgroup analysis was performed to assess the intermediate risk profile in MSH6 carriers relative to MLH1/MSH2 and PMS2 carriers. We compared overall adenoma detection rates, adenoma burden, age at first adenoma occurrence, and 10-year cumulative detection rates. Risk factors for AA and PCCRC were also identified. Multiple testing and multivariate analyses were performed.

The adenoma detection rates were similar across the 4 genes. However, MLH1/MSH2 carriers had a higher overall AA detection rate compared with MSH6/PMS2 carriers (14.5% vs 11.9%; P = .04) and showed higher cumulative AA detection rates over 10 years (21.6% vs 19.7%; P = .04). Subgroup analysis indicated that MSH6 carriers had an intermediate AA detection rate positioned between MLH1/MSH2 carriers and PMS2 carriers. Multivariate analysis indicated that AAs (odds ratio, 2.12; 95% confidence interval, 1.08-4.17; P=.03) and repeated AA detection (odds ratio, 4.62; 95% confidence interval, 1.70-12.57; P < .01) were independent risk factors for PCCRC.

Carriers of MLH1/MSH2 pathogenic variants are at a higher risk of developing AAs compared with those with MSH6/PMS2 mutations, with MSH6 carriers exhibiting an intermediate risk profile. AAs are an independent risk factor for PCCRC. LS patients with AAs should be identified as high risk and undergo enhanced colonoscopy surveillance.

We herein report a patient with Lynch-like syndrome in whom a brain tumor (glioblastoma) developed after repeated resection of colorectal cancer. The patient had a significant family history of cancer. Immunohistochemical expression of mismatch repair proteins was decreased in both brain and colon tumors, but no pathogenic variant of the related genes was detected. Although brain tumors occasionally develop in Lynch syndrome, they have not been reported in cases of Lynch-like syndrome. This first report of Lynch-like syndrome with the development of glioblastoma suggests the need for further investigation on the surveillance of brain tumors in patients with this syndrome.

Up to 95% of individuals with cancer-predisposing germline pathogenic variants in the U.S. remain unidentified, particularly among historically underserved populations.

In this 2-arm randomized controlled trial, we compared the proportion of high-risk patients identified and recommended for hereditary cancer syndrome genetic testing when risk assessment was performed by a digital tool vs usual clinician interview.

New gynecology patients at an urban academic clinic were randomized 1:1 to either a digital risk stratification tool or usual clinician-driven interview for genetic risk assessment. Eligibility for genetic testing was determined by criteria set forth by the National Comprehensive Cancer Network. The primary outcome was the proportion of high-risk patients identified and recommended for hereditary cancer syndrome genetic testing. The secondary outcomes were completion of genetic testing and exploration of patient factors including social determinants of health.

From January to December 2023, 100 patients enrolled in the study; 51 were randomized to genetic cancer risk assessment via digital tool and 49 via usual clinician interview. Thirty-nine (39%) patients self-identified as Hispanic, 23 (23%) as non-Hispanic White, 20 (20%) as non-Hispanic Black, 11 (11%) as Asian, 2 (2%) as mixed race, and 5 (5%) preferred not to answer. Most patients had Medicaid insurance (68; 68%), and 32 (32%) reported having a household income of less than $40,000. In the intervention arm, 44 (86%) completed the digital tool. Twenty-one (21%) patients were identified by study personnel as high-risk and met criteria for genetic testing (intervention: 8; control: 13). Use of the genetic cancer risk assessment tool was associated with a higher likelihood of high-risk patients being identified and recommended for genetic testing (7 [88%] vs 2 [15%]; P=.002). Among high-risk patients, 4 (50%) in the intervention arm and 2 (15%) in the control arm proceeded with genetic testing for hereditary cancers (P=.146). Within the intervention arm, social determinants of health did not impact use of the digital tool.

In a historically underserved population, the use of a digital genetic cancer risk stratification tool led to increased identification and counseling high-risk patients identified and recommended for genetic testing. The integration of a digital risk stratification tool may work toward mitigating disparities in utilization of genetic services.

As demand for genetic cancer risk assessment (GCRA) continues to increase, so does the sense of urgency to scale up efforts to triage patients, facilitate informed consent, and order genetic testing for cancer risk. The National Society of Genetic Counselors outlines the elements of informed consent that should be addressed in a GCRA session. While this practice resource aims to improve health equity, research on how well the elements of informed consent are implemented in practice is lacking. This retrospective and prospective mixed-methods study assessed how adequately the elements of informed consent are addressed during pre-test GCRA among 307 community clinicians (CC) and 129 cancer genetic counselors (GC), and barriers they face to addressing these elements. Results revealed that more than 90% of both cohorts consistently addressed components of at least 5 of the 10 elements of informed consent during a pre-test consultation. Technical aspects and accuracy of the test and utilization of test results were the most similarly addressed elements. Notably, GCs more often review the purpose of the test and who to test, general information about the gene(s), and economic considerations whereas CCs more often review alternatives to testing. Both cohorts reported psychosocial aspects of the informed consent process as the least adequately addressed element. Time constraints and patient-related concerns were most often cited by both cohorts as barriers to optimal facilitation of informed consent. Additional barriers reported by CCs included provider lack of awareness, experience, or education, and availability of resources and institutional support. Findings from this study may contribute to the development of alternative delivery models that incorporate supplementary educational tools to enhance patient understanding about the utility of genetic testing, while helping to mitigate the barrier of time constraints. Equally important is the use of this information to develop continuing education tools for providers.

Female Lynch syndrome carriers have an increased risk of developing endometrial cancer. Regardless, research on endometrial carcinoma tumorigenesis is scarce and no uniform, evidence-based gynaecological management guidelines exist. We therefore described gynaecological surveillance and surgery outcomes in a nation-wide Lynch syndrome cohort.

For this retrospective cohort study, female Lynch syndrome carriers, prospectively registered in the Dutch Lynch syndrome database (StOET), were included up to February 28th 2022. Carriers were linked to the Dutch national pathology (PALGA) database. The number of carriers with/without gynaecological surveillance, number of index carriers with endometrial carcinoma before Lynch syndrome diagnosis were assessed, as well as uptake of risk-reducing surgery and characteristics of endometrial carcinomas including the requisite for adjuvant therapy according to current guidelines. Overall survival after endometrial carcinoma diagnosis was analyzed using Kaplan Meier time to event analyses, cumulative incidence was calculated after adjusting for competing risks (death and prophylactic hysterectomy).

In total, 1046 registered female Lynch syndrome carriers were eligible for surveillance, of whom 313 (30.0%) did not have surveillance and 21.4% (n = 224 of 1046) opted for prophylactic hysterectomy. In carriers with surveillance, more cases of endometrial carcinoma and hyperplasia were found than in those without (37 endometrial carcinomas (7.3%) and 28 hyperplasias (5.5%) in 506 carriers with surveillance versus 14 (2.6%) and 4 (0.7%) in 540 carriers without surveillance, respectively); carriers with surveillance were generally younger than those without (median 56 years [IQR 48-65] versus median 65 years [IQR 49-75] at database assembly, respectively; p < 0.0001). Endometrial carcinomas were predominantly of endometrioid type and FIGO stage IA, regardless of surveillance. Adjuvant external beam radiotherapy was required in one patient in both groups. Overall survival after endometrial carcinoma diagnosis did not differ between carriers with or without surveillance or carriers with endometrial carcinoma before LS diagnosis (p = 0.51). For all endometrial carcinomas together, including index carriers, cumulative incidence was 22.7% at age 70.

In a nation-wide cohort of Lynch syndrome carriers, nearly one-third of eligible carriers did not undergo gynaecological surveillance. Endometrial carcinomas diagnosed during surveillance were slightly more often stage FIGO IA, but this did not seem to substantially decrease the requisite for adjuvant therapy or affect overall survival, questioning effectiveness of current gynaecological management. Prospective research should further assess this, as well as patient preferences.

None.

Previous research indicates that population genomic screening can benefit individuals who act on the genetic results. However, there remains a significant gap between individuals receiving genetic information and acting on current risk management recommendations, prompting exploration of interventions to close this gap. This study aimed to determine the feasibility and acceptability and conduct a pilot implementation of existing evidence-based interventions (EBIs) for adherence to disease management for select genetic conditions among individuals ascertained through a population genomic screening program.

Surveys of and interviews with individuals who received a genomic screening result were conducted to assess barriers to guideline-recommended care and assess the acceptability of problem-solving (PS) and motivational interviewing (MI) EBIs to facilitate adherence to recommendations. A design thinking workshop was conducted with clinicians to co-develop an MI- and PS-based intervention that would fit with current workflows to be piloted. Post-pilot engagement sessions with implementers determined acceptability and feasibility of the MI/PS pilot program for clinical implementation and elicited proposed adaptations for improvement.

PS and MI EBIs were reported to be acceptable and feasible to individuals with a result, and barriers to performing recommended management were identified. The pilot program included outreach by genetic counselors to individuals with a result, review of a checklist of barriers, and delivery of PS or MI as appropriate to facilitate care. The protocol as piloted was deemed acceptable and feasible for clinicians to deliver, with adaptations suggested.

These results will inform an effectiveness trial to address gaps in adherence in patients who have received actionable genomic results.

Lynch syndrome represents the most common hereditary cause of both colorectal and endometrial cancer. It is caused by defects in mismatch repair genes, as well as EPCAM. Universal screening of colon tumors for Lynch syndrome via microsatellite instability (MSI) and/or immunohistochemistry (IHC) can identify patients and families at risk to develop further cancers and potentially impact surveillance and treatment options. The approach to implementation of universal screening, taking ethical considerations into account, is critical to its effectiveness, with patient perspectives providing valuable insight.

Patients whose colon tumors underwent universal screening at Penn State Hershey Medical Center over a period of 2.5 years were mailed a survey on universal screening in 2017. Along with the survey, they received a recruitment letter and a summary explanation of research. The survey included both multiple choice and free-response questions that covered topics including respondent knowledge of Lynch syndrome, attitudes toward universal screening and experiences with the screening protocol as implemented.

Sixty-six of 297 possible patients (22.2%) responded to the survey, including 13 whose screening results raised concern for Lynch syndrome. 75.8% of respondents supported universal tumor screening without informed consent. 92.4% preferred receiving screening results regardless of outcome. Respondents described benefits to screening for themselves and their families.

While broadly supporting universal tumor screening without informed consent, respondents also wanted more information shared about the screening policy, as well as their results. These patient preferences should be one of many factors considered when implementing universal screening and can also inform practices regarding both tumor profiling and universal genetic testing, which is becoming more prevalent.

In the USA, up to 95% of individuals harbouring cancer-predisposing germline pathogenic variants have not been identified despite recommendations for screening at the primary care level.

Our primary objective is to use a two-arm, single-institution randomised controlled trial to compare the proportion of eligible patients that are recommended genetic testing for hereditary cancer syndromes using a digital tool versus clinician interview for genetic cancer risk assessment in an urban academic gynaecology clinic. New gynaecology patients will be consented and randomised 1:1 to either the intervention arm, in which a digital tool is used for genetic cancer risk assessment, or usual care, in which the clinician performs genetic cancer risk assessment. Individuals will be considered eligible for hereditary cancer syndrome genetic testing if criteria set forth by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology are met. Eligible patients are 18 years or older, speak and read English, have not yet undergone hereditary cancer genetic testing and have access to a smartphone. The study aims to enrol 50 patients in each arm to allow for 80% power with two-tailed alpha of 5% to detect a 20% difference in proportion of eligible patients recommended for genetic testing. The primary outcome is the proportion of eligible individuals recommended genetic testing in the digital tool arm versus usual care arm, analysed using the χ2 or Fisher's exact test as appropriate for sample size. The secondary outcome is completion of genetic testing, as well as exploration of patient factors, particularly social determinants of health, which may affect the receipt, utilisation and experience with genetic services.

This study has been approved by the Weill Cornell Institutional Review Board (Protocol No. 21-11024123). Participants will be informed of the benefits and risks of participation prior to consent. Dissemination of data will be deidentified and conducted through academic conferences and journals. Patients identified to be eligible for genetic testing who did not receive counselling from their providers will be contacted; participants will not receive direct notification of trial results.

This trial is registered at clinicaltrials.gov (NCT05562778) in September 2022.

This is protocol version 1, as of 22 May 2024.

USA, currently recruiting.

Genetic predisposition to cancers such as breast, ovarian, uterine and pancreatic. DEIDENTIFIED INDIVIDUAL CLINICAL TRIAL PARTICIPANT-LEVEL DATA IDP SHARING STATEMENT: IDP will not be shared.

NCT05562778.

Prior studies have estimated a small number of individuals with melanoma (2%-2.5%) have germline cancer predisposition, yet a recent twin study suggested melanoma has the highest hereditability among cancers.

To determine the incidence of hereditary melanoma and characterize the spectrum of cancer predisposition genes that may increase the risk of melanoma.

Four hundred individuals with melanoma and personal or family history of cancers underwent germline testing of >80 cancer predisposition genes. Comparative analysis of germline data was performed on 3 additional oncologic and dermatologic data sets.

Germline pathogenic/likely pathogenic (P/LP) variants were identified in 15.3% (61) individuals with melanoma. Most variants (41, 67%) involved genes considered unrelated to melanoma (BLM, BRIP1, CHEK2, MLH1, MSH2, PMS2, RAD51C). A third (20, 33%) were in genes previously associated with familial melanoma (BAP1, BRCA2, CDKN2A, MITF, TP53). Nearly half (30, 46.9%) of P/LP variants were in homologous repair deficiency genes. Validation cohorts demonstrated P/LP rates of 10.6% from an unselected oncologic cohort, 15.8% from a selected commercial testing cohort, and 14.5% from a highly selected dermatologic study.

Cohorts with varying degrees of selection, some retrospective.

Germline predisposition in individuals with melanoma is common, with clinically actionable findings diagnosed in 10.6% to 15.8%.

Lynch syndrome is an inherited condition which leads to an increased risk of colorectal, endometrial and ovarian cancer. Risk-reducing surgery is generally recommended to manage the risk of gynaecological cancer once childbearing is completed. The value of gynaecological colonoscopic surveillance as an interim measure or instead of risk-reducing surgery is uncertain. We aimed to determine whether gynaecological surveillance was effective and cost-effective in Lynch syndrome.

We conducted systematic reviews of the effectiveness and cost-effectiveness of gynaecological cancer surveillance in Lynch syndrome, as well as a systematic review of health utility values relating to cancer and gynaecological risk reduction. Study identification included bibliographic database searching and citation chasing (searches updated 3 August 2021). Screening and assessment of eligibility for inclusion were conducted by independent researchers. Outcomes were prespecified and were informed by clinical experts and patient involvement. Data extraction and quality appraisal were conducted and results were synthesised narratively. We also developed a whole-disease economic model for Lynch syndrome using discrete event simulation methodology, including natural history components for colorectal, endometrial and ovarian cancer, and we used this model to conduct a cost-utility analysis of gynaecological risk management strategies, including surveillance, risk-reducing surgery and doing nothing.

We found 30 studies in the review of clinical effectiveness, of which 20 were non-comparative (single-arm) studies. There were no high-quality studies providing precise outcome estimates at low risk of bias. There is some evidence that mortality rate is higher for surveillance than for risk-reducing surgery but mortality is also higher for no surveillance than for surveillance. Some asymptomatic cancers were detected through surveillance but some cancers were also missed. There was a wide range of pain experiences, including some individuals feeling no pain and some feeling severe pain. The use of pain relief (e.g. ibuprofen) was common, and some women underwent general anaesthetic for surveillance. Existing economic evaluations clearly found that risk-reducing surgery leads to the best lifetime health (measured using quality-adjusted life-years) and is cost-effective, while surveillance is not cost-effective in comparison. Our economic evaluation found that a strategy of surveillance alone or offering surveillance and risk-reducing surgery was cost-effective, except for path_PMS2 Lynch syndrome. Offering only risk-reducing surgery was less effective than offering surveillance with or without surgery.

Firm conclusions about clinical effectiveness could not be reached because of the lack of high-quality research. We did not assume that women would immediately take up risk-reducing surgery if offered, and it is possible that risk-reducing surgery would be more effective and cost-effective if it was taken up when offered.

There is insufficient evidence to recommend for or against gynaecological cancer surveillance in Lynch syndrome on clinical grounds, but modelling suggests that surveillance could be cost-effective. Further research is needed but it must be rigorously designed and well reported to be of benefit.

This study is registered as PROSPERO CRD42020171098.

This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR129713) and is published in full in Health Technology Assessment; Vol. 28, No. 41. See the NIHR Funding and Awards website for further award information.

Women with Lynch Syndrome (LS) have a high risk of colorectal and endometrial cancer. They are recommended regular colonoscopies, and some choose prophylactic hysterectomy. The aim of this study was to determine the impact of hysterectomy on subsequent colonoscopy in these women.

A total of 219 LS women >30 years of age registered in the clinical registry at Section for Hereditary Cancer, Oslo University Hospital, were included. Data included hysterectomy status, other abdominal surgeries, and time of surgery. For colonoscopies, data were collected on cecal intubation rate, challenges, and level of pain. Observations in women with and without hysterectomy, and pre- and post-hysterectomy were compared.

Cecal intubation rate was lower in women with hysterectomy than in those without (119/126 = 94.4% vs 88/88 = 100%, p = 0.025). Multivariate regression analysis showed an increased risk of challenging colonoscopies (OR,3.58; CI: 1.52-8.43; p = 0.003), and indicated a higher risk of painful colonoscopy (OR, 3.00; 95%CI: 0.99-17.44, p = 0.052), in women with hysterectomy compared with no hysterectomy. Comparing colonoscopy before and after hysterectomy, we also found higher rates of reported challenging colonoscopies post-hysterectomy (6/69 = 8.7% vs 23/69 = 33.3%, p < 0.001).

Women with hysterectomy had a lower cecal intubation rate and a higher number of reported challenging colonoscopy than women with no hysterectomy. However, completion rate in the hysterectomy group was still as high as 94.4%. Thus, LS women who consider hysterectomy should not be advised against it.

Germline genetic sequencing is now at the forefront of cancer treatment and preventative medicine. Cascade genetic testing, or the testing of at-risk relatives, is extremely promising as it offers genetic testing and potentially life-saving risk-reduction strategies to a population exponentially enriched for the risk of carrying a cancer-associated pathogenic variant. However, many relatives do not complete cascade testing due to barriers that span individual, relationship, healthcare community, and societal/policy domains. We have reviewed the published research on cascade testing. Our aim is to evaluate barriers to cascade genetic testing for hereditary cancer syndromes and explore strategies to mitigate these barriers, with the goal of promoting increased uptake of cascade genetic testing.

The Precision Medicine Initiative was launched upon the potential of genomic information to tailor medical care. Cascade genetic testing represents a powerful application of precision medicine and involves the process of familial diffusion or the "cascade" of genomic risk information. When an individual (proband) is found to carry a cancer-associated germline pathogenic mutation, the information should be cascaded or shared with at-risk relatives. First degree relatives have a 50% likelihood of carrying the same cancer-associated mutation. This process of cascade testing offers at-risk relatives the opportunity for genetic testing and, for those who also carry the cancer-associated mutation, genetically targeted primary disease prevention through intensive cancer surveillance, chemoprevention and risk-reducing surgery, reducing morbidity and preventing mortality. Cascade testing has been designated by the Centers for Disease Control and Prevention as a Tier 1 genomic application for hereditary breast and ovarian cancer. In this manuscript we describe a cascade genetic testing and in particular focus on its potential to provide necessary care to medically underserved and vulnerable populations.

DNA sequencing of tumour tissue has become the standard care for many solid cancers because of the option to detect somatic variants that have significant therapeutic, diagnostic and prognostic implications. Variants found within the tumour may be either somatic or germline in origin. Somatic cancer gene panels are developed to detect acquired (somatic) variants that are relevant for therapeutic or molecular characterisation of the tumour, expanding gene panels now include genes which may also inform patient management such as cancer predisposition syndromes (CPS) genes. Identifying germline cancer predisposition variants can alter cancer management, the risk of developing new primary cancers and risk for cancer in at-risk family members. This paper discusses the clinical, technical and ethical challenges related to identifying and reporting potential germline pathogenic variants that are detected on tumour sequencing. It also highlights the existence of the eviQ national guidelines for CPS with advice on germline confirmation of somatic findings to pathology laboratories in Australia.

Patients with a personal or family history of cancer may have elevated risk of developing future cancers, which often remains unrecognized due to lapses in screening. This pilot study assessed the usability and clinical outcomes of a cancer risk stratification tool in a gynecologic oncology clinic.

New gynecologic oncology patients were prompted to complete a commercially developed personal and family history-based risk stratification tool to assess eligibility for genetic testing using National Comprehensive Cancer Network criteria and estimated lifetime breast cancer risk using the Tyrer-Cuzick model. After use of the risk stratification tool, usability was assessed via completion rate and the System Usability Scale, and health literacy was assessed using the BRIEF Health Literacy Screening Tool.

130 patients were prompted to complete the risk stratification tool; 93 (72%) completed the tool. Race and ethnicity and insurance type were not associated with tool completion. The median System Usability Scale score was 83 out of 100 (interquartile range, 60-95). Health literacy positively correlated with perceived usability. Public insurance and race or ethnicity other than non-Hispanic White was associated with lower perceived usability. Sixty (65%) patients met eligibility criteria for genetic testing, and 21 (38% of 56 eligible patients) were candidates for enhanced breast cancer screening based on an estimated lifetime breast cancer risk of ≥20%.

A majority of patients completed the digital cancer risk stratification tool. Older age, lower health literacy, public insurance, and race or ethnicity other than non-Hispanic White were associated with lower perceived tool usability.

Lynch syndrome (LS) is the most frequent inherited colorectal cancer syndrome.

To assess the burden of adenoma in LS patients under 50 years-old followed in the PRED-IdF network.

From January 2010 to January 2019, all patients under 50 years of age with a confirmed LS germline mutation were included. The main objective was the description of adenomas characteristics according to path_MMR.

We analyzed data from 708 patients (mean age 34.8 ± 8.6), of which 41.8 % were male. Among these patients, 37.6% had path_MLH1, 45.4% path_MSH2, 13.9% path_MSH6, 2.9% path_PMS2, and 1.2% path_EpCAM. The analysis included 1721 (70.9%) follow-up colonoscopies. A total of 682 adenomas were detected, including 140 (20.5%) advanced adenomas. The adenoma detection rates during the first and follow-up colonoscopies were 19.2% and 20.5%, respectively. Most adenomas were <10 mm (57.9%), located in the proximal colon (334, 48.9%), and presented as non-polypoid lesions (493, 72.3%). The median growth time for adenomas was 23 months (range 9-114) irrespective of the path_MMR mutation (p = 0.62).

LS patients under 50 years of age have a high burden of adenomas, particularly small non-polypoid adenomas located in the proximal colon. These results highlight the need for intensive screening, with a particular focus on the proximal colon.

Multidisciplinary hereditary tumor clinics are a collaborative format to identify and treat patients with genetic cancer predispositions. The hereditary renal cancer clinic at Indiana University is comprised of a urologic oncologist, medical oncologist, clinical geneticist, and genetic counselor. The clinic holds regular tumor board meetings, where patient histories, pedigrees, imaging, pathology, and management plans are collectively reviewed and discussed. Here we report the contemporary experience for our hereditary renal cancer clinic, with description and analysis of referral patterns, patient profiles, and genetic testing outcomes.

A retrospective review of an IRB-approved, prospectively maintained database of patients seen in the hereditary renal cancer clinic was performed. Patient characteristics, genetic testing results, and disease characteristics were reported and analyzed.

A total of 142 patients seen in clinics from January 2018 to June 2023 were included. Patient's median age was between 40 and 49 years old, and 88.7% were Caucasian. The most common reasons for referral were early-onset renal tumors (40%), known hereditary renal cancer syndrome (29%), and hereditary renal cancer syndrome screening (13%). Of those with a tissue diagnosis of renal cell carcinoma, 46.2% were clear cell subtype. The presence of nonrenal syndromic features concerning for hereditary renal tumor syndrome was predictive of pathogenic mutation identification (OR 13.45, P < 0.0001). Patient race and presence of multifocal tumors were not predictive of pathogenic mutation identification. When restricting analysis to patients with an established renal malignancy, high-grade tumor histology was predictive of a pathogenic mutation (OR 8.17, P = 0.012), though higher pathologic stage and nonclear cell histology were not. Referral for early-onset renal tumor (age < 45 years) predicted lower likelihood of pathogenic mutations (OR 0.10, P = 0.0002). FH gene mutations were the most commonly identified pathogenic mutations. Genetic testing of family members (cascade testing) was recommended to 9 patients seen in clinic; a pathogenic mutation was subsequently identified in all but one of these families.

These findings are useful for referring physicians and patients in determining patient referral to hereditary cancer clinics, and for counseling patients undergoing genetic testing. Data from non-Caucasian patients and evolving implications of variants of unclear significance (VUS) may represent future research directions for hereditary renal cancer clinics.

We sought to explore patient-reported utility of all types of cancer results from genomic sequencing (GS).

Qualitative study, using semi-structured interviews with patients who underwent GS within a trial. Thematic analysis employing constant comparison was used. Two coders coded transcripts, with use of a third coder to resolve conflicts.

25 patients participated: female (22), >50 years (18), European (12), Ashkenazi Jewish (5), Middle Eastern (3), or other ethnicity (5), with breast cancer history (20). Patients' perceptions of the utility of cancer GS results hinged on whether they triggered clinical action. For example, when patients were enrolled into high-risk breast cancer surveillance programs for low/moderate risk breast cancer genes, they perceived the results to be very "useful" and of moderate-high utility. In contrast, patients receiving low/moderate risk or primary variants of uncertain significance results without clinical action perceived results as "concerning," leading to harms, such as hypervigilance about cancer symptoms. Overall, having supportive relatives or providers enhanced perceptions of utility.

Patients' perceptions of cancer GS results hinged on whether they triggered clinical management. Consequently, patients who received results without clinical action became hypervigilant, experiencing harms. Our findings call for a need to develop practice interventions to support patients with cancer undergoing GS.

To evaluate rates of familial disclosure of hereditary cancer syndrome information.

A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines (PROSPERO no.: CRD42020134276). Key electronic databases were searched to identify studies evaluating hereditary cancer syndrome cascade relative disclosure. Eligible studies were subjected to meta-analysis.

Thirty-four studies met inclusion criteria. Among 11,711 included relatives, 70% (95% CI 60 - 78%) were informed of their risk of carrying a cancer-associated pathogenic variant; of 2,875 relatives informed of their risk who were evaluated for uptake of cascade testing, 43% (95% CI 27 - 61%) completed testing. Rates of disclosure were higher among female vs male relatives (79% [95% CI 73% - 84%] vs 67% [95% CI 57% - 75%]) and first-degree vs second-degree relatives (83% [95% CI 77% - 88%] vs 58% [95% CI 45 - 69%]).

Nearly one-third of at-risk relatives remain uninformed of their risk of carrying a cancer-associated pathogenic variant. Even among those informed, fewer than half subsequently complete genetic testing, representing a critical missed opportunity for precision cancer prevention.

Five studies evaluating interventions to improve disclosure rates were generally ineffective. Urgent work is needed to elucidate barriers to relative disclosure by probands to develop targeted interventions that can optimize proband-mediated cascade genetic testing rates.

Lynch syndrome is one of the most common genetic predispositions to many cancers, most of which do not have a consensus recommendation for screening.

We studied in our region the value of a systematized and coordinated follow-up program for patients with Lynch syndrome on all organs at risk.

A multicenter prospective cohort evaluation was performed, from January 2016 to June 2021.

One hundred and seventy-eight patients were prospectively included (104 women (58%), median age 44 years, range 35-56 years) with a median follow-up of 4 years (range 2.5-5 years), corresponding to a total of 652 patient-years. The overall cancer incidence rate was 13.80 per 1000 patient-years. Seven of nine cancers (78%) were detected during the follow-up program, with all cancers identified at an early stage. The detection rate of adenomas during colonoscopies was 24%.

These preliminary data suggest that coordinated prospective follow-up of Lynch syndrome is capable of detecting the majority of incident cancers, particularly for locations not covered by an international follow-up recommendation. However, these results need to be confirmed by larger-scale studies.

Most individuals with a hereditary cancer syndrome are unaware of their genetic status to underutilization of hereditary cancer risk assessment. Chatbots, or programs that use artificial intelligence to simulate conversation, have emerged as a promising tool in health care and, more recently, as a potential tool for genetic cancer risk assessment and counseling. Here, we evaluated the existing literature on the use of chatbots in genetic cancer risk assessment and counseling.

A systematic review was conducted using key electronic databases to identify studies which use chatbots for genetic cancer risk assessment and counseling. Eligible studies were further subjected to meta-analysis.

Seven studies met inclusion criteria, evaluating five distinct chatbots. Three studies evaluated a chatbot that could perform genetic cancer risk assessment, one study evaluated a chatbot that offered patient counseling, and three studies included both functions. The pooled estimated completion rate for the genetic cancer risk assessment was 36.7% (95% CI, 14.8 to 65.9). Two studies included comprehensive patient characteristics, and none involved a comparison group. Chatbots varied as to the involvement of a health care provider in the process of risk assessment and counseling.

Chatbots have been used to streamline genetic cancer risk assessment and counseling and hold promise for reducing barriers to genetic services. Data regarding user and nonuser characteristics are lacking, as are data regarding comparative effectiveness to usual care. Future research may consider the impact of chatbots on equitable access to genetic services.

Background: The association between Lynch syndrome (LS) and a higher risk of upper tract urothelial carcinoma is well established, but its effect on the risk of bladder and kidney cancers remains controversial. This review aimed to compare the relative risk (RR) of bladder and kidney cancer in confirmed LS germline mutation carriers compared to the general population. Methods: Medline, Embase, Cochrane Central, and Google Scholar were searched on 14 July 2022 for studies published in English that reported on the rates of urological cancer in adults with confirmed LS germline mutation. The quality of included studies was assessed using Cochrane’s tool to evaluate risk of bias in cohort studies. Random effects meta-analysis estimated the pooled relative risk of bladder and kidney cancer in LS carriers compared to the general population. The quality of the overall evidence was evaluated using GRADE. Results: Of the 1839 records identified, 5 studies involving 7120 participants from 3 continents were included. Overall, LS carriers had a statistically significantly higher RR of developing bladder cancer (RR: 7.48, 95% CI: 3.70, 15.13) and kidney cancer (RR: 3.97, 95% CI: 1.23, 12.81) compared to unaffected participants (p < 0.01). The quality of the evidence was assessed as “low” due to the inclusion of cohort studies, the substantial heterogeneity, and moderate-to-high risk of bias. Conclusion: Lynch syndrome is associated with a significant increase in the relative risk of kidney and bladder cancer. Clinicians should adopt a lower threshold for germline mutation genetic testing in individuals who present with bladder cancer. Further studies evaluating the role and cost-effectiveness of novel urine-based laboratory tests are needed. High-quality studies in histologically proven renal cell carcinoma and their underlying germline mutations are necessary to strengthen the association with LS.

Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC). In order to detect CRCs amongst LS patients, regular colonoscopies are recommended. However, an international agreement on an optimal surveillance interval has not yet been reached. In addition, few studies have investigated factors that could potentially increase the CRC risk amongst LS patients.

The primary aim was to describe the frequency of CRCs detected during endoscopic surveillance and to estimate the interval from a clean colonoscopy to CRC detection amongst LS patients. The secondary aim was to investigate individual risk factors, including sex, LS genotype, smoking, aspirin use and body mass index (BMI), on CRC risk amongst patients that develop CRC before and during surveillance.

Clinical data and colonoscopy findings from 366 LS patients' 1437 surveillance colonoscopies were collected from medical records and patient protocols. Logistic regression and Fisher's exact test were used to investigate associations between individual risk factors and CRC development. Mann-Whitney U test was used to compare the distribution of TNM stages of CRC detected before surveillance and after index.

CRC was detected in 80 patients before surveillance and in 28 patients during surveillance (10 at index and 18 after index). During the surveillance programme, CRC was detected within 24 months in 65% of the patients, and after 24 months within 35% of the patients. CRC was more common amongst men, previous and current smokers, and the odds of developing CRC also increased with an increasing BMI. CRCs were more often detected amongst MLH1 and MSH2 carriers during surveillance, compared to the other genotypes.

We found that 35% of the CRC cases detected during surveillance were found after 24 months. MLH1 and MSH2 carriers were at higher risk of developing CRC during surveillance. Additionally, men, current or previous smokers, and patients with a higher BMI were at higher risk of developing CRC. Currently, LS patients are recommended a "one-size-fits-all" surveillance program. The results support the development of a risk-score whereby individual risk factors should be taken into consideration when deciding on an optimal surveillance interval.

Lynch syndrome (LS), an autosomal dominant disorder caused by pathogenic germline variants in DNA mismatch repair (MMR) genes, represents the most common hereditary colorectal cancer (CRC) syndrome. Lynch syndrome patients are at high risk of CRC despite regular endoscopic surveillance.

Our aim was to investigate the diagnostic performance of artificial intelligence (AI)-assisted colonoscopy in comparison to High-Definition white-light endoscopy (HD-WLE) for the first time.

Patients ≥18 years with LS, with a pathogenic germline variant (MLH1, MHS2, MSH6), and at least one previous colonoscopy (interval 10-36 months) were eligible. Patients were stratified by previous CRC and affected MMR gene with a 1:1 allocation ratio (AI-assisted vs. HD white-light endoscopy) in this exploratory pilot trial.

Between Dec-2021 and Dec-2022, 101 LS patients were randomised and 96 patients were finally analyzed after exclusion of 5 patients due to insufficient bowel preparation. In the HD-WLE arm, adenomas were detected in 12/46 patients compared to 18/50 in the AI arm (26.1% [95% CI 14.3-41.1] vs. 36.0% [22.9-50.8]; p = 0.379). The use of AI-assisted colonoscopy especially increased detection of flat adenomas (Paris classification 0-IIb) (examinations with detected flat adenomas: 3/46 [6.5%] vs. 10/50 [20%]; p = 0.07; numbers of detected flat adenomas: 4/20 vs. 17/30, p = 0.018). The median withdrawal time did not differ significantly between HD-WLE and AI (14 vs. 15 min; p = 0.170).

We here present first data suggesting that real-time AI-assisted colonoscopy is a promising approach to optimize endoscopic surveillance in LS patients, in particular to improve the detection of flat adenomas.

Cascade genetic testing for hereditary cancer syndromes offers affected relatives the opportunity to pursue cancer screening and risk-reducing surgery and thus reduces morbidity and mortality. The purpose of this study was to measure the long-term utilization of targeted cancer prevention and quality of life among at-risk relatives offered clinician-facilitated cascade genetic testing.

In a pilot study, at-risk relatives of patients with a hereditary cancer syndrome were contacted directly by the clinical team and offered telephone genetic counseling and genetic testing via an at-home, mailed saliva kit. Two-year follow-up results evaluating the use of targeted cancer prevention strategies and the quality of life for enrolled relatives were reported. Quality-of-life was measured with validated surveys, and scores were compared to the time of initial contact by the Wilcoxon signed-rank test.

Ninety-five at-risk relatives were enrolled in the initial pilot study, and 72 (76%) participated in the 2-year follow-up; 57 of these (79%) had completed genetic testing. Twenty-five of those 57 relatives (44%) were found to harbor an inherited pathogenic variant. Guideline-based cancer surveillance was recommended to 18 relatives; 13 (72%) completed at least one recommended screening, and six (33%) completed all recommended screenings. Risk-reducing surgery was recommended to 10 relatives; four (40%) completed a total of eight procedures. Quality-of-life surveys demonstrated low levels of anxiety, depression, distress, and uncertainty.

The 2-year follow-up of the original pilot study revealed that clinician-facilitated cascade testing resulted in genetically targeted cancer screening and prevention with preserved quality of life. These results, to be confirmed by larger randomized controlled trials, suggest that medical systems should consider supporting clinician-facilitated cascade testing programs.

Evidence-based guidelines recommend cascade genetic counseling and testing for hereditary cancer syndromes, providing relatives the opportunity for early detection and prevention of cancer. The current standard is for patients to contact and encourage relatives (patient-mediated contact) to undergo counseling and testing. Direct relative contact by the medical team or testing laboratory has shown promise but is complicated by privacy laws and lack of infrastructure. We sought to compare outcomes associated with patient-mediated and direct relative contact for hereditary cancer cascade genetic counseling and testing in the first meta-analysis on this topic.

We conducted a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO No.: CRD42020134276). We searched key electronic databases to identify studies evaluating hereditary cancer cascade testing. Eligible trials were subjected to meta-analysis.

Eighty-seven studies met inclusion criteria. Among relatives included in the meta-analysis, 48% (95% CI, 38 to 58) underwent cascade genetic counseling and 41% (95% CI, 34 to 48) cascade genetic testing. Compared with the patient-mediated approach, direct relative contact resulted in significantly higher uptake of genetic counseling for all relatives (63% [95% CI, 49 to 75] v 35% [95% CI, 24 to 48]) and genetic testing for first-degree relatives (62% [95% CI, 49 to 73] v 40% [95% CI, 32 to 48]). Methods of direct contact included telephone calls, letters, and e-mails; respective rates of genetic testing completion were 61% (95% CI, 51 to 70), 48% (95% CI, 37 to 59), and 48% (95% CI, 45 to 50).

Most relatives at risk for hereditary cancer do not undergo cascade genetic counseling and testing, forgoing potentially life-saving medical interventions. Compared with patient-mediated contact, direct relative contact increased rates of cascade genetic counseling and testing, arguing for a shift in the care delivery paradigm, to be confirmed by randomized controlled trials.

Guidelines recommend universal mismatch repair (MMR) tumour testing of colorectal adenocarcinomas (CRCs) to screen for Lynch syndrome (LS). However, its implementation remains disjointed and referral for genetic testing dismal, particularly among minorities. We aimed to increase referral, cancer genetic testing and eventually LS diagnosis by developing the CLEAR LS (Closed Loop Enhanced Assessment and Referral for Lynch Syndrome) intervention, a systems approach which in the second phase was automated.

This is a cohort study of all patients diagnosed with CRC at an academic centre between 1 January 2012, when implementation of universal CRC testing began, and 31 January 2021. The original cohort spanned through 31 May 2015. Tumour testing included MMR immunohistochemistry, followed by BRAF V600E/MLH1 promoter methylation testing when indicated. The intervention included a manual phase (1 June 2015 through 31 July 2018), which systematised pathology screening and cancer genetics (CG) referral mechanisms, and an automated phase (1 August 2018 through 31 January 2021) using computer programming.

A total of 249/1541 CRC (17.38%) had MMR loss of expression and 129 (8.37%) qualified for CG evaluation. Referral was 27.58% in the original cohort and 92.1% in the intervention (p<0.001). Patients seen by CG among referred were 27.58% in the original cohort and 74.3% in the intervention (p two-sided<0.001). The distribution of race/ethnicity among patients qualifying and referred for CG evaluation was not significantly different across cohorts. LS diagnosis increased from 0.56% (original cohort) to 1.43% (intervention). Cost per new diagnosis of LS decreased from US$173 675 to $87 960 from original cohort to intervention.

Implementation of systematic case identification and referral support mechanisms significantly increased the proportion of patients undergoing genetic testing and doubled the percentage of patients diagnosed with LS with no referral differences across racial/ethnic groups.

Lynch syndrome is associated with the most common form of heritable bowel cancer. There remains limited level 1 evidence on survival outcomes and rate of metachronous tumor associated with Lynch syndrome colorectal cancer.

A systematic literature search of original studies was performed on Ovid searching MEDLINE, Embase, Cochrane Database of Systematic Reviews, American College of Physicians ACP Journal Club, Database of Abstracts of Reviews of Effects DARE, and Clinical Trials databases from inception of database to February 2021. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline was followed. The data were pooled using a random-effects model. All of the P values were 2-tailed, and statistical analysis was performed using RevMan v. 5.3 Cochrane Collaboration.

From 1,942 studies, 15 studies met the inclusion criteria and were included for qualitative and quantitative synthesis. The five-year overall survival was 89.5% (82.0-94.1%), P < .01; I² = 89%. The ten-year overall survival was 80.5% (68.7-88.6%), P < .01; I² = 81%. The fifteen-year overall survival was 70% (33.7%-91.5%), P < .01; I² = 93%. Univariate meta-regression analysis showed no statistically significant difference in 5-year overall survival by sex, age, MLH1, MSH2, MSH6, nor tumor location (right versus left colon). The metachronous tumor rate was 12% to 33% with a follow-up period of up to 15 years, significantly lower in patients who underwent subtotal/total colectomy (0-6%).

The overall survival of patients with colorectal cancer with Lynch syndrome was approximately 90% at 5 years, 80% at 10 years, and 70% at 15 years. The metachronous tumor rate was approximately 10% to 30% at up to 15 years, significantly improved by subtotal/total colectomy.

Use of germline genetic testing among patients with cancer is increasing because of (1) the availability of multigene panel tests that include multiple cancer susceptibility genes in a single test, (2) decreased costs of these tests and improvements in insurance coverage, and (3) US Food and Drug Administration-approval of genotype-directed therapies such as poly(ADP-ribose) polymerase inhibitors for individuals with certain cancers and pathogenic germline variants in BRCA1 and BRCA2 (with possible benefits with other genes in the homologous repair deficiency pathway). In addition, National Comprehensive Cancer Network guidelines have already endorsed germline genetic testing for all patients with certain cancer types (epithelial ovarian cancer, exocrine pancreatic cancer, and high-grade/metastatic prostate cancer), regardless of age or personal/family history of cancer. Herein, we debate the pros and cons of offering germline multigene panel testing to all patients diagnosed with any GI cancer. The authors agree that it may just be a matter of time before germline multigene panel testing is offered to all patients with cancer; however, this article will highlight some of the benefits, risks, and limitations of this approach so that research can help fill some of the gaps to ensure that genetic medicine continues to be implemented in ways that improve real-world patient care and outcomes.