Lynch syndrome is an autosomal dominant cancer predisposition syndrome and the most common cause of hereditary colorectal cancer. In addition to colorectal cancer, it confers substantially increased risks for several ext...Lynch syndrome is an autosomal dominant cancer predisposition syndrome and the most common cause of hereditary colorectal cancer. In addition to colorectal cancer, it confers substantially increased risks for several extracolonic malignancies. While there is broad consensus regarding the effectiveness of endoscopic colorectal surveillance, recommendations for surveillance of gastric, small bowel, and pancreatic cancers vary considerably among guidelines issued by leading professional societies. These discrepancies largely reflect the limited availability of robust, high-quality evidence. In this narrative review, we summarize the cancer risks for gastric, small bowel, and pancreatic malignancies in Lynch syndrome carriers, discuss recent studies evaluating the outcomes of surveillance strategies, and provide an overview of current guideline recommendations. Furthermore, we highlight emerging approaches that may enhance surveillance strategies in the future. In recent years, increasing research efforts have focused on surveillance for less frequent Lynch syndrome-associated malignancies, however, prospective data from large, well-characterized cohorts remain scarce. Such data are essential to harmonize existing guidelines and to enable the development of personalized surveillance strategies for individuals affected by Lynch syndrome.
Swedish family and cancer data constitute the largest source on familial cancer in the world. We analyze here familial risks in prostate cancer (PC) with focus on multiple affected brothers and comparation of full-brothe...Swedish family and cancer data constitute the largest source on familial cancer in the world. We analyze here familial risks in prostate cancer (PC) with focus on multiple affected brothers and comparation of full-brothers to maternal and paternal half-brothers. Age-specific incidence and standardized incidence ratios (SIRs) were calculated for PC in brothers. Curves for relative risk (RR) by diagnostic age were plotted for risk distributions. A total of 115,066 PCs were diagnosed in 1.2 million men. Familial SIR for full brothers was 2.23, for maternal half-brothers it was 1.92 and paternal half-brothers was 1.34. Considering SIRs with least possible detection bias (7+ years after first brother's diagnosis) the above SIRs were 2.06, 1.66 and 1.41. SIRs in full brothers increased stepwise by the number of affected brothers reaching 21.33 when 6 brothers were affected. Age-RR curves for two affected brothers declined evenly from RR 2.8 at age 45 to below 2.0 at age 80. When four or more brothers were affected, a discrete high-risk peak (RR 4-7) was detected between ages 60 and 69. Data on full-brothers and half-brothers indicate that familial risk in PC is largely genetic which is also supported by discrete RR peaks in high-risk families at ages matching preferential penetrance age for known predisposition genes of PC. Familial risk increased already when two brothers were affected calling for clinical vigilance concerning family history. Family history should deserve a place as an inclusion criterium in schemes for PC screening.
Biallelic pathogenic variants in the MBD4 gene have recently been associated with an autosomal recessive cancer predisposition syndrome deemed "MBD4-associated neoplasia syndrome (MANS)". Early reports of individuals wit...Biallelic pathogenic variants in the MBD4 gene have recently been associated with an autosomal recessive cancer predisposition syndrome deemed "MBD4-associated neoplasia syndrome (MANS)". Early reports of individuals with MANS highlight the propensity to develop young onset colorectal polyposis and hyper-mutated acute myeloid leukemia (AML). In the following case series, we present four patients with MANS from three families with polyps and AML, as well as additional features previously less described, such as schwannoma and thyroid cancer. This series increases the total number of reported cases by 27%, with the intention of achieving a more robust understanding of the full phenotypic spectrum of MANS.
BACKGROUND: The Lynch syndrome INtegrative Epidemiology And GEnetics (LINEAGE) consortium was established to address gaps in understanding genotype-specific cancer risks and risk-modifiers in contemporary North American...BACKGROUND: The Lynch syndrome INtegrative Epidemiology And GEnetics (LINEAGE) consortium was established to address gaps in understanding genotype-specific cancer risks and risk-modifiers in contemporary North American Lynch syndrome (LS) populations. LINEAGE is a multi-center, longitudinal cohort to systematically collect data on risk factors, adherence to care, quality of surveillance, and patient-, provider-, and system-level factors associated with incident LS-associated cancers. METHODS: LINEAGE recruits individuals with confirmed pathogenic or likely pathogenic variants in LS-associated genes from participating institutions. Data includes retrospective and prospective collection, encompassing clinical abstraction (demographics, surgical history, endoscopic data, treatments), patient-reported surveys (behavioral/lifestyle factors, quality of life, procedures), endoscopist-level data, and biosample metadata. A standardized REDCap database, data harmonization protocols, and a virtual biobank support reproducibility and linkage of clinical data and biosamples. Rigorous quality assurance/quality control processes are embedded for data integrity. RESULTS: Participating centers will contribute data to determine gene-specific risks, and gene-environment interactions for Lynch-associated, and other cancers. We will evaluate associations with exposure to, and quality of cancer risk-reduction care, including endoscopic surveillance, risk-reduction surgery, and chemoprevention. The inclusion of provider-level variables, such as endoscopist training and experience, enables unique research into modifiers of post-endoscopy cancer risk. The linked biosample resources will further facilitate mechanistic studies and biomarker discovery. CONCLUSIONS: LINEAGE provides a robust platform for advancing LS research by integration of clinical, pathological, epidemiological and genetic data across institutions. Its standardized, collaborative framework enhances the validity and generalizability of risk estimates that will guide decision-making and policy for surveillance to ultimately reduce morbidity and mortality for individuals with Lynch syndrome.
Melanson A, Alsuhaibani M, Viezel-Mathieu A
… +9 more, Dionisopoulos T, Basik M, Boileau JF, Martel K, Prakash I, Meterissian S, Vorstenbosch J, Foulkes WD, Wong SM
BACKGROUND: Women with germline pathogenic variants (GPV) in BRCA1/2, PALB2, or other high penetrance genes may consider risk reducing mastectomy (RRM) with or without reconstruction to reduce their risk of developing br...BACKGROUND: Women with germline pathogenic variants (GPV) in BRCA1/2, PALB2, or other high penetrance genes may consider risk reducing mastectomy (RRM) with or without reconstruction to reduce their risk of developing breast cancer. Few studies have characterized reconstructive trends in this patient population. METHODS: We conducted a retrospective cohort study of female patients with a confirmed GPV in a high penetrance breast cancer susceptibility gene who underwent RRM between 2003 and 2024. Clinicodemographic and surgical data were extracted from the electronic medical record. The Chi-squared test and Mantel-Haenszel test for trend were used to evaluate factors and temporal trends associated with reconstruction. RESULTS: Of 443 female GPV carriers who underwent RRM, 394 (88.9%) elected to undergo breast reconstruction. Factors significantly associated with reconstruction included younger age (p < 0.001), premenopausal status (p < 0.001), and more recent year of RRM (p = 0.04). In women undergoing reconstruction, the median age was 43 years (IQR 35–52) compared to 55 years (IQR 39–65) in those electing for no reconstruction (p < 0.001). There was a significant trend towards increased use of reconstruction over the study period (85.2% prior to 2012 vs. 97.0% after 2022, p < 0.01). In 375 carriers with reconstructive details available, implant-based reconstruction was the most common (94.1%), although autologous/flap based reconstructive procedures increased over time (2.3% of all reconstructive procedures prior to 2012 vs. 12.6% after 2022, p = 0.003). There was a trend towards decreasing use of tissue expanders over time (86.1% prior to 2012 vs. 26.3% after 2022), whereas direct-to-implant reconstruction (either single-staged or staged following reduction mastopexy) became the dominant reconstructive approach over the study period (11.6% prior to 2012 vs. 61.1% after 2022; p < 0.001). Among 353 patients undergoing implant-based techniques, the use of prepectoral implants increased dramatically over the study period (0% prior to 2012 to 94.0% after 2022, p < 0.001). CONCLUSIONS: In BRCA1/2, PALB2, and other high penetrance GPV carriers undergoing RRM, the use of reconstruction increased from 85% prior to 2012 to 97% of all carriers in 2022. Implant-based techniques were the most commonly used, although autologous/flap-based reconstruction techniques gradual increased over time. Further research examining patient reported outcomes, recovery time, and the financial impact of different reconstructive approaches are warranted.
Evidence of benefit for pancreatic ductal adenocarcinoma (PDAC) surveillance is accumulating, including earlier staging, extended survival, and improved psychological function. This study aimed to assess the 5-year psych...Evidence of benefit for pancreatic ductal adenocarcinoma (PDAC) surveillance is accumulating, including earlier staging, extended survival, and improved psychological function. This study aimed to assess the 5-year psychological impact of high-risk PDAC surveillance, performed at St Vincent’s Hospital, Sydney, Australia. Participants were offered annual endoscopic ultrasound (EUS) or magnetic resonance imaging (MRI), with frequency increasing if clinically indicated. The impact of event scale (IES), comprising intrusion and avoidance subscales, and the psychological consequences questionnaire (PCQ), which assesses emotional, physical and social domains, were administered at baseline, 1-month, 1-year and 5-years post-baseline EUS. Generalized linear mixed-effects models were used to assess for differences in reported outcomes. Of the 143 participants under surveillance, 108 underwent annual investigations, and 35 had one or more episode(s) of intensified surveillance. Overall, screening compliance was high, though understandably, increased deferrals occurred during COVID-19 pandemic restrictions. Two participants were diagnosed with pancreatic neoplasms and half had pre-malignant pancreatic lesions that remained stable (n = 45) or showed progression (n = 28). There was a significant reduction in IES intrusion and an increase in positive PCQ emotional, physical and total scores at 5-years. Negative PCQ scores remained stable compared to baseline. There was no difference in IES, negative PCQ or positive PCQ scores based on EUS/MRI findings. Individuals undergoing intensified surveillance reported significantly lower positive PCQ physical and total scores, but there was no difference in negative PCQ or IES scores. These data provide reassurance regarding the acceptability and psychological safety of PDAC surveillance, despite frequent abnormal findings and intensified investigation.
Lynch syndrome predisposes to multiple cancer types, including urological malignancies. However, no evidence-based recommendations for surveillance of urological malignancies currently exist. In this systematic review, w...Lynch syndrome predisposes to multiple cancer types, including urological malignancies. However, no evidence-based recommendations for surveillance of urological malignancies currently exist. In this systematic review, we aim to describe the current evidence regarding surveillance for these cancers. A systematic literature search was conducted using MEDLINE, searching for urological malignancies, Lynch syndrome, and surveillance including the results of the surveillance methods. Sensitivity and specificity were calculated, when possible, preferably for pooled data from each surveillance method. The risk of bias was assessed using the Newcastle–Ottawa Scale. After full text-screening, nine studies published in 2008–2025 met the inclusion criteria, including two on prostate cancer and seven on urothelial cancer. Prostate cancer-antigen (PSA) surveillance led to 38 prostate cancer diagnoses in 865 individuals with Lynch syndrome, with 71% being clinically significant prostate cancers. In 1564 individuals, 11 urothelial carcinomas were diagnosed by different surveillance methods and 15 diagnoses were missed. Sensitivity of urinalysis, urine cytology, urine MSI, and CT and cystoscopy was 11%, 30%, 100%, and 100% respectively. Specificity was 90%, 97%, 99%, and 100% respectively for these methods. Further data is needed but for prostate cancer surveillance PSA shows promise, while for MSH2 carriers at least, urine microsatellite instability analysis shows promise as a urothelial cancer surveillance test.
Cancer vaccines offer a promising strategy for cancer prevention, particularly in hereditary cancer syndromes such as Lynch syndrome (LS). LS is characterized by a high lifetime risk of developing various malignancies du...Cancer vaccines offer a promising strategy for cancer prevention, particularly in hereditary cancer syndromes such as Lynch syndrome (LS). LS is characterized by a high lifetime risk of developing various malignancies due to defects in DNA mismatch repair, leading to an accumulation of mutations, particularly frameshift insertion/deletions (indels) within microsatellite loci. These indels create shared tumour-specific neoantigens, which are unique to LS and can be recognized by the immune system and trigger cancer cell killing. Importantly, these neoantigens are also present in precancerous lesions, making LS an ideal target for immune-interception strategies aimed at prevention. Over the years, a variety of vaccine designs targeting different antigens along with a range of delivery platforms have been explored for different types of tumours, each with its own advantages and limitations. In this review, we provide an overview of the key antigens and delivery platforms used in cancer preventive vaccine development for LS, evaluate their limited clinical outcomes to date, and explore the future directions of preventive vaccine immunotherapy. A particular focus is placed on the promising potential of dendritic cell vaccination therapy as a future approach in this field.
Li–Fraumeni syndrome (LFS) is a hereditary syndrome caused by TP53 variants, conferring a high risk of early-onset malignancies, particularly breast cancer. TP53 variants also increase susceptibility to radiation-induced...Li–Fraumeni syndrome (LFS) is a hereditary syndrome caused by TP53 variants, conferring a high risk of early-onset malignancies, particularly breast cancer. TP53 variants also increase susceptibility to radiation-induced tumors, complicating therapeutic strategies. This report illustrates a representative case and reviews current recommendations and related challenges. A literature review was conducted on patients with LFS who developed secondary malignancies within previously irradiated fields. We describe a 31-year-old woman with prior breast augmentation and left-sided breast cancer treated with chemotherapy, lumpectomy, axillary dissection, and adjuvant radiotherapy. A TP53 variant was identified post-treatment. 22 months after completing radiotherapy, imaging revealed two suspicious nodules adjacent to the left implant. Despite negative biopsies, mastectomy and implant removal uncovered an undifferentiated pleomorphic sarcoma within the capsule. Subsequently, extensive resection with a latissimus dorsi flap was performed. Histopathological analysis revealed residual chondroblastic osteosarcoma infiltrating muscle tissue. The literature indicates increased radiosensitivity and a higher risk of secondary malignancies in patients with TP53 pathogenic variants. Current guidelines favor mastectomy over breast-conserving surgery and recommend avoiding radiotherapy when feasible. Early genetic testing and multidisciplinary planning are essential to optimize oncologic safety and functional outcomes.
The BAP1 gene encodes a tumor suppressor protein implicated in BAP1 tumor predisposition syndrome (BAP1-TPDS), a hereditary condition associated with an increased risk of uveal and skin melanoma, mesothelioma, and renal...The BAP1 gene encodes a tumor suppressor protein implicated in BAP1 tumor predisposition syndrome (BAP1-TPDS), a hereditary condition associated with an increased risk of uveal and skin melanoma, mesothelioma, and renal cancer. In this case report, we describe a male patient diagnosed with mesothelioma carrying a germline BAP1 variant. The patient exhibited severe nail abnormalities affecting all ten fingernails and several toenails. To our knowledge, the association between onychopapilloma and pathogenic germline BAP1 variants has only been reported once in the literature. The patient had experienced nail abnormalities since adolescence. Based on these findings, we propose that polydactylous onychopapilloma may serve as a clinical marker of BAP1-TPDS in otherwise asymptomatic individuals, and could potentially aid in early identification of at-risk carriers.
Germline PALB2 variants confer a moderate/high-risk for breast cancer (BC). Recent reports described an increasing attention in suggesting bilateral prophylactic mastectomy (BPM), for healthy carriers, or contraleral ris...Germline PALB2 variants confer a moderate/high-risk for breast cancer (BC). Recent reports described an increasing attention in suggesting bilateral prophylactic mastectomy (BPM), for healthy carriers, or contraleral risk-reducing mastectomy (CRRM) and/or therapeutic mastectomy for women with BC. In this study, we aimed to calculate systematically the overall number of these procedures reported in literature. We revised all articles using systematic research through the PUBMED database. Overall numbers, frequencies, geographic distribution, family history, and post-operative histopathological analysis of BPM or CRRM were the main outcomes considered. Among 51 studies, 10 articles fulfilled our aim. All BPM or CRRM were performed in North America. One-hundred and forty-two (6.6%) were PALB2 positive, from 2,135 tested women; a total of 84 women were treated, 35 (41.7%) were healthy carriers and 49 (58.3%) received a CRRM for a previous or contextual diagnosis of BC, respectively. A positive family history was reported in 80% of these groups, and a post-operative tumor was identified in 2.6% of breast specimens. In conclusion, very few studies are reported, only in North America, but about of 2/3 (~ 60%) of the screened women received BPM or CRRM, with a high familial history for BC and a low detection rate of tumor in breast post-operative specimens.
Over 97% of individuals with hereditary cancer predisposition remain unidentified, limiting access to life-saving prevention and screening. In British Columbia (BC), access to publicly funded genetic testing is restricte...Over 97% of individuals with hereditary cancer predisposition remain unidentified, limiting access to life-saving prevention and screening. In British Columbia (BC), access to publicly funded genetic testing is restricted to individuals with a family history of cancer. A novel solution, population-based testing (PBT), would remove the family history requirement, providing unrestricted access for all residents. This qualitative study explored the factors influencing public willingness to participate in a PBT program in BC. We recruited BC residents through a market research company to participate in online, one-to-one, semi-structured interviews. Interested individuals were purposively sampled to ensure maximum representation in terms of age, ethnicity, and residence. Transcribed sessions were analyzed in NVivo v14. A thematic analysis was employed within a descriptive qualitative approach to identify and interpret patterns within the transcripts. Twenty 60-min interviews were conducted on Zoom from June to December 2024. Three key factors influenced potential participation in PBT: perceived utility of genetic testing, ethical and privacy concerns, and health system support. The perceived utility of genetic testing influenced individuals to assess genetic risk to reduce uncertainty and manage their health. Ethical concerns, such as the misuse of genetic data by insurers or employers, complicate decision-making. Health system support included affordable testing, continuity of care, and emotional and educational resources. Novel PBT programs should address cultural, socioeconomic and geographical inequities, while safeguarding the privacy of the public. Key to success will be the availability of emotional, educational, and financial support for individuals using PBT.
Crocioni M, Nardelli C, Lema Fernandez AG
… +9 more, Bardelli V, Pierini V, Matteucci C, Beggiato E, Olivi M, Vigliani V, Pelle A, Lanzarone G, Mecucci C
Constitutional RUNX1 gene variants are associated with Familial Platelet Disorder (FPD) and predispose to a variety of hematological malignancies, included Acute Myeloid Leukemia (AML) and, albeit less frequently, Acute...Constitutional RUNX1 gene variants are associated with Familial Platelet Disorder (FPD) and predispose to a variety of hematological malignancies, included Acute Myeloid Leukemia (AML) and, albeit less frequently, Acute Lymphoblastic Leukemia (ALL). In this study, we report on a proband with primary diagnosis of AML, followed by T-ALL after transplant, and a positive familial history for leukemia over three generations. A new heterozygous germline pathogenic RUNX1 (c.681dup, p.(Leu228ThrfsTer33)) variant was found in the proband and his affected mother.
We aim to compare clinical practices in the gynecological management of women with Lynch syndrome across Europe and assess the need for multidisciplinary gynecological care for this high-risk population. European gynecol...We aim to compare clinical practices in the gynecological management of women with Lynch syndrome across Europe and assess the need for multidisciplinary gynecological care for this high-risk population. European gynecologists involved in the clinical care of women with Lynch syndrome were invited to complete a cross-sectional survey regarding their clinical practices and organization of care. All participating gynecologists were based in hospitals that are members of the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS). A total of 33 gynecologists (57%) from 25 unique hospitals across 12 countries participated in the survey. National guidelines on the gynecological management of women with Lynch syndrome were absent in a significant number of European countries. Local multidisciplinary team meetings were available in 61% of hospitals. Considerable heterogeneity was reported in the organization of care, as well as in surveillance, prevention, and treatment strategies. Standardized European guidelines for the gynecological care of women with Lynch syndrome are warranted to promote uniformity. Gynecologists specialized in hereditary cancer should take the lead in developing and implementing these guidelines. Hospitals managing women with Lynch syndrome should have the resources to organize multidisciplinary team meetings, which are crucial for the effective implementation of these guidelines and the improvement of personalized care.
An increased lifetime risk of ovarian cancer is observed among women with a family history of ovarian cancer, with or without breast cancer, as well as among carriers of pathogenic germline variants in ovarian cancer (OC...An increased lifetime risk of ovarian cancer is observed among women with a family history of ovarian cancer, with or without breast cancer, as well as among carriers of pathogenic germline variants in ovarian cancer (OC) predisposition genes. Over the past two decades, additional OC–associated genes beyond BRCA1/2 have been identified, highlighting the need for updated genetic evaluation in women previously classified as high-risk without a known PV to ensure correct diagnosis and prevent overtreatment. This retrospective, quality assurance cohort study aimed to evaluate whether updated multigene panel sequencing and genetic counseling improve risk stratification. All women enrolled in the OC surveillance program at Copenhagen University Hospital Herlev between 2018 and 2023 and received counseling prior to the implementation of the revised 2017 guidelines in Denmark, were included. Among 674 women (median age 40.9), 174 had a BRCA1 PV, 168 had a BRCA2 PV, 55 had PVs in moderate-risk genes, and 277 were enrolled based on family history of OC ± BC alone. Of these 277, 216 (78%) underwent updated genetic testing and counselling; 165 (76%) had no increased risk of OC and were released from gynecological surveillance. Over a mean follow-up of 48 months, none developed OC, and one developed BC, corresponding to a negative predictive value of 99% for the updated risk assessment. Updated genetic testing and counseling significantly improve risk stratification in women previously classified as increased risk of OC based solely on family history. This supports re-evaluation of at-risk women and families to guide appropriate surveillance, reduce unnecessary follow-up and interventions, and align clinical practice with evolving guidelines.
This study examined the uptake and timing of cascade testing in families with Lynch syndrome followed at a single Genetics Service in Northern Italy, with the aim of identifying family and individual factors that may inf...This study examined the uptake and timing of cascade testing in families with Lynch syndrome followed at a single Genetics Service in Northern Italy, with the aim of identifying family and individual factors that may influence uptake of testing in at-risk relatives. All living blood relatives aged ≥ 18 years and eligible for the first step of cascade testing were included. Forty-eight families were examined. Most probands were women (77.1%) mainly affected by endometrial (55.3%) or colorectal cancer (42.6%); the branch segregating the pathogenic variant was known/suspected in 51.1% of families. Overall, the cascade testing uptake was 19.5%. At the family level, uptake ranged from 0 in 47.9 to 100% in 4.2% of families. Binary logistic regression confirmed age and degree of kinship as significant predictors; younger relatives were more likely to undergo testing (OR = 0.97 per year, p < .001), while testing likelihood declined across kinship degrees (12-month testing: 27.7% first-degree, 10.4% second-degree, 5.7% more distant relatives; Log Rank p < .001) with Odds Ratios of 0.27 for second-degree and 0.07 for third-degree or beyond. Neither sex (p = .487) nor health status (p = .271) were significantly associated with uptake. Kaplan–Meier analysis showed that uptake occurred mostly within the first 12 months after the proband’s result (86.7% of those tested), after which it plateaued. These real-world findings highlight substantial gaps in cascade testing implementation and provide evidence to guide future strategies aimed at increasing uptake and strengthening family communication of genetic risk in the Italian context.
Lynch syndrome is a hereditary cancer predisposition condition associated with an elevated lifetime risk of colorectal, endometrial, ovarian, and several other malignancies. This review provides an updated overview of ev...Lynch syndrome is a hereditary cancer predisposition condition associated with an elevated lifetime risk of colorectal, endometrial, ovarian, and several other malignancies. This review provides an updated overview of evidence-based prevention strategies for gynaecological cancers in patients with Lynch syndrome. Risk-reducing hysterectomy with bilateral salpingo-oophorectomy is the most effective intervention for lowering cancer incidence and mortality, but is associated with surgical morbidity and requires careful consideration of reproductive plans and the adverse consequences of premature menopause. Gynaecological surveillance using transvaginal ultrasound and endometrial biopsy is widely implemented as an alternative; however, available evidence is heterogeneous and indicates no benefit in reducing mortality. Novel approaches—such as biomarker-based detection using DNA methylation analysis of cervicovaginal samples, liquid biopsy techniques, and microbiome profiling—offer promising, non-invasive alternatives but require prospective validation in Lynch-specific populations. Chemoprevention with hormonal agents and aspirin may reduce cancer risk, while vaccine-based prevention strategies are under active investigation. Adoption of a healthy lifestyle is recommended for overall health, although its impact on gynaecological cancer risk in Lynch syndrome remains uncertain. Future research should prioritise prospective trials to establish optimal cancer prevention protocols, validate novel biomarkers and preventive cancer vaccine strategies, and evaluate the long-term effectiveness, acceptability, and cost-effectiveness of combined preventive approaches to improve outcomes in this high hereditary-risk population.