Familial Cancer最新文献

{"title":"Updated cancer risks in lynch syndrome.","authors":"Christine M Drogan, Sonia S Kupfer","doi":"10.1007/s10689-026-00598-5","DOIUrl":"10.1007/s10689-026-00598-5","url":null,"abstract":"<p><p>Lynch syndrome, one of the most common hereditary cancer predisposition syndromes, is caused by pathogenic variants in the mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and the EPCAM gene. Individuals who inherit pathogenic variants in Lynch-associated genes experience increased lifetime risk of colorectal, endometrial, and several other cancer types. Risks of Lynch-associated cancers vary by the affected gene and within each gene, especially for lower penetrance genes. This poses challenges for clinicians to provide patients and families with accurate cancer risk estimates and determine individualized surveillance protocols. Compounding this challenge is that study designs and potential biases could yield different risk estimates. In this review, we present up-to-date Lynch syndrome cancer risk estimates and discuss how study design could impact these risk estimates.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 4","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Moderate-risk variants in hereditary breast and ovarian cancer: seven-year experience from a specialized center.","authors":"Annika Krückel, Matthias W Beckmann, Lena Brückner, Peter A Fasching, Paul Gass, Julia Gocke, Carolin C Hack, Felix Heindl, Manuel Hörner, Emelie Kunze, Carolin Müller-Wirtz, Niklas Amann","doi":"10.1007/s10689-026-00609-5","DOIUrl":"10.1007/s10689-026-00609-5","url":null,"abstract":"<p><p>Moderate-risk gene variants represent an increasingly recognized component of hereditary breast and ovarian cancer (HBOC) predisposition, yet their clinical interpretation and management remain less standardized than those of high-penetrance genes. This study provides a seven-year real-world evaluation of genetic variants in ATM, BARD1, CHEK2, RAD51C, and RAD51D in individuals undergoing germline testing at a specialized HBOC center, with a particular focus on variant distribution and associated clinical management. We retrospectively analyzed germline testing data from 3416 individuals evaluated at the HBOC center Erlangen between 2018 and 2024. Testing indications included predictive as well as diagnostic and therapeutic testing in the context of breast and gynecologic neoplasms. Variant classifications followed ACMG/IARC (American College of Medical Genetics and Genomics/ International Agency for Research on Cancer) criteria. Clinical recommendations, including participation in the intensified breast cancer surveillance (IBCS) program and risk-reducing surgery, were extracted from structured counseling documentation. (Likely) Pathogenic variants in moderate-risk genes were identified across all clinical subgroups. CHEK2 represented the most frequently altered moderate-risk gene, followed by ATM. In contrast, (likely) pathogenic variants in BARD1, RAD51C, and RAD51D were observed solely among individuals undergoing predictive testing or presenting with breast malignancies. A small subset of individuals carried more than one (likely) pathogenic variant in HBOC susceptibility genes. Most women with moderate-risk variants were enrolled in the IBCS program, although in justified cases participation was withheld based on patient-specific risk factors. An isolated moderate-risk variant generally did not warrant a recommendation for risk-reducing breast surgery. Risk-reducing salpingo-oophorectomy (RRSO) was primarily discussed with individuals harboring RAD51C or RAD51D variants. Individualized modifications to the recommendations were applied especially in cases with complex genotypes comprising multiple (likely) pathogenic variants. In conclusion, this study demonstrates considerable heterogeneity in germline variants among individuals evaluated for HBOC susceptibility and highlights the particular challenges associated with interpreting moderate-risk gene alterations. The findings underscore the importance of individualized clinical assessment and support the use of real-world data to inform evidence-based surveillance and prevention strategies in hereditary cancer care.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 4","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149192373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histopathological and immunohistochemical analyses do not indicate timing of prophylactic hysterectomy: a retrospective analysis of endometrial biopsies in Lynch syndrome carriers.","authors":"Lotte van Leeuwen, Ellis L Eikenboom, Floris H Groenendijk, Monique E van Leerdam, Manon C W Spaander, Helena C van Doorn, Anja Wagner","doi":"10.1007/s10689-026-00611-x","DOIUrl":"10.1007/s10689-026-00611-x","url":null,"abstract":"<p><p>Women with Lynch syndrome are at increased risk of endometrial cancer. Gynecological surveillance is advised, but also prophylactic hysterectomy is an option. This study aimed to gain more insight in tumorigenesis in Lynch carriers to be able to personalize prophylactic hysterectomy timing. To this aim endometrial cancer surveillance in Lynch syndrome carriers was assessed using data from the Dutch Lynch syndrome database linked to the Dutch National Pathology Databank (PALGA). Eligible participants were Lynch syndrome carriers under surveillance, who underwent hysterectomy and had ≥ 1 endometrial biopsy within five years prior to surgery. Pathology reports, describing the histopathological features of the samples, were collected and, if available, samples were revised by a specialized pathologist. Additionally loss of expression of ARID1A, PTEN, PAX2, and mismatch repair (MMR) proteins was studied. Pathology reports from 32 Lynch syndrome carriers were analyzed: 16 had normal endometrium at hysterectomy, five had hyperplasia without atypia, six had endometrial intra-epithelial neoplasia (EIN), and five had endometrial cancer. Prior to hysterectomy, hyperplasia with or without atypia or endometrial cancer was reported in 3% of biopsies in the histopathological normal group, 26% in endometrial hyperplasia without atypia group, 26% in the EIN group, and 36% in the endometrial cancer group. Upon revision, combined neoplastic development of tissue and loss of protein expression were observed in 12% of the normal group, 36% of endometrial hyperplasia without atypia, 36% of EIN, and 50% of endometrial cancer group. So, increasing tissue disorganization and loss of protein expression appeared to correlate with progression to (pre)malignancy. However, no specific marker or consistent pattern emerged that could guide clinical decisions on prophylactic hysterectomy for individual patients. These findings highlight the complexity of endometrial cancer development in Lynch syndrome and underscore the need for further research to improve surveillance strategies and optimize timing of prophylactic surgery.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 4","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149192381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of mainstream genetic testing for breast cancer patients: five-year data from the Parkville Familial Cancer Centre.","authors":"Catherine Beard, Anita Skandarajah, Geoffrey J Lindeman, Aisha Ward, Katrina Monohan, Christy Atkinson, Gregory Bruce Mann, Paul A James","doi":"10.1007/s10689-026-00610-y","DOIUrl":"10.1007/s10689-026-00610-y","url":null,"abstract":"<p><p>Mainstream genetic testing is a model of care where non-genetics health professionals arrange genetic testing for their patients directly. The Parkville Familial Cancer Centre (PFCC) provides a breast cancer mainstream program; initial two-year outcomes previously reported. With an evolving health landscape, the program has been refined with ongoing evaluation, and we now report on outcomes from the first five years of program operation. Program operation and refinement is outlined, including patient eligibility criteria and gene panel use during the study period. Demographics and outcomes for patients who underwent mainstream genetic testing between September 2017 and March 2022 have been analysed, as well as characteristics of the mainstream clinicians and uptake of genetic testing for at-risk relatives. During the study period, 657 patients underwent mainstream genetic testing at ten hospitals in Victoria, Australia. Pathogenic variant (PV) detection rate was 11.5%, and variant of unknown significance rate was 6.5%. A subset of PV carriers were further analysed, and 75.8% had a change in their treatment plan as a result of the PV. The PFCC saved 1,210 appointments due to the mainstream program. Demand for mainstream genetic testing is increasing, with eligibility criteria expanding. The PFCC mainstream program PV detection rate, PV proband relative cascade testing engagement and PFCC resources saved remain high, in line with other studies. Whilst mainstream models of care can evolve and be tailored, it is paramount that FCC-supported mainstream programs can be sustained as demand increases.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 4","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pan-cancer prevalence of microsatellite instability and Lynch syndrome in India.","authors":"Harsh Sheth, Jyoti Sadhwani, Bhawna Sirohi, Senthilkumar Ramasamy, Yashwant Kashyap, Pankaj Shah, Mithun Shah, Suresh Advani, Lidiya Thomas, Vipul D Yagnik, Avinash Tank, Chirag Shah, Raja Pramanik, Bhavesh Thakkar, Darshan Bhansali, Manish Gandhi, Tarang Patel, Natoo Patel, Ashok Patel, Ruchir Patel, Ravindra Gaadhe, Chintan Shah, Bhavin Shah, Gaurang Modi, Ankita Jakhar, Ava Desai, Chirantan Bose, Amit Sehrawat, Dipak Limbachiya, Chandni Patel, Prachi Soni, Sunil Trivedi, Kshipra Chauhan, Frenny Sheth, Jayesh Sheth, D Timothy Bishop, John Burn, Abhinav Jain","doi":"10.1007/s10689-026-00607-7","DOIUrl":"10.1007/s10689-026-00607-7","url":null,"abstract":"<p><p>Lynch syndrome (LS) is underdiagnosed in India, particularly outside colorectal cancer (CRC), because pan-cancer data on microsatellite instability (MSI), mismatch repair deficiency (MMRd), and germline predisposition remain limited. We consecutively recruited 519 patients with CRC and extracolonic cancers from 17 centres in India between 2019 and 2025, and applied a tumour-first approach using MSI testing by PCR-fragment length analysis (PCR-FLA) across all tumours, MMR immunohistochemistry (MMR-IHC) in extracolonic tumours, BRAF V600E testing in MSI-high (MSI-H) CRCs, and germline whole exome sequencing in MSI-H/BRAF wildtype CRCs and MSI-H/MMRd extracolonic tumours. MSI-H/MMRd status was identified in 24.9% (129/519) of tumours, and 51.2% (66/129) patients harboured pathogenic or likely pathogenic germline variants consistent with LS. CRC showed the highest LS yield, followed by endometrial and ovarian cancers, whereas several extracolonic tumour groups showed lower yields, in part reflecting cohort composition and tumour-specific MSI/MMRd prevalence. MLH1 accounted for most LS diagnoses (69.7%, 46/66) followed by MSH2 (18.2%, 12/66). Two recurrent MLH1 variants, c.306G>T and c.156delA, together accounted for 36.4% of all LS cases. Haplotype analysis supported c.156delA as a novel founder variant originating in Gujarat. Concordance between PCR-FLA and MMR-IHC in extracolonic tumours was 93.8%, supporting combined tumour-based screening in pan-cancer workflows. These findings establish the clinical utility of pan-cancer tumour-first LS detection in India and support broader implementation of reflex MSI/MMRd testing, germline confirmation, and cascade testing to improve surveillance, chemoprevention, and risk-reducing management in India.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 4","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A frequently occurring MSH2 variant in Iraqi and Chaldean patients with Lynch syndrome: evidence for a putative founder variant.","authors":"Mikaela Bradley, Tara Rangarajan, Dana Zakalik","doi":"10.1007/s10689-026-00602-y","DOIUrl":"10.1007/s10689-026-00602-y","url":null,"abstract":"<p><strong>Background: </strong>Lynch syndrome (LS) is the most common cause of hereditary colorectal and endometrial cancer. LS is caused by germline pathogenic variants (PV) in the mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and EPCAM. Little is known about LS in Iraqi/Chaldean and broader Middle Eastern and North African populations. We describe our institution's experience with a unique MSH2 PV in a cohort of Iraqi/Chaldean patients. Records of patients with LS and Iraqi/Chaldean ancestry seen in a high-volume cancer genetics center between January 2008 and March 2024 were analyzed. A total of 483 LS patients were identified, of whom 60 (12.4%) reported Iraqi/Chaldean ancestry. Of those, 53 individuals (88.3%) from 22 unique families harbored the same PV in MSH2, c.932delA (p.N311Tfs*20) and were analyzed in this study. This variant was detected only in our Iraqi/Chaldean population. Of individuals with this variant, 28 (52.8%) had at least one LS-related cancer diagnosis (17 colorectal, 12 endometrial, 7 renal/urothelial, 6 ovarian, one sebaceous carcinoma), of whom 16 (57.1%) had multiple malignancies. The average age of colorectal cancer onset was 49.6 years. Additionally, 14 families (63.6%) underwent cascade testing, identifying 31 of the MSH2 carriers in this cohort and 25 true negatives. This is the first report of a recurrent MSH2 c.932delA PV in Iraqi/Chaldean patients with LS. These findings suggest a putative LS founder variant in the Iraqi/Chaldean population, and further studies are needed to characterize LS in this population.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 4","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A systematic review of cancer risks associated with MITF variants.","authors":"Luigi Monti, Lea Godino, Clio Dessinioti, Alex Stratigos, Olga Papadodima, Alexander Pintzas, Delia Nicoară, Yvette Albert, Stefania Boccia, Sara Barbato, Giulia Erini, Sara Miccoli, Giovanni Innella, Daniela Turchetti","doi":"10.1007/s10689-026-00603-x","DOIUrl":"10.1007/s10689-026-00603-x","url":null,"abstract":"<p><p>The MITF E318K variant has been associated with melanoma risk, while risk associated with other variants or of other cancers remains uncertain. We performed a systematic review with meta-analysis of 11 retrospective case-control studies to evaluate cancer risks associated with germline MITF variants. Across 8,606 melanoma patients and 17,953 controls, the E318K variant was detected in 2.1% and 0.8% of individuals, respectively, corresponding to a significantly increased melanoma risk (OR 2.55, 95% CI 1.90-3.43). The association was stronger in patients with multiple primary melanomas, with carrier frequencies up to 2.6% compared to 1.0% in single melanoma cases and ORs reaching 4.45 in individual studies. Phenotypic analyses showed enrichment of high nevus burden (> 200 nevi), with ORs up to 12.4 in multiple melanoma cohorts. No consistent association with age at onset or pigmentary traits was observed. Evidence for non-melanoma cancers was limited and heterogeneous: a single study reported increased renal cancer risk (OR 7.64), whereas larger cohorts failed to replicate this finding; an association with pheochromocytoma/paraganglioma was observed (OR 3.19) but lacks confirmation. No other MITF variants demonstrated significant cancer risk. These findings support MITF E318K as a moderate-penetrance melanoma susceptibility allele, particularly associated with multiple primary melanomas.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 4","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The clinical and phenotypic spectrum of PTEN hamartoma tumor syndrome: a retrospective cohort study.","authors":"Einat Ritter, Aasem Abu Shtaya, Revital Kariv, Sari Lieberman, Elizabeth Half, Maria Postnikov, Guy Rosner, Hana Strul, Nathan Gluck, Lior Katz, Ephrat Levy-Lahad, Dalit May, Ido Laish, Yael Goldberg, Elez Vainer, Zohar Levi, Maya Aharoni Golan","doi":"10.1007/s10689-026-00604-w","DOIUrl":"10.1007/s10689-026-00604-w","url":null,"abstract":"<p><p>PTEN Hamartoma Tumor Syndrome (PHTS) is a rare condition characterized by a complex phenotype including gastrointestinal hamartomas and increased lifetime malignancy risk. To characterize the clinical phenotype, genetic landscape, and spectrum of malignancies within a large cohort of adult PHTS carriers. A retrospective cohort study of adult patients (≥ 18 years) followed at specialized high-risk clinics who met PHTS diagnostic criteria based on either: (1) identification of a germline PTEN pathogenic/likely pathogenic variant, or (2) fulfillment of clinical criteria according to National Comprehensive Cancer Network (NCCN) guidelines. A total of 62 individuals were included (62.9% male; median age at inclusion 39.5, IQR, 28-52). All fulfilled diagnostic criteria for PHTS. PTEN pathogenic or likely pathogenic variant were identified in 50 individuals (80.6%). Colonic polyps were present in 40 patients. Malignancies were reported in 61% (n = 38), most frequently breast (n=13) and thyroid (n=7). Three individuals (4.8%) had rare soft tissue tumors: one with a desmoid tumor at age 18, one with concurrent axillary osteosarcoma and bilateral chest liposarcoma, and one with a skull-base sarcoma. Macrocephaly was observed in 33.8% (n = 21), and developmental delay, including autism spectrum disorder, in 8 patients (12.9%). One case of PTEN mosaicism was identified through tumor sequencing after negative blood genetic testing. Five individuals (8%) were treated with Sirolimus. This large cohort highlights the broad clinical spectrum and substantial cancer burden in PHTS, including rare soft tissue tumors. Constitutional mosaicism should be considered when clinical suspicion persists despite negative germline testing.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 4","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13585824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk of desmoid tumor based on APC pathogenic variant location and surgical history in familial adenomatous polyposis: a U.S. community cohort study.","authors":"Prakash I Thomas, Holly E Carwana, Sheng-Fang Jiang, Janet Song, Dan Li","doi":"10.1007/s10689-026-00606-8","DOIUrl":"10.1007/s10689-026-00606-8","url":null,"abstract":"<p><p>Desmoid tumors (DT) are a leading cause of morbidity and mortality in patients with familial adenomatous polyposis (FAP), yet available data on DT risk remain limited and have been largely derived from large registries or tertiary referral centers. Risk in community-based U.S. populations is poorly defined, which hinders presurgical counseling. We conducted a retrospective cohort study of patients with pathogenic or likely pathogenic variants (PV/LPV) in APC identified through the Kaiser Permanente Northern California Electronic Database, a community-based system serving 4.6 million members. We evaluated the association of APC PV/LPV location and prior abdominal surgery with DT risk using multivariable logistic regression, adjusting for sex, race and ethnicity, and family history. Among 328 patients with FAP, 36 (11.0%) developed DT. DT risk was highest when the APC variant was centrally located (codon 600-1600). Family history was independently associated with increased risk (adjusted odds ratio [aOR] 4.34; 95% confidence interval [CI] 1.12-16.86). All colorectal surgeries were associated with a significantly elevated DT risk: ileostomy (aOR 12.07; 2.10-69.47), subtotal colectomy with ileorectal anastomosis (aOR 9.03; 1.63-49.96), and total proctocolectomy with ileal pouch-anal anastomosis (aOR 10.98; 2.12-56.81). In contrast, non-colorectal surgery was not associated with increased risk (aOR 0.73). In this large community-based U.S. cohort, central APC variant location, family history, and colorectal surgery were associated with increased DT risk. Our findings extend the current literature on DT risk in FAP and help refine presurgical risk-stratification and counseling for these patients.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 4","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An update on APC I1307K homozygosity: observations from a large multigene panel testing cohort.","authors":"Leah Zaretsky, Marcy E Richardson, Taylor Coleman, Carrie Horton, Magan Trottier, Maggie Feng, Linda M Polfus, Aimee L Lucas","doi":"10.1007/s10689-026-00600-0","DOIUrl":"10.1007/s10689-026-00600-0","url":null,"abstract":"<p><p>Numerous studies have demonstrated that Ashkenazi Jewish individuals heterozygous for APC c.3902T > A; p.Ile1307Lys have 1.7-fold increased odds of colorectal adenocarcinoma (CRC). The cancer risk for homozygotes is unknown, and published data is based on small sample sizes. Here, we aim to quantitatively evaluate the odds of CRC in homozygotes from a clinical diagnostic setting. Analyses comparing the demographic and clinical histories among heterozygotes (n = 340) or homozygotes (n = 74) were compared to individuals with MSH6-associated Lynch syndrome (n = 372) and individuals from a pan-cancer panel of up to 90 genes who were negative for APC I1307K, MSH6 (likely) pathogenic (LP/P) variants, and other reportable LP/P variants after exclusions, henceforth referred to as wildtype (WT, n = 19,809). Comparisons included Fisher's exact or two-sample t-test and multivariate logistic regression. Homozygotes demonstrated a trend toward increased odds of CRC compared to WT (OR: 2.48; p = 0.074), and there was no difference between heterozygotes and WT (OR: 0.94; p = 0.83). MSH6-positive individuals had increased odds of CRC relative to homozygotes (OR: 3.54; p < 0.0001) but this was not significant in the logistic regression (OR: 1.19; p = 0.78). While homozygotes but not heterozygotes demonstrated an increase in CRC OR compared to WT, there was no statistically distinct odds of CRC between heterozygotes and homozygotes in this cohort. While the ORs herein support that the observed increase in CRC for homozygotes was more modest than that observed for MSH6-related Lynch syndrome in this cohort, current sample size and selection bias limit precise risk estimation and do not allow for distinction between modestly increased risk and no risk of CRC.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 4","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13585870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}