Fam. Cancer [JOURNAL]
Sun
200 papers
Peutz-Jeghers Syndrome and lung cancer: does the risk meet the threshold for lung cancer screening?
Shareef F, Konjeti M, Gupta S … +1 more , Weiss JM
Fam Cancer · 2026 Jul · PMID 42397638 · Full text
Peutz-Jeghers Syndrome (PJS) is caused by germline pathogenic variants in the STK11 gene and is associated with elevated lifetime risks for several cancers, including lung cancer. Currently, no formal recommendations exi...
Peutz-Jeghers Syndrome (PJS) is caused by germline pathogenic variants in the STK11 gene and is associated with elevated lifetime risks for several cancers, including lung cancer. Currently, no formal recommendations exist for lung cancer screening in PJS. This structured narrative review compares lung cancer risk in PJS with lung cancer risk in individuals currently eligible for screening based on age and smoking history. PubMed and Web of Science were searched from 1/1/1980 to 9/11/2023 using the terms "Peutz-Jeghers Syndrome" AND "Cancer." Studies reporting lung cancer risk in PJS were included. Reported lung cancer risks were compared to 5-year, 10-year, and lifetime lung cancer risks in the general population based on age and pack-years of smoking. Seventeen studies were included. Across the studies, the incidence of lung cancer ranged from 0.8 to 13.3%. Studies that included lung cancer risk relative to the general population reported a relative risk range of 2.9-22.9. Cumulative risk was reported in 5 studies and surpassed 5% by age 60 (range 7 to 17%). Guidelines for low-dose CT (LDCT) lung cancer screening for individuals aged 50-80 with a smoking history of at least 20 pack-years are associated with a similar or higher threshold for lung cancer risk. The lifetime lung cancer risk for individuals with PJS is similar to current guideline-based risk thresholds for screening based on age and smoking status. Given their elevated lifetime risk, individuals with PJS may be candidates for LDCT for lung cancer screening and should be formally studied to elucidate the risks, benefits, and optimal implementation in this patient population.
Transitioning from the Prospective Lynch Syndrome Database (PLSD) to the International Lynch Syndrome Database (ILSD).
Dominguez-Valentin M
Fam Cancer · 2026 Jul · PMID 42384222 · Full text
Abstract loading — click title to view on PubMed.
Expanding access to hereditary cancer genetic testing: a quality improvement initiative of mainstreaming in a diverse urban gynecology clinic.
Raghunandan A, Davis-Rivera L, Ahsan MD … +7 more , Chandler IR, Lopez S, Ozarowski AL, Primiano M, Pardo C, Sharaf RN, Frey MK
Fam Cancer · 2026 Jun · PMID 42360549 · Publisher ↗
Most individuals with hereditary cancer syndromes remain undiagnosed and cannot benefit from cancer mitigation strategies. Mainstreaming, or the process of integrating genetic testing into routine care, can expand access...
Most individuals with hereditary cancer syndromes remain undiagnosed and cannot benefit from cancer mitigation strategies. Mainstreaming, or the process of integrating genetic testing into routine care, can expand access, but implementation in primary care settings has proven challenging. In a quality improvement initiative, stakeholder feedback guided the development of care algorithms, patient/provider resources, and streamlined lab workflows for mainstreaming in an urban, diverse, Medicaid-predominant benign gynecology clinic. The mainstreaming initiative was launched in December 2024; over the subsequent four months, 274 consecutive patients presented for gynecologic care and 32 (11.7%) completed same-day genetic testing. This model demonstrates a feasible and scalable approach to integrating genetic testing into benign gynecology clinics serving diverse patient populations.
When screentime fails: initiative to improve completion of hereditary cancer genetic testing after telemedicine counseling.
Murray IR, Ahsan MD, Mitchell L … +7 more , Gioia S, Primiano M, Ozarowski AL, Karimaghaie T, Lopez S, Sharaf RN, Frey MK
Fam Cancer · 2026 Jun · PMID 42348011 · Publisher ↗
Telemedicine has broadened access to genetic counseling while maintaining high levels of patient satisfaction. However, emerging evidence suggests lower completion rates of genetic testing following virtual visits compar...
Telemedicine has broadened access to genetic counseling while maintaining high levels of patient satisfaction. However, emerging evidence suggests lower completion rates of genetic testing following virtual visits compared with in-person encounters. This study evaluated genetic testing completion rates among patients who underwent cancer risk assessment via telemedicine and assessed the effect of a structured follow-up telephone reminder on genetic testing completion. We conducted a retrospective review of a quality improvement initiative - Genetic Engagement via Navigation and Encouragement (GENE CALL) - designed to address incomplete genetic testing following telemedicine counseling. The study included all patients who underwent virtual cancer risk assessment between September 2023 and July 2024 at a single urban academic cancer genetics program. Patients who expressed interest in genetic testing but had not scheduled specimen collection were contacted by telephone as a reminder. During the call, patients were asked about ongoing interest in testing and barriers to scheduling; they were also offered assistance completing specimen collection. Among 647 patients evaluated via telemedicine, 469 (72.5%) expressed interest in genetic testing. Of these, 290 (61.8%) had scheduled or completed testing, while 179 (38.2%) had not. Among those who had not scheduled testing, 120 (67.0%) were successfully reached by telephone, and 98 (81.7%) confirmed ongoing interest in completing testing. At 3-month follow-up, 48 (40.0%) of the 120 contacted patients had completed testing, compared with 13 (22.0%) of 59 patients who were not reached (p = 0.017). Telephone follow-up is an effective strategy to improve genetic testing completion after virtual counseling.
The impact of international care networks on the clinical management of constitutional mismatch repair deficiency (CMMRD): a review of recent developments.
Vasen HFA, Wimmer K, van Kouwen M … +6 more , Guerrini-Rousseau L, Gattini D, Stengs L, Tabori U, Colas C, Das A
Fam Cancer · 2026 Jun · PMID 42348008 · Full text
Constitutional mismatch repair deficiency (CMMRD) is a rare and likely the most penetrant cancer predisposition syndrome caused by biallelic germline variants in a mismatch repair gene. Patients typically develop a spect...
Constitutional mismatch repair deficiency (CMMRD) is a rare and likely the most penetrant cancer predisposition syndrome caused by biallelic germline variants in a mismatch repair gene. Patients typically develop a spectrum of malignancies, including brain tumors, gastrointestinal cancers, and hematological neoplasms within the first two decades of life. Since its initial description in 1999, two international consortia, the International Replication Repair Deficiency Consortium (IRRDC) and Care for CMMRD (C4CMMRD), have been established to better understand the syndrome, leading to the creation of diagnostic guidelines and surveillance protocols. This review summarizes recent data on the CMMRD tumor spectrum and discusses the consortia's updated diagnostic criteria and management guidelines, including novel blood-based assays for detecting constitutional microsatellite instability. Furthermore, we present the initial results and subsequent adjustments to international surveillance protocols. Finally, we discuss the demonstrated efficacy of immune checkpoint inhibitor (ICI) treatment, a key therapeutic advancement for CMMRD patients.
Monoallelic NTHL1 p.(Gln90*) and cancer risk: evidence from a large Turkish cohort.
Ertürkmen Aru E, Büke A, Saat H … +3 more , Bahsi T, Sezer A, Erdem HB
Fam Cancer · 2026 Jun · PMID 42319512 · Publisher ↗
Biallelic loss-of-function variants in NTHL1 are associated with an autosomal recessive cancer predisposition syndrome, whereas the cancer risk associated with monoallelic NTHL1 variants remains uncertain. The recurrent...
Biallelic loss-of-function variants in NTHL1 are associated with an autosomal recessive cancer predisposition syndrome, whereas the cancer risk associated with monoallelic NTHL1 variants remains uncertain. The recurrent truncating variant p.(Gln90*), the first described and most frequently observed pathogenic NTHL1 variant, is commonly detected in the monoallelic state in population databases and diagnostic multigene panels, creating a clinical challenge in cancer risk interpretation. We aimed to assess the cancer risk associated with monoallelic NTHL1 p.(Gln90*) in a large Turkish cohort. We retrospectively analyzed 8,100 individuals who underwent hereditary cancer syndrome multigene panel testing and 10,000 individuals analyzed by exome sequencing for non-oncologic indications at a tertiary referral center. Carriers of the NTHL1 c.268C>T, p.(Gln90*) (rs150766139) variant were evaluated. Carrier frequencies were compared between cohorts and with population-based datasets using a carrier-rate-based analytical approach. The NTHL1 p.(Gln90*) variant was identified in 0.36% of individuals in the hereditary cancer testing cohort and in 0.27% of individuals in the exome sequencing cohort, with no significant difference in carrier frequency. Monoallelic NTHL1 p.(Gln90*) carriers were not enriched in the hereditary cancer testing cohort compared with population-based controls. All biallelic carriers presented with colorectal and/or breast cancer, consistent with established phenotypes. Notably, 19.2% of monoallelic carriers harbored additional pathogenic or likely pathogenic variants in established cancer susceptibility genes. In conclusion, the absence of enrichment among monoallelic carriers compared with hereditary cancer testing and population-based control cohorts, together with the frequent detection of co-occurring pathogenic variants, supports a zygosity-dependent interpretation of the NTHL1 p.(Gln90*) variant. Monoallelic NTHL1 p.(Gln90*) and Cancer Risk: Evidence From a Large Turkish Cohort.
Von Hippel-Lindau disease: pathophysiological and clinical advances.
van Alfen SJ, van der Tuin K, van de Kooij B … +2 more , Links TP, Zandee WT
Fam Cancer · 2026 Jun · PMID 42313274 · Full text
Von Hippel-Lindau (VHL) disease is a hereditary tumor predisposition syndrome caused by pathogenic germline variants in the VHL gene. Patients with VHL disease have an increased risk of developing characteristic VHL dise...
Von Hippel-Lindau (VHL) disease is a hereditary tumor predisposition syndrome caused by pathogenic germline variants in the VHL gene. Patients with VHL disease have an increased risk of developing characteristic VHL disease-associated lesions such as clear cell renal cell carcinoma, retinal angioma, central nervous system hemangioblastoma, pancreatic neuroendocrine tumors and pheochromocytomas. Loss of the VHL gene results in increased levels of the α-subunits of the heterodimeric hypoxia inducible factor (HIF). This drives transcription of HIF target genes which are involved in, amongst others: angiogenesis, erythropoiesis and iron metabolism. HIFs have been recognized as major drivers of VHL disease pathology and based on this notion, the HIF-2α inhibitor belzutifan was developed, which has marked a major breakthrough in the treatment of this disease. Belzutifan has now been approved for the treatment of a variety of VHL disease-associated lesions by the Food and Drug Administration and the European Medicines Agency. Interestingly, recent studies suggest that pVHL has functions beyond controlling HIF levels, and loss of these HIF-independent functions may further contribute to tumorigenesis in VHL disease. This review summarizes the most recent advances in pathophysiology, genotype-phenotype correlation, treatment guidelines, and potential future treatment options related to VHL disease.
Determinants of the quality of life of patients with NF2-related schwannomatosis and validation of the Dutch NFTI-QOL questionnaire.
Tops AL, Goemans D, Aten E … +5 more , Schopman JE, Koot RW, Gelderblom H, Jansen JC, Hensen EF
Fam Cancer · 2026 Jun · PMID 42313268 · Full text
NF2-Related Schwannomatosis (NF2-SWN) is a rare tumor predisposition syndrome characterized by heterogeneous clinical manifestations that substantially impact quality of life (QOL). In this diverse patient population, a...
NF2-Related Schwannomatosis (NF2-SWN) is a rare tumor predisposition syndrome characterized by heterogeneous clinical manifestations that substantially impact quality of life (QOL). In this diverse patient population, a disease-specific QOL instrument is essential for both research and clinical decision-making. Insight into factors associated with QOL may further facilitate the tailoring of management strategies to individual patient needs. This study aimed to validate the Dutch version of the NF2 Impact on Quality of Life questionnaire (NFTI-QOL) and to identify factors associated with QOL in Dutch patients with NF2. Following forward‑ and backward‑translation, the NFTI-QOL was administered to NF2-SWN patients alongside the SF‑36, EQ‑5D and PANQOL. The NFTI-QOL was repeated after one week. Demographic and clinical data were extracted from medical records. To provide clinical context, questionnaires were also administered to patients with sporadic vestibular schwannoma (sVS). 64 NF2-SWN and 51 sVS patients completed the questionnaires. The NFTI-QOL demonstrated good validity and reliability. In multivariate linear regression, dizziness (β = 2.533, p = 0.027) and facial weakness (β = 4.064, p = 0.008) were significantly associated with QOL, whereas hearing complaints were not. Surprisingly, overall QOL did not differ between NF2-SWN and sVS patients, whereas patients with sVS even reported poorer hearing-related QOL. The Dutch NFTI-QOL is a reliable instrument for assessing QOL in NF2-SWN patients. Dizziness and facial weakness were associated with lower QOL, while hearing problems were not.
Homozygous TP53 alterations: a case of a biallelic splice variant and a brief review of the literature.
Yildirim SF, Ceylan AC
Fam Cancer · 2026 Jun · PMID 42283896 · Publisher ↗
Biallelic germline variants in TP53 are exceedingly rare, and their clinical consequences remain poorly defined. Here, we report a female infant born to consanguineous parents who presented with early-onset, aggressive c...
Biallelic germline variants in TP53 are exceedingly rare, and their clinical consequences remain poorly defined. Here, we report a female infant born to consanguineous parents who presented with early-onset, aggressive choroid plexus carcinoma causing death at age 4. Molecular analysis identified a homozygous synonymous variant in the last nucleotide of exon 4 in TP53 (NM_000546.6:c.375G > A, p.Thr125 =). This variant has been previously shown to cause aberrant splicing and partial loss of p53 function, and has been associated with variable penetrance in heterozygous carriers. Both parents, who were first cousins, were heterozygous carriers, and no malignancy history was present at the time of diagnosis. Following identification of carrier status, the couple underwent preimplantation genetic testing and subsequently had a child who did not inherit the familial TP53 variant. This report represents one of the very few documented cases of biallelic TP53 variants and underscores the phenotypic heterogeneity associated with TP53 homozygosity. The case highlights the importance of genetic evaluation in pediatric patients with rare aggressive tumors, particularly in consanguineous families, and demonstrates the critical role of genetic counseling and surveillance in affected relatives.
RPS20 as a colorectal cancer predisposition gene: an integrated review of the literature and evaluation in 9738 cases and 161,403 controls.
Amanullah A, Fernández-Tajes J, Gul G … +5 more , Thorn S, Soriano I, Ward JC, Sherwood K, Tomlinson I
Fam Cancer · 2026 Jun · PMID 42274899 · Publisher ↗
Germline variants in Ribosomal Protein S20 (RPS20) have been reported to predispose to colorectal cancer (CRC) based on occurrence in a total of 3455 CRC cases and co-segregation with disease in 3 families. RPS20 encodes...
Germline variants in Ribosomal Protein S20 (RPS20) have been reported to predispose to colorectal cancer (CRC) based on occurrence in a total of 3455 CRC cases and co-segregation with disease in 3 families. RPS20 encodes a component of the ribosomal 40 S subunit, but the mechanism by which the variants might influence CRC risk remains unclear. The current study assessed the association of RPS20 variants with CRC predisposition in whole-genome sequencing (WGS) data from 9738 CRC cases and 161,403 cancer-free controls from the COloRectal tumour Gene Identification consortium (CORGI) study, 100,000 Genomes (100kGP) and UK Biobank (UKB). One hundred and sixty-eight CORGI cases and 23 100kGP cases were recruited based on a family history of CRC. After excluding common polymorphisms, we identified one putative loss-of-function RPS20 variant in cases (p.Ile89fs), and none in controls. This individual was not from a multiplex family, and hence co-segregation analysis of the variant and disease was not possible. One in-frame deletion and one missense variant predicted to be probably pathogenic were found in controls. We also reviewed the evidence on RPS20 and CRC risk from the literature. We concluded that the combined data do not show conclusively that RPS20 is a proven CRC predisposition gene. Its inclusion in diagnostic gene panels for CRC cannot be justified until and unless stronger supporting evidence becomes available in the future.
Protecting the health of donor-conceived offspring.
Flugelman AA, Adashi EY, Levi Z
Fam Cancer · 2026 Jun · PMID 42274847 · Publisher ↗
Genetic screening of gamete donors bears critical importance for protecting donor-conceived offspring. This case report describes a woman in her forties who discovered through genealogical testing that she carries a Lync...
Genetic screening of gamete donors bears critical importance for protecting donor-conceived offspring. This case report describes a woman in her forties who discovered through genealogical testing that she carries a Lynch syndrome-related pathogenic MSH2 variant inherited from an anonymous sperm donor. Her genetic father died of colorectal cancer at a young age, and among her identified genetic half-siblings, one had already developed advanced colorectal cancer. Had the donor been screened for actionable pathogenic variants-such as the Lynch syndrome-associated mutation identified in this case, for which surveillance and preventive measures are available-this information could have enabled early surveillance, prevention, and informed reproductive decision-making for both the donor and offspring. We review current screening approaches, which rely on family history assessment that while requiring a three-generation pedigree per regulatory guidelines, may be incomplete due to the donor's young age, limited family knowledge, or low disease penetrance, and on targeted genetic panels that may miss actionable pathogenic variants. Recent advances in population genomic screening, including expanded carrier screening and testing for adult-onset conditions, now make screening for actionable pathogenic variants in gamete donors increasingly feasible. We address ethical considerations including donor autonomy, the right to know genetic information, and information disclosure policies. We examine international legal frameworks governing gamete donation and genetic screening. Our recommendations include comprehensive genetic screening of all donors for actionable pathogenic variants, centralized registries linking donors to offspring, standardized protocols for updating families with new genetic information, and clear policies addressing donor anonymity in the genomic era. Implementation of these recommendations would significantly reduce preventable morbidity and mortality in donor-conceived individuals while respecting the rights of all parties involved.
Characterization of the molecular and clinical features of Multilocus Inherited Neoplasia Allelic Syndrome (MINAS) cases in the Turkish population.
Akcan MB, Duru A, Erdoğan KM … +12 more , Özer Kaya Ö, Keşan S, Kırbıyık Ö, Türk TS, Altunbaş Yalabık F, Kutbay YB, Anlaş Ö, Saka Güvenç M, Koç A, Ünal OÜ, Özyılmaz B, Özdemir TR
Fam Cancer · 2026 Jun · PMID 42258060 · Publisher ↗
Multilocus Inherited Neoplasia Allelic Syndrome (MINAS) is a rare genetic syndrome characterized by the presence of multiple pathogenic/likely pathogenic(P/LP) variants in different cancer predisposition genes within the...
Multilocus Inherited Neoplasia Allelic Syndrome (MINAS) is a rare genetic syndrome characterized by the presence of multiple pathogenic/likely pathogenic(P/LP) variants in different cancer predisposition genes within the same individual. Patients with MINAS may face early age at onset and multiple primary malignancies. In our study, we aimed to characterize the prevalence and clinical landscape of MINAS in a major Turkish hereditary cancer cohort. We retrospectively analyzed NGS oncorisk panel results of 5000 individuals who presented to the Medical Genetics Unit of İzmir City Hospital between 2024 and 2025 with a preliminary diagnosis of hereditary cancer syndrome due to a personal and/or family history of malignancy. Our diagnostic workflow uniquely integrated Single Nucleotide Variant (SNV) detection with Copy Number Variation (CNV) calling. MINAS prevalence was 0.86% (43/5000). Dual-gene alterations were detected in 42 patients, while one featured a triple-gene alteration (BRIP1-CHEK2-MUTYH). The most frequent combination was BRCA2-CHEK2 (n = 6). Notably, CNVs were identified in 7% of cases, highlighting the necessity of structural variant analysis. Malignancy was present in 70% (30/43) of carriers, with a median age at first diagnosis of 47 years (range: 31-77). Early-onset cancer (< 40 years) was observed in 32% of cases. Our findings represents the largest Turkish MINAS cohort to date. While phenotypes often align with the most penetrant allele, spesific instances may hint at the potential for synergistic effects in certain individuals. Management should transition toward personalized, multi-variant surveillance strategies incorporating both SNV and CNV data.
Colonoscopy findings and polyp pathology in CHEK2 carriers: a single center experience.
Rosario J, Zhou S, Bartell N … +1 more , Marino D
Fam Cancer · 2026 Jun · PMID 42228287 · Publisher ↗
Checkpoint kinase 2 is a moderate-penetrance cancer susceptibility gene associated with increased colorectal cancer risk. Recent guideline updates recommend average-risk colorectal cancer screening for carriers; however,...
Checkpoint kinase 2 is a moderate-penetrance cancer susceptibility gene associated with increased colorectal cancer risk. Recent guideline updates recommend average-risk colorectal cancer screening for carriers; however, real-world colonoscopy data remain limited. We performed a retrospective review of individuals with confirmed pathogenic or likely pathogenic checkpoint kinase 2 variants identified through an institutional hereditary cancer registry from 2011 to 2024. Colonoscopy and pathology reports were analyzed for demographics, cancer history, bowel preparation quality, and polyp characteristics including number, size, histology, and location. Among 144 patients undergoing 154 colonoscopies, median age at examination was 54 years. Polyps were identified in 51% of patients. Tubular adenomas were most common (28.6%), followed by hyperplastic polyps (18.3%) and sessile serrated lesions (10.4%). Advanced neoplasia, defined using conventional advanced adenoma-based criteria (size > 1 cm, villous features, high-grade dysplasia, or classified as intramucosal or invasive carcinoma) as well as including sessile serrated lesions ≥1 cm, were identified in 4.6%. Polyps measuring at least 1 centimeter were observed in 7.1%, and colorectal cancer was diagnosed in 1.3%. Proximal-only polyps were identified in 22.1% of examinations. Detection of tubular adenomas and proximal lesions increased with successive colonoscopies. This single-center experience demonstrates a moderate polyp burden with low rates of advanced neoplasia and colorectal cancer, supporting current recommendations for average-risk screening while highlighting the relevance of careful proximal examination.
Association of gestational choriocarcinoma in a mother and Li-Fraumeni syndrome in her child: The result of a single event?
Sallé J, Brundler MA, Perrier R … +2 more , Brindle M, Lafay-Cousin L
Fam Cancer · 2026 May · PMID 42183905 · Publisher ↗
Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome caused by germline TP53 mutations. LFS is typically inherited but can also arise de novo. In children with LFS, the most common malignancies are adrenocortic...
Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome caused by germline TP53 mutations. LFS is typically inherited but can also arise de novo. In children with LFS, the most common malignancies are adrenocortical carcinomas, brain tumors, and soft tissue sarcomas. Herein, we present a 5.5-year-old girl with a novel TP53 germline mutation (NM_000546.4, c.132_147dup; p.Ile50Alafs*7) associated with an unusual and aggressive oncologic phenotype in the context of LFS. Over five years, the patient successively developed undifferentiated sarcoma, Burkitt lymphoma and extra-skeletal osteosarcoma. There was no family history of LFS, but the proband's mother had died shortly after her pregnancy from a gestational choriocarcinoma caused by the same TP53 mutation as the proband. We present the first case of a TP53 mutation from non-carrier parents affecting both mother and child to date. We describe the pathogenic variant and the possible mechanism underlying the co-occurrence of the proband's LFS and her mother's gestational choriocarcinoma.
Genotypic and phenotypic characteristics of germline TP53 variant carriers: experience from two cancer genetic counseling units.
Mirete BG, Arias AF, Payá PR … +6 more , Revert MV, Garcia DS, Marín MM, Benítez-Fuentes JD, González IC, Heras ABS
Fam Cancer · 2026 May · PMID 42171906 · Publisher ↗
Germline TP53 pathogenic or likely pathogenic variants underlie Li-Fraumeni syndrome (LFS), but with broader use of multigene panel (MGP) testing, carriers are increasingly identified outside classic criteria. We retrosp...
Germline TP53 pathogenic or likely pathogenic variants underlie Li-Fraumeni syndrome (LFS), but with broader use of multigene panel (MGP) testing, carriers are increasingly identified outside classic criteria. We retrospectively studied 36 carriers from 18 families evaluated at two Spanish hereditary cancer units (2005-2023). Clinical data were obtained from medical records, and variants were functionally classified using the Giacomelli model and IARC thresholds as dominant-negative with loss of function (DNE_LOF), non-dominant-negative without loss of function (noDNE_noLOF), non-dominant-negative with loss of function, or not assessed. Descriptive statistics summarized the tumor spectrum and group comparisons were performed using the Mann-Whitney U test (α = 0.05). Overall, 23 of 36 carriers (63.9%) developed at least one malignancy; 58.3% were female and the median age at first cancer was 36 years (range 27-54). Patients identified through MGP testing had later onset compared with those meeting clinical LFS criteria (median 42 [37-58] versus 27 [4-30] years; p = 0.011). Breast cancer was the most frequent tumor (65% of first cancers, median age 37 [30-47]), whereas none of the MGP-ascertained carriers developed LFS "core" tumors (sarcoma, brain tumor, adrenocortical carcinoma). Fifteen distinct germline variants were identified; 80% were missense, mainly in exons 5-8. DNE_LOF (median 30 [25-38.5]) were associated with earlier onset compared with noDNE_noLOF (47 [37-63]; p = 0.034). Eight carriers (34.7%) developed second primaries after a median interval of 6 years, and four developed third primaries. Functional classification may contribute to risk stratification; however, these findings are exploratory and hypothesis-generating, and require validation in larger prospective cohorts.
Why patient organizations are important to improve care for people with Lynch syndrome.
Seppen J
Fam Cancer · 2026 May · PMID 42159804 · Full text
Improving health care requires patient involvement. For people with Lynch syndrome, general and specific areas can be identified in which it is important for health care professionals to collaborate with patients to impr...
Improving health care requires patient involvement. For people with Lynch syndrome, general and specific areas can be identified in which it is important for health care professionals to collaborate with patients to improve care. This collaboration is mutually beneficial; better care for the patients, reduction of work load and higher chance of funding of research proposals for health care professionals. Patient organizations are comprised of patients that are often more educated and motivated to participate in discussions and workshops. In addition, patient organizations have access to a network of patients that can provide a broad overview of the needs and requirements of this group. Thus, patient organizations are the partners of choice in the collaboration of health care providers and patients. In this commentary, I outline the areas in which physicians and patients should collaborate; Providing information, research and clinical trial design, and psychological care and peer support.
Personalized risk estimates of advanced neoplasia development in individuals with a family history of colorectal cancer.
Greuter MJE, Akwiwu EU, Hennink SD … +11 more , Bisseling TM, Spanier MBW, German Consortium for Familial Intestinal Cancer, Nagtegaal ID, Canfell K, Dekker E, Klausch T, Lansdorp-Vogelaar I, van Leerdam ME, Hoogerbrugge N, Coupé VMH
Fam Cancer · 2026 May · PMID 42133209 · Full text
To optimize surveillance in individuals with a family history (FH) of colorectal cancer (CRC), knowledge on the incidence rate of non-advanced adenomas (nAAs) and their progression rate to advanced neoplasia (AN) is cruc...
To optimize surveillance in individuals with a family history (FH) of colorectal cancer (CRC), knowledge on the incidence rate of non-advanced adenomas (nAAs) and their progression rate to advanced neoplasia (AN) is crucial. We jointly estimated personalized adenoma incidence and progression rates using a novel statistical approach. We used data of individuals with ≥ 1 first-degree relative with CRC who underwent ≥ 2 colonoscopies (n = 876 individuals; n = 2384 colonoscopies). Interval-censored data on timing and yield (no adenomas/nAA/AN) of each colonoscopy were available. nAA incidence and progression time from nAA to AN were estimated using a Bayesian progressive three-state model. Over a median follow-up of 6 years (interquartile range 5-6), 60 (6.8%) individuals developed AN (2 CRC, 58 AA) while 246 (28.1%) developed a nAA. The 5-year risk of developing nAA from baseline was estimated to be 29% (95% Crl: 21-39%). This risk was significantly associated with age and FH type. Estimated risk of progressing to AN within 5 years since nAA onset was 29% (95% Crl: 21-39%), and was significantly associated with having advanced adenomas at baseline. This resulted in a 5-year risk of transitioning from 'no adenomas' to AN of 7% (95% Crl: 5-9%). We showed that only 7% of individuals develop AN (primarily AAs) within the current 5-year colonoscopy surveillance interval. Future studies should evaluate whether this relatively low risk justifies slight extension of the surveillance interval or the use of fecal testing to guide colonoscopy timing. Furthermore, surveillance intensity could potentially be tailored based on age and FH.
Impaired glucose tolerance in women with BRCA1 versus BRCA2 pathogenic or likely pathogenic variants: Results from a prospective cohort study.
Grandi G, Piombino C, Sighinolfi G … +18 more , Barbieri E, Venturelli M, Melotti C, Lippi Bruni R, Grisendi V, Cuoghi Costantini R, Grippa M, Zattarin E, Tenedini E, Razzaboni E, Brigante G, D'Amico R, Nanni B, Menozzi R, Cortesi L, Dominici M, La Marca A, Toss A
Fam Cancer · 2026 May · PMID 42132994 · Full text
BACKGROUND: Estrogens exert a beneficial effect on metabolism. Women carrying BRCA likely pathogenic/pathogenic variants (LP/PV) are at increased risk of premature menopause and may therefore be at higher risk of develop...
BACKGROUND: Estrogens exert a beneficial effect on metabolism. Women carrying BRCA likely pathogenic/pathogenic variants (LP/PV) are at increased risk of premature menopause and may therefore be at higher risk of developing metabolic disorders later in life. In this single-center prospective cohort study, we investigated whether the specific BRCA mutation (BRCA1 vs. BRCA2) has a differential impact on metabolism in women. METHODS: Eligible participants were BRCA LP/PV carriers who were premenopausal or underwent menopause -either natural or iatrogenic- within the 5 years prior to enrollment. Blood samples for lipid and glucose panels were obtained every 6 months, for a total of four time points. Body composition variables were evaluated at baseline and at the final follow-up using bioimpedance analysis. Glucose tolerance was assessed using the homeostatic model assessment for insulin resistance (HOMA-IR). Associations between lipid and glucose profile and patient characteristics were evaluated using univariable and multivariable linear regression models. RESULTS: Fifty-seven BRCA1 and 58 BRCA2 LP/PV carriers were included in the final analysis. At baseline, BRCA1 LP/PV carriers had a higher body mass index (BMI) (27.3 vs. 24.6 kg/m, p = 0.01) and higher fat mass (27.3 vs. 21.9 kg, p = 0.013) than BRCA2 LP/PV carriers. Insulin levels and HOMA-IR were consistently higher in BRCA1 than in BRCA2 LP/PV carriers at all time points, and this difference was not attributable to age, BMI, menopausal status, risk-reducing salpingo-oophorectomy, previous chemotherapy or use of cholesterol-lowering agents. The lipid profile was similar between the groups, although BRCA1 LP/PV carriers showed a tendency toward a less favorable profile (higher LDL and lower HDL). CONCLUSIONS: These prospective results suggest that BRCA1 LP/PV carriers might have impaired glucose tolerance and a greater tendency toward insulin resistance compared with BRCA2 LP/PV carriers: this first report needs further independent confirmations from other cohorts.
Association between breast cancer, pancreatic cancer, and melanoma in a CDKN2A variant common in the Hispanic population.
Parkhurst ES, Natoli JL, Wei X … +2 more , Luna DA, Maarup TJ
Fam Cancer · 2026 May · PMID 42126713 · Publisher ↗
Pathogenic and likely pathogenic variants (P/LP) in the CDKN2A gene are associated with melanoma-pancreatic cancer susceptibility syndrome. The lifetime risk for melanoma is estimated to be 28-76%, while the lifetime ris...
Pathogenic and likely pathogenic variants (P/LP) in the CDKN2A gene are associated with melanoma-pancreatic cancer susceptibility syndrome. The lifetime risk for melanoma is estimated to be 28-76%, while the lifetime risk of pancreatic cancer is > 15%. A common CDKN2A variant in the Hispanic population, c.146 T > C, has conflicting interpretations of pathogenicity, with some laboratories calling this variant LP and others calling it uncertain significance (VUS), which leads to inconsistent clinical recommendations for cancer screening. The objective of this study was to determine if there is an association between the CDKN2A c.146 T > C variant and melanoma, pancreatic cancer, and/or breast cancer. We conducted a retrospective cohort study of the Southern California Kaiser Genetics Hereditary Cancer Database from January 2013 to January 2024. We determined the presence of melanoma, pancreatic cancer, and breast cancer among 202 individuals with the CDKN2A c.146 T > C variant ("c.146 T > C group") and compared them to 190 individuals with Hispanic ancestry and a negative germline panel ("negative control group") as well as 53 individuals with a CDKN2A P/LP variant other than c.146 T > C ("positive control group"). Multiple logistic regression was utilized to produce adjusted odds ratios (aOR), 95% confidence intervals (CI), and p-values. The adjusted odds of melanoma (aOR 6.1, 95% CI 1.3 to 27.9), pancreatic cancer (aOR 13.9, 95% CI 1.7 to 113.4), and breast cancer (aOR 3.2, 95% CI 1.8 to 5.6) were significantly higher in the c.146 T > C group compared to the negative control group. When the c.146 T > C group was compared to the positive control group, the adjusted odds of melanoma (aOR 0.9, 95% CI 0.1 to 8.0), pancreatic cancer (aOR 12.2, 95% CI 0.3 to 511.4), and breast cancer (aOR 1.9, 95% CI 0.4 to 8.4) were not significantly different. Although CDKN2A c.146 T > C is a relatively common variant in the Hispanic population, our data shows it may confer cancer risks similar to other CDKN2A P/LP variants. Increased risk of breast cancer has previously been reported with CDKN2A leading to questions about whether the increased breast cancer risk seen in this study is variant specific. Given the prevalence of this variant in an underserved population, our results suggest that the risks of cancer associated with this Hispanic variant warrant counseling and clinical follow-up.
Factors influencing uptake of risk-reducing mastectomy among unaffected Israeli BRCA1/BRCA2 pathogenic variant carriers.
Laitman Y, Aharon K, Schloss T … +2 more , Margolin L, Friedman E
Fam Cancer · 2026 May · PMID 42126651 · Full text
Women harboring pathogenic variant (PV) in the BRCA1 or BRCA2 genes (= BRCA) have an elevated lifetime risk for breast cancer (BC). One of the main options for active BC risk reduction is bilateral risk-reducing mastecto...
Women harboring pathogenic variant (PV) in the BRCA1 or BRCA2 genes (= BRCA) have an elevated lifetime risk for breast cancer (BC). One of the main options for active BC risk reduction is bilateral risk-reducing mastectomy (RRM). Understanding the factors influencing that decision is important for genetic-counselling and risk mitigation strategy planning. A structured questionnaire was circulated to BRCA carriers, members of the Good Genes NGO in Israel. Data on RRM uptake and timing, factors previously reported to be associated with decision to undergo RRM (e.g., psychosocial, family history, counselling/health-system factors) were obtained. Comparison between carriers who elected to undergo RRM with those who opted for early detection schemes were performed using logistic regression and chi square statistical analyses. Of cancer free women (n = 391), 272 (69.6%) elected to adhere to the recommended surveillance scheme and 119 (30.4%) elected to undergo RRM. The major reasons for electing RRM over surveillance were active BC risk reduction (4.96 ± 0.23), fear of developing BC (4.86 ± 0.50), and having at least one relative with BC diagnosed under age 45 years. Support group discussions emerged as a stronger determinant of RRM uptake than primary care physician or religious guidance. In conclusion, among healthy Israeli BRCA carriers the decision to undergo RRM was influenced by a complex interplay of factors-active BC risk reduction, fear of cancer diagnosis in the context of having one relative with early onset BC and support group discussions were the major drivers of RRM in Israeli BRCA1 carriers.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe