Familial Cancer最新文献

Hereditary cancer predisposition disorders account for up to 10% of all pediatric cancers. Genetic counseling for families of the proband includes risk assessment and recommendations for cascade genetic testing for parents and siblings, but there is no standardized method for cascade testing in place resulting in variability in how clinics approach cascade genetic testing. We explored the uptake and outcomes associated with a family-based approach to cascade testing, for non-syndromic cancer predisposition disorders, at a pediatric cancer genetics clinic serving an ethnically diverse patient population. A retrospective chart review was conducted to evaluate test uptake in the parents and siblings of 106 pediatric probands. The study included 99 mothers, 97 fathers, 116 full siblings, and 53 half siblings who were recommended testing due to genetic risk. Of these relatives, 156 (43%) had documentation of completed cascade testing within twenty-four months after the proband's result disclosure. Completion of cascade testing varied by the type of family member and degree of relatedness. 41% of mothers (41/99) were tested in comparison to 26% of fathers (26/97) and 70.6% of full siblings (82/116) were tested compared to 13.2% of half siblings (7/53). Statistical analysis using chi-squared tests revealed that siblings were more likely to have completed testing than parents (p < 0.001). Furthermore, amongst parents, mothers were more likely to complete testing than fathers (p = 0.03) and amongst siblings, full siblings were more likely to complete testing than half siblings (< 0.001). The proband's age (p = 0.008), parents' preferred language (p = 0.002), and interpreter use during visit (p = 0.004) were the factors associated with differences in test uptake amongst siblings, whereas the proband's race/ethnicity (p = 0.019) was the only factor associated with differences in test uptake amongst parents. The most common barriers noted in charts for lack of test completion included country of residence, lack of insurance, and loss to follow-up. In conclusion, we found that test uptake differed significantly among relatives of a proband with siblings being more likely to test than parents. We also found differences in the demographic and clinical factors associated with test uptake in parents and siblings. Future studies need to validate these differences and further explore the underlying cause of variation in test uptake among relatives.

Despite its clinical value, cascade genetic testing (CGT) in hereditary cancer syndromes remains underutilized for a number of reasons, including ineffective family communication of genetic risk information. Therefore, alternative strategies are being explored to improve CGT uptake rates; one such strategy is direct contact with at-risk relatives by healthcare professionals with proband consent. It is unclear how Italian laws and regulations pertaining to CGT-including the EU General Data Protection Regulation (GDPR)-should be understood and implemented in the context of such alternative strategies. The authors constructed a hypothetical case about CGT, reviewed laws and regulations on informed consent, privacy, and the right not to know, and analyzed how those laws and regulations might apply to different communicative strategies relevant to the case and aimed at supporting CGT. A constitutionally consistent reading of Italian law and of the GDPR, an integral part of the Italian privacy framework, suggests that multiple communicative approaches may be legally permissible in Italy to support the CGT process. This includes direct contact by healthcare professionals with proband consent, provided certain conditions are met. Understanding the effectiveness of such approaches in improving CGT uptake will require further research efforts.

In the Emilia-Romagna region (Northern Italy), the identification and management of women at familial/hereditary risk of breast and ovarian cancer is guided by a well-established regional protocol. Here we report the results of the experience of private supplementation of public healthcare service in offering the possibility to undergo BRCA1/2 testing and/or multigene panel testing (MGPT) within a well-defined pathway to women unfulfilling regional criteria. Out of 177 patients referred to our center who underwent BRCA1/2 testing, 175 tested negative while two (1.1%) resulted carriers of pathogenic variants in BRCA2; 69 patients also underwent MGPT, and in four cases (5.8%) a pathogenic variant were found (two in ATM and one in CHEK2 and RAD51C, respectively). Overall, this private supplementation of territorial public healthcare system has made it possible to confirm the validity of regional criteria for genetic testing access (concordance: 98.9%), but also to identify carriers of pathogenic variants of BRCA1/2 that would have escaped regional protocol, to support the effectiveness of MGPT for the identification of rare cases (not BRCA) at mild/high risk, and to provide reassurance to women who were found to be non-carriers of pathogenic variants, who may benefit from a more accurate assessment of their risk.

Deciphering the spectrum and founder disease-causing variants (DCVs) in specific populations can shape and facilitate the diagnostic process of Lynch Syndrome (LS). The aim of this report was to comprehensively update on the genetic landscape of LS in the ethnically diverse Israeli-Jewish population. The cohort included 1080 carriers from 588 families; some from underrepresented, understudied Israeli ethnic groups recruited from 8 genetic institutes and high-risk clinics throughout the country. Variant classification was performed according to the American College of Medical Genetics criteria. A total of 157 DCVs were identified, 12 are reported here for the first time, and 9 reclassified. MSH2 DCVs were identified in 286 families (49%). Most DCVs (125/157, 80%) were noted in one or two families only. Sixteen DCVs, each detected in ≥ 5 families, and accounted for LS in 378/588 (64%) families. Constitutional mismatch repair deficiency (CMMRD) was diagnosed in 7 families. Twenty-five carriers (2.3%) had an additional DCV or risk alleles in another cancer susceptibility gene. In conclusion, MMR gene variant distribution in Israel is diverse. MSH2 is most commonly mutated due to founder DCVs. Though the 16 prevalent LS-associated DCVs were frequently detected in our cohort, none of them is frequently reported in the general population. These data should facilitate variant interpretation, spouse and cascade testing.

Colorectal cancer (CRC) is a common cancer in Ireland. Of all CRCs, 2-4% are attributable to Lynch Syndrome (LS), the most common CRC predisposition syndrome. LS is caused by constitutional pathogenic variants (PVs) affecting mismatch repair (MMR) genes with resultant MMR protein deficiency (dMMR). Screening of all CRCs with MMR immunohistochemistry (IHC) testing is advocated to increase the detection of LS. However, successful implementation requires appropriate downstream management. In Ireland the traditional pathway involves referral to cancer genetics services to assess eligibility for genetic testing. Cancer genetics services in Ireland face many challenges in providing uniform access to timely healthcare with current wait times for assessment in excess of 1 year. An increasingly adopted pathway is that of mainstreaming, whereby genetic testing is managed locally by a multidisciplinary team member. Our institution therefore implemented an Advanced Nurse Practitioner (ANP)-led service with responsibility for the LS Diagnostic Pathway and mainstream genetic testing. Data was extracted from a prospectively maintained database of all newly diagnosed CRC patients discussed at our institutions CRC multidisciplinary meeting (MDM) between January 1st, 2023, and May 31st, 2024. MMR IHC testing was performed in 97.9% of the 385 patients diagnosed with CRC. The median time from histological confirmation of CRC to the availability of the MMR IHC report was 6 days. All 51 patients (100%) who required sequential tumor testing underwent BRAF V600 ± MLH1 promoter methylation testing. Additionally, 100% of the 14 patients eligible for mainstream genetic testing were referred to the ANP-led genetics service. The median time from the initial MDM discussion to the initiation of genetic testing was 69 days, while the median time from testing to the availability of results was 19 days. Patients received their results within a median of 21 days. MMR IHC testing increases the detection of LS through identification of dMMR tumours. Successful downstream delivery of clinical services, however, requires appropriate subsequent management, in a resource-limited environment. Our institutional experience demonstrates the feasibility, efficiency, and effectiveness of an ANP-led mainstreaming model of care for hereditary colorectal cancer.

Serrated Polyposis Syndrome (SPS) is characterized by multiple and/or large serrated polyps in the colon and an increased risk of colorectal cancer (CRC). The etiology is largely unknown, but in a subset of patients with SPS, monoallelic pathogenic variants in RNF43 are detected. To date, however, the penetrance and phenotypic spectrum of patients carrying pathogenic variants (PV) in RNF43 are poorly described. We present eight patients both with and without serrated polyps from four unrelated families with likely pathogenic variants (LPV) in RNF43 and compare the results to current literature. The patients were referred to genetic counseling due to suspicion of hereditary cancer. They underwent genetic testing with custom NGS gene panels including RNF43 as part of a routine genetic work-up. Three LPVs, one multi-exon deletion and two nonsense variants, were detected in four families. Family I had a history of CRC and serrated polyps, but in the three other families (II‒IV) there was no history of CRC or serrated polyps. Colonoscopies in the probands of these families did not reveal any serrated polyps and/or CRC despite some of them being relatively old. Our findings suggest that the penetrance of RNF43-related disease is much lower than previously thought, and raise questions about the connection between RNF43 and disease. The results highlight the complexity of genetic counseling in RNF43 positive families- particularly in families without polyposis. Further research is needed to elucidate the role of RNF43 in the risk of SPS and CRC.

As genetic testing becomes increasingly accessible and affordable, the uniform and accurate interpretation of genetic variants becomes essential. The ACMG/AMP joint guidelines provide the basis for systematic and uniform interpretation of pathogenicity of genetic variants. However, the application of these in routine clinical interpretation at-scale has largely been limited by the lack of resources providing harmonized data especially at a population-scale. Here we describe BRCAIndica, a resource for BRCA1 and BRCA2 variants conforming to the ACMG & AMP joint guidelines to aid uniform clinical interpretation of genetic tests with a specific focus on variants reported in the Indian population. We collected and harmonized variants from across several resources including population-scale datasets, literature survey and other variant datasets. We then classified them according to the ACMG/AMP guidelines.We have collected a total of 10,490 unique variants, of which 2261 Pathogenic and 43 Likely Pathogenic variants belong to BRCA1 and 2694 Pathogenic and 20 Likely Pathogenic variants to BRCA2 respectively. BRCAIndica can be accessed at:https://clingen.igib.res.in/brcaindica/ . In conclusion, BRCAIndica is a powerful resource that offers researchers and clinicians with ACMG/AMP annotated BRCA variants.

Risk reduction salpingo-oophorectomy (RRSO) is usually performed in women with hereditary breast and ovarian cancer (HBOC) syndrome for BRCA1 and BRCA2 gene mutation carriers, resulting in surgical menopause, which is more associated with a high risk of cardiovascular and metabolic disease than in premenopausal and natural menopausal women. This study assessed the prevalence of cardiovascular and metabolic outcomes in women who underwent salpingo-oophorectomy as a preventive measure against HBOC. This meta-analysis assessed prevalence rates for four metabolic/cardiovascular conditions: myocardial infarction, hypertension, hypercholesterolemia, and type 2 diabetes mellitus. DerSimonian and Laird random-effects models were applied to all analyses, with 95% confidence interval (CI). Heterogeneity was assessed with I². We used OpenMeta Analyst software for statistical analysis. A total of five retrospective studies and one observational study involving 1,320 patients were included. The average body mass index (BMI) was 25.97 kg/m2 and the average waist circumference was 87.94 cm. The analysis across a mean 4.94-year follow-up revealed prevalence rates for acute myocardial infarction of 1.5% (95% CI 0.3-2.7; P = 0.077; I²=56.25%), hypertension of 28% (95% CI 6.9-49.1; P < 0.001; I² = 98.42%), hypercholesterolemia of 27.2% (95% CI 6.8-47.6; P < 0.001; I²=98.67%), and type 2 diabetes mellitus of 3.3% (95% CI 1.1-5.5; P < 0.001; I²=82.44%). Our findings suggest that there is no marked increase in cardiovascular risk among women with HBOC undergoing RRSO.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal vascular dysplasia characterized by the presence of mucocutaneous telangiectasia and arteriovenous malformations in solid organs. The Curaçao criteria and/or detection of ALK1, ENG, and SMAD4 gene mutations are used for diagnosis. Juvenile Polyposis Syndrome (JPS) is diagnosed according to the number and localization of juvenile polyps, and family history of JPS. Both entities have a low prevalence. Mutation of SMAD4 leads to a combined syndrome of these two conditions called HHT-JPS Overlap Syndrome. We aim to describe the clinical characteristics associated with this condition focusing on long term follow up and review of the literature. A cross-sectional descriptive study of HHT-JPS cases from an HHT Institutional Registry was designed. Patients were eligible for this case series if they fulfilled both HHT and JPS diagnostic criteria and/or mutation on SMAD4. A comprehensive review was conducted on the clinical phenotype associated with HHT and its gastrointestinal involvement. Fourteen patients from eleven families in 788 previously HHT-diagnosed patients met the inclusion criteria. The ages ranged between 25 and 70 years old and 12 were females. In addition to the typical signs/symptoms of HHT, two distinct phenotypes were observed. Nine patients predominantly exhibited initially upper, while five showed predominantly initially lower gastrointestinal involvement. Numerous musculoskeletal and cardiovascular anomalies were also identified. The observed phenotypic diversity, particularly in gastrointestinal involvement, underscores the need for tailored clinical approaches. Comprehensive assessments identified associated musculoskeletal and cardiovascular anomalies, emphasizing the systemic nature of HHT-JPS.

The discovery of "mismatch repair deficient (MMRd)-crypt foci" in non-neoplastic intestinal mucosa in Lynch syndrome (LS) has significantly enhanced our understanding of how tumors and tumor immunity form and evolve in LS. In this study, we report the frequent presence of "mismatch repair proficient (MMRp)-crypt foci" in both non-neoplastic and neoplastic intestinal mucosa in a patient with constitutional MMR deficiency (CMMRD), who carried a germline MSH6 pathogenic variant (c.3261dupC) in trans with an MSH6 likely pathogenic variant (c.3724_3726del) and whose tissues were otherwise deficient in MMR globally. The MMRp-crypts occurred at a rate of 1.1/100 crypts in non-neoplastic intestinal mucosa and were readily discernible in adenomas > 1 cm. Sequencing analysis revealed normalization of the MSH6c.3261dupC variant in MMRp-adenoma crypts, indicating reverse frameshifting of the exon 5 C8 microsatellite. Interestingly but not surprisingly, the MMRp-adenoma crypts remained microsatellite-instability-high (MSI-H), and shared oncogenic APC mutations with the background MMRd-adenoma. Contrasting with MSH6-CMMRD, no PMS2-CMMRD individuals (0/5) harbored MMRp-crypts. In conclusion, our study documents distinct MMRp-crypts in MSH6-CMMRD, a phenomenon in keeping with MSH6 being a frequent target of MSI-H due to its coding microsatellite and suggesting that MSH6-CMMRD can potentially serve as a unique model system to further our understanding of MSH6's role in MSI-H tumor formation and evolution. Our findings also bear diagnostic implications; when using MMR immunohistochemistry as an ancillary tool in detecting CMMRD, awareness of these MMRp crypts can help avoid diagnostic pitfalls.