UNASSIGNED: A family history of colorectal cancer (CRC) in a first-degree relative is a well-established risk factor for CRC. When individuals have 2 parents with CRC, the impact on risk is uncertain, and there are no established guidelines for surveillance. We sought to define the surveillance practices and outcomes in individuals with a family history of CRC in both parents.
UNASSIGNED: We identified probands with a family history of CRC in both parents from our Hereditary Gastrointestinal Cancer Database. Charts were retrospectively reviewed for colonoscopy surveillance patterns and incidence of adenomas and CRC.
UNASSIGNED: Sixty-six patients met the inclusion criteria. Forty-two patients (64%) had genetic testing, and no pathogenic germline mutations were identified. During a mean surveillance period of 144 ± 82.2 months and a mean surveillance interval of 33.4 ± 16.6 months, a total of 3.2 ± 8.9 adenomas were found per patient. These were small (median 6.5 mm), and 96% exhibited only low-grade dysplasia. Six patients (9%) were diagnosed with CRC at a mean age of 61.5 ± 11.3 years, corresponding to an incidence rate of 14 cases/10,000 person-years. Patients with CRC were older at first colonoscopy than those without cancer (59 vs 46 years, P = .03), and half of these cases were diagnosed at this first colonoscopy.
UNASSIGNED: Among patients with a family history of CRC in both parents, cases of CRC were seen primarily in those who significantly delayed their first colonoscopy. Initiation of colonoscopy at age 40 should be recommended to individuals with CRC in both parents, consistent with recommendations for those with 1 first-degree relative with CRC.

Cancer is a major global public health challenge, affecting both quality of life and mortality. Recent advances in genetic research have uncovered hereditary cancer syndromes (HCS) that predispose individuals to malignant neoplasms. While traditional single-gene testing has focused on high-penetrance genes, the past decade has seen a shift toward multigene panels, which facilitate the analysis of multiple genes associated with specific HCS. This approach reveals variants in less-studied gene regions and improves our understanding of cancer predisposition. In a study composed of Russian patients with clinical signs of HCS, we used a multigene hereditary cancer panel and revealed 21.6% individuals with pathogenic or likely pathogenic genetic variants. BRCA1/BRCA2 mutations predominated, followed by the CHEK2 and ATM variants. Of note, 16 previously undescribed variants were identified in the MUTYH, GALNT12, MSH2, MLH1, MLH3, EPCAM, and POLE genes. The implications of the study extend to personalized cancer prevention and treatment strategies, especially in populations lacking extensive epidemiological data, such as Russia. Overall, our research provides valuable genetic insights that give the way for further investigation and advances in the understanding and management of hereditary cancer syndromes.

Introduction  Cancer is a multifactorial disease dependent on the influence of genetic and environmental factors. About 10% of cancers are associated with germline mutations, which predispose to a higher risk of developing cancer. Currently, the use of panels that identify susceptibility and/or association genes cancer has been increasingly used, both in clinical practice and in scientific research. Objective  To investigate genetic mutations in patients with a profile for hereditary cancer in individuals from a region of northeast Brazil, where there is a high frequency of endogenous and consanguineous marriages. Methods  A set of 17 genes ( BRCA1 , BRCA2 , APC , TP53 , PTEN , RET , VHL , RB1 , CDKN2 , CDH1 , CHEK2 , MLH1 , MSH2 , MSH6 , MUTYH , XPA , and XPC ) associated with cancer and hereditary syndromes were analyzed. Fifteen patients with a hereditary cancer profile were evaluated. Results  The pathogenic variant found was c.1187G > A (p.Gly396Asp), rs36053993 in the MUTYH gene in a male patient diagnosed with melanoma at the age of 43 years and a family history for this tumor. This gene encodes an important enzyme related to DNA repair and has been associated with other types of cancer, this is the first report of an association with melanoma, the biological plausibility of this association is given once the MUTYH protein is expressed in the skin tissue and is responsible for repairing damage caused, for example, by sun exposure. Conclusion  The results of this study suggest that this mutation may be important for the hereditary predisposition to melanoma, but a broader investigation of this mutation is needed.

UNASSIGNED: The increase in incidence of colorectal cancer in young patients of African ancestry coupled with increased aggressiveness has warranted investigation of the heritable nature of these cancers. Only a limited number of published reports of hereditary colorectal cancer in indigenous African populations have been reported and no systematic screening of these groups has been performed previously. We aimed to investigate causative germline variants and to establish the incidence of pathogenic/likely pathogenic germline variants in the known colorectal cancer genes in indigenous African colorectal cancer patients using a next-generation sequencing (NGS) multigene panel.
UNASSIGNED: Patients were selected from two hospitals in Cape Town and Johannesburg, South Africa. Patients with unresolved molecular diagnosis with an age of onset below or at 60 years were selected. Germline DNA samples were analyzed using a 14-gene NGS panel on the Ion Torrent platform. Variant calling and annotation were performed, and variants were classified according to the American College of Medical Genetics and Genomics guidelines. Observed variants were verified by Sanger sequencing and/or long-range PCR.
UNASSIGNED: Out of 107 patients, 25 (23.4%) presented with a pathogenic/likely pathogenic germline variant (PGV). Fourteen PGVs in at least one mismatch repair (MMR) gene were identified and verified in 12 patients (11.2%). Of these MMR gene variants, five were novel. The remaining 10 PGVs were in the APC, BMPR1A, MUTYH, POLD1, and TP53 genes.
UNASSIGNED: The high incidence of PGVs associated with early-onset colorectal cancer in indigenous African patients has important implications for hereditary colorectal cancer risk management. These findings pave the way for personalized genetic screening programs and cascade testing in South Africa. The next step would involve further screening of the unresolved cases using tools to detect copy number variation, methylation, and whole exome sequencing.

The use of multigene panel testing for patients with a predisposition to Hereditary Breast and Ovarian Cancer syndrome (HBOC) is increasing as the identification of mutations is useful for diagnosis and disease management. Here, we conducted a retrospective analysis of BRCA1/2 and non-BRCA gene sequencing in 4630 French HBOC suspected patients. Patients were investigated using a germline cancer panel including the 13 genes defined by The French Genetic and Cancer Group (GGC)-Unicancer. In the patients analyzed, 528 pathogenic and likely pathogenic variants (P/LP) were identified, including BRCA1 (n = 203, 38%), BRCA2 (n = 198, 37%), PALB2 (n = 46, 9%), RAD51C (n = 36, 7%), TP53 (n = 16, 3%), and RAD51D (n = 13, 2%). In addition, 35 novel (P/LP) variants, according to our knowledge, were identified, and double mutations in two distinct genes were found in five patients. Interestingly, retesting a subset of BRCA1/2-negative individuals with an expanded panel produced clinically relevant results in 5% of cases. Additionally, combining in silico (splicing impact prediction tools) and in vitro analyses (RT-PCR and Sanger sequencing) highlighted the deleterious impact of four candidate variants on splicing and translation. Our results present an overview of pathogenic variations of HBOC genes in the southeast of France, emphasizing the clinical relevance of cDNA analysis and the importance of retesting BRCA-negative individuals with an expanded panel.

Psoriasis is a chronic multifactorial skin disorder with an immune basis. It is characterized by patches of skin that are usually red, flaky and crusty, and that often release silvery scales. The patches appear predominantly on the elbows, knees, scalp and lower back, although they may also appear on other body areas and severity may be variable. The majority of patients (about 90%) present small patches known as \"plaque psoriasis\". The roles of environmental triggers such as stress, mechanical trauma and streptococcal infections are well described in psoriasis onset, but much effort is still needed to unravel the genetic component. The principal aim of this study was to use a next-generation sequencing technologies-based approach together with a 96 customized multigene panel in the attempt to determine if there are germline alterations that can explain the onset of the disease, and thus to find associations between genotypes and phenotypes. To this aim, we analyzed a family in which the mother showed mild psoriasis, and her 31-year-old daughter had suffered from psoriasis for several years, whereas an unaffected sister served as a negative control. We found variants already associated directly to psoriasis in the TRAF3IP2 gene, and interestingly we found a missense variant in the NAT9 gene. The use of multigene panels in such a complex pathology such as psoriasis can be of great help in identifying new susceptibility genes, and in being able to make early diagnoses especially in families with affected subjects.

UNASSIGNED: Genetic testing for at-risk patients with breast cancer should be routinely offered. Knowledge generated may influence both treatment decisions and cancer prevention strategies among the patients themselves and their relatives. In this study, we report on the prevalence and patterns of germline mutations, using commercially available next-generation sequencing (NGS)-based multi-gene panels (MGP).
UNASSIGNED: Consecutive at-risk breast cancer patients, as determined by international guidelines, were offered germline genetic testing using a 20-gene NGS-based panel at a reference lab. Samples of peripheral blood were obtained for DNA extraction and genetic variants were classified as benign/likely benign (negative), pathogenic/likely pathogenic (positive) or variants of uncertain significance (VUS).
UNASSIGNED: A total of 1310 patients, median age (range) 43 (19-82) years, were enrolled. Age ≤45 years (n = 800, 61.1%) was the most common indication for testing. Positive family history of breast, ovarian, pancreatic or prostate cancers, and triple-negative disease were among the common indications. Among the whole group, 184 (14.0%) patients had pathogenic/likely pathogenic variants; only 90 (48.9%) were in BRCA1 or BRCA2, while 94 (51.9%) others had pathogenic variants in other genes; mostly in APC, TP53, CHEK2 and PALB2. Mutation rates were significantly higher among patients with positive family history (p = 0.009); especially if they were 50 years or younger at the time of breast cancer diagnosis (p < 0.001). Patients with triple-negative disease had relatively higher rate (17.5%), and mostly in BRCA1/2 genes (71.4%). Variants of uncertain significance (VUS) were reported in 559 (42.7%) patients; majority (90.7%) were in genes other than BRCA1 or BRCA2.
UNASSIGNED: Pathogenic mutations in genes other than BRCA1/2 are relatively common and could have been missed if genetic testing was restricted to BRCA1/2. The significantly high rate of VUS associated with multi-gene panel testing can be disturbing.

Over the last decade, the implementation of multigene panels for hereditary tumor syndrome has increased at our institution (Inselspital, University Hospital Berne, Switzerland). The aim of this study was to determine the prevalence of variants of unknown significance (VUS) in patients with suspected Lynch syndrome and suspected hereditary breast and ovarian cancer syndrome, the latter in connection with the trend toward ordering larger gene panels.
Retrospectively collected data from 1057 patients at our institution showed at least one VUS in 126 different cases (11.9%). In patients undergoing genetic testing for BRCA1/2, the prevalence of VUS was 6%. When < 10 additional genes were tested in addition to BRCA1/2, the prevalence increased to 13.8%, and 31.8% for > 10 additional genes, respectively. The gene most frequently affected with a VUS was ATM. 6% of our patients who were tested for Lynch syndrome had a VUS result in either MLH1, MSH2 or MSH6.
Our data demonstrate that panel testing statistically significantly increases VUS rates due to variants in non-BRCA genes. Good genetic counseling before and after obtaining results is therefore particularly important when conducting multigene panels to minimize patient uncertainty due to VUS results.

Many individuals who previously received negative genetic test results are eligible for updated testing. This study examined intention to communicate updated genetic test results to relatives in participants who previously received negative genetic test results.
Women with a personal or family history of breast or ovarian cancer who tested negative for BRCA1/2 before 2013 were enrolled between April 2018 and October 2019. Proportions were calculated to assess intention to communicate updated genetic test results to living immediate family, extended family, and all family. Potential predictors of intentions from the theory of planned behavior (attitudes, subjective norms, perceived behavioral control) were assessed. The three outcomes were analyzed using generalized linear models with a quasi-binomial probability distribution.
110 women completed the baseline assessment prior to updated testing. Participants intended to communicate genetic test results to 90% of immediate family, 51% of extended family, and 66% of all living relatives. Participants with higher subjective norms (aOR = 1.93, 95% CI: 1.08-3.57) had higher intentions to communicate genetic test results to extended family, while participants with more positive attitudes (aOR = 1.27, 95% CI: 1.01-1.60) had higher intentions to communicate to all family. Placing higher importance on genetic information was associated with higher intentions to communicate to immediate family (aOR = 1.40, 95% CI: 1.06-1.83). Lower subjective numeracy was associated with higher intentions to communicate to extended family (aOR = 0.50, 95% CI: 0.32-0.76).
Attitudes and subjective norms were predictors of intention to communicate updated genetic information to at-risk biological relatives, and predictors may vary by degree of relationship.

UNASSIGNED: BRCA1 and BRCA2 germline pathogenic variants (GPVs) account for most of the 5-10% of breast cancer (BC) that is attributable to inherited genetic variants. BRCA1 GPVs are associated with the triple negative subtype, whereas BRCA2 GPVs are likely to result in higher grade, estrogen-receptor positive BCs. The contribution of other genes of high and moderate risk for BC has not been well defined and risk estimates to specific BC subtypes is lacking, especially for an admixed population like Brazilian.
UNASSIGNED: The aim of this study is to evaluate the value of a multigene panel in detecting germline mutations in cancer-predisposing genes for Brazilian BC patients and its relation with molecular subtypes and the predominant molecular ancestry.
UNASSIGNED: A total of 321 unrelated BC patients who fulfilled NCCN criteria for BRCA1/2 testing between 2016-2018 were investigated with a 94-genes panel. Molecular subtypes were retrieved from medical records and ancestry-specific variants were obtained from off-target reads obtained from the sequencing data.
UNASSIGNED: We detected 83 GPVs in 81 patients (positivity rate of 25.2%). Among GPVs, 47% (39/83) were identified in high-risk BC genes (BRCA1/2, PALB2 and TP53) and 18% (15/83) in moderate-penetrance genes (ATM, CHEK2 and RAD51C). The remainder of the GPVs (35% - 29/83), were identified in lower-risk genes. As for the molecular subtypes, triple negative BC had a mutation frequency of 31.6% (25/79), with predominance in BRCA1 (12.6%; 10/79). Among the luminal subtypes, except Luminal B HER2-positive, 18.7% (29/155) had GPV with BRCA1/2 genes contributing 7.1% (11/155) and non-BRCA1/2 genes, 12.9% (20/155). For Luminal B HER2-positive subtype, 40% (16/40) had GPVs, with a predominance of ATM gene (15% - 6/40) and BRCA2 with only 2.5% (1/40). Finally, HER2-enriched subtype presented a mutation rate of 30.8% (4/13) with contribution of BRCA2 of 7.5% (1/13) and non-BRCA1/2 of 23% (3/13). Variants of uncertain significance (VUS) were identified in 77.6% (249/321) of the patients and the number of VUS was increased in patients with Asian and Native American ancestry.
UNASSIGNED: The multigene panel contributed to identify GPVs in genes other than BRCA1/2, increasing the positivity of the genetic test from 9.6% (BRCA1/2) to 25.2% and, considering only the most clinically relevant BC predisposing genes, to 16.2%. These results indicate that women with clinical criteria for hereditary BC may benefit from a multigene panel testing, as it allows identifying GPVs in genes that directly impact the clinical management of these patients and family members.