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Background Health‐care providers increasingly have to discuss uncertainty with patients. Awareness of uncertainty can affect patients variably, depending on how it is communicated. To date, no overview existed for health‐care professionals on how to discuss uncertainty. Objective To generate an overview of available recommendations on how to communicate uncertainty with patients during clinical encounters. Search strategy A scoping review was conducted. Four databases were searched following the PRISMA‐ScR statement. Independent screening by two researchers was performed of titles and s, and subsequently full texts. Inclusion criteria Any (non‐)empirical papers were included describing recommendations for any health‐care provider on how to orally communicate uncertainty to patients. Data extraction Data on provided recommendations and their characteristics (eg, target group and strength of evidence base) were extracted. Recommendations were narratively synthesized into a comprehensible overview for clinical practice. Results Forty‐seven publications were included. Recommendations were based on empirical findings in 23 publications. After narrative synthesis, 13 recommendations emerged pertaining to three overarching goals: (a) preparing for the discussion of uncertainty, (b) informing patients about uncertainty and (c) helping patients deal with uncertainty. Discussion and conclusions A variety of recommendations on how to orally communicate uncertainty are available, but most lack an evidence base. More substantial research is needed to assess the effects of the suggested communicative approaches. Until then, health‐care providers may use our overview of communication strategies as a toolbox to optimize communication about uncertainty with patients. Patient or public contribution Results were presented to stakeholders (physicians) to check and improve their practical applicability.

Kristijan Ramadan and colleagues report the identification of three individuals from two families with biallelic inactivating mutations in SPRTN causing early onset hepatocellular carcinoma and defects in the DNA replication stress response. Functional studies confirmed critical roles for SPRTN in G2/M checkpoint response and DNA replication. Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1 ) 1 , 2 , 3 , 4 , 5 , 6 , 7 in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis 1 , 2 , 3 , 4 , 5 , 6 , 7 . Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.

BackgroundLi–Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the classical diagnostic criteria harbour TP53 germline mutations. However, TP53 germline mutations may also occur in less obvious phenotypes. As a result, different criteria are in use to decide which patients qualify for TP53 mutation analysis, including the LFS, Li–Fraumeni-like (LFL) and Chompret criteria. We investigated which criteria for TP53 mutation analysis resulted in the highest mutation detection rate and sensitivity in Dutch families. We describe the tumour spectrum in TP53-positive families and calculated tumour type specific relative risks.MethodA total of 180 Dutch families referred for TP53 mutation analysis were evaluated. Tumour phenotypes were verified by pathology reports or clinical records.ResultsA TP53 germline mutation was identified in 24 families. When the Chompret criteria were used 22/24 mutations were detected (sensitivity 92%, mutation detection rate 21%). In LFS and LFL families 18/24 mutations were found (sensitivity 75%). The two mutations detected outside the ‘Chompret group’ were found in a child with rhabdomyosarcoma and a young woman with breast cancer. In the mutation carriers, in addition to the classical LFS tumour types, colon and pancreatic cancer were also found significantly more often than in the general population.ConclusionWe suggest TP53 mutation testing for all families fulfilling the Chompret criteria. In addition, TP53 mutation testing can be considered in the event of childhood sarcoma and breast cancer before 30 years. In addition to the risk for established LFS tumour types, TP53-positive individuals may also have an elevated risk for pancreatic and colon cancer.

BackgroundIn approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6 or MYD88.MethodsWe sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.ResultsPredicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population.ConclusionsBased on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.

To the Editor: Zhang et al. (Dec. 10 issue) 1 report the prevalence of mutations in predisposition genes among children and adolescents with cancer. One of their main conclusions is that family history does not predict the presence of an underlying germline mutation. However, it is not clear how the authors obtained information about family history. There are important differences between an in-depth interview by a clinical geneticist and a query about additional cancer in the family by a pediatrician. Moreover, information on family history was available in only 58 patients (61%) and missing in the remaining 37 patients (39%); selection . . .

Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3′ end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions. We obtained clinical data for 194 carriers of a 3′ end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6, or a combined EPCAM–MSH2 deletion. 93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65–85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM–MSH2 deletion (69% [95% CI 47–91], p=0·8609) or mutations in MSH2 (77% [64–90], p=0·5892) or MLH1 (79% [68–90], p=0·5492), but was higher than noted for carriers of MSH6 mutation (50% [38–62], p<0·0001). By contrast, women with EPCAM deletions had a 12% [0–27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM–MSH2 deletion (55% [20–90], p<0·0001) or of a mutation in MSH2 (51% [33–69], p=0·0006) or MSH6 (34% [20–48], p=0·0309), but did not differ significantly from that noted for MLH1 (33% [15–51], p=0·1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer. EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers. Sacha Swarttouw-Hijmans Foundation, Dutch Cancer Society, Deutsche Krebshilfe (German Cancer Aid), Hong Kong Cancer Fund, Hungarian Research Grant OTKA, Norwegian EEA Financial Mechanism (Hungarian National Institute of Oncology), and US National Cancer Institute.

Uncertainty is increasingly discussed during genetic counseling due to innovative techniques, e.g., multigene panel testing. Discussions about uncertainty may impact counselees variably, depending on counselors’ communication styles. Ideally, the discussion of uncertainty enables counselees to cope with uncertainty and make well-informed decisions about testing. We examined the impact of how counselors convey uncertainty and address counselees’ uncertainty, and explored the role of individual characteristics. Therefore, a randomized controlled experiment using videos was conducted. Former counselees (N = 224) viewed one video depicting a genetic consultation about multigene panel testing. The extent of counselors’ communication of uncertainty (comprehensive vs. the essence) and their response to counselees’ uncertainty expressions (providing information vs. providing space for emotions vs. normalizing and counterbalancing uncertainty) were systematically manipulated. Individual characteristics, e.g., uncertainty tolerance, were assessed, as well as outcome variables (primary outcomes: feelings of uncertainty and information recall). No effects were found on primary outcomes. Participants were most satisfied when the essence was communicated, combined with providing information or providing space responses (p = 0.002). Comprehensive information resulted in less perceived steering toward testing (p = 0.005). Participants with lower uncertainty tolerance or higher trait anxiety were less confident about their understanding when receiving comprehensive information (p = 0.025). Participants seeking information experienced less uncertainty (p = 0.003), and trusted their counselor more (p = 0.028), when the counselor used information providing responses. In sum, the impact of discussing uncertainty primarily depends on individual characteristics. Practical guidelines should address how to tailor the discussion of uncertainty.

Background Faecal immunochemical testing (FIT) is suboptimal in detecting advanced neoplasia (AN). To increase the sensitivity and yield of a FIT-based screening programme, FIT could be combined with risk factors for AN. We evaluated the incremental yield of adding a family history questionnaire (FHQ) on colorectal cancer (CRC) and Lynch syndrome-associated tumours to the Dutch FIT-based screening programme. Methods Six thousand screen-naive individuals, aged 59–75 years, were invited to complete a FIT (FOB-Gold, cut-off 47 µg Hb/g faeces) and a validated online FHQ. Participants with a positive FIT and/or positive FHQ, confirmed after genetic counselling, were referred for colonoscopy. Yield of detecting AN per 1000 invitees for the combined strategy was compared with the FIT-only strategy. Results Of the 5979 invitees, 1952 (32.6%) completed the FIT only, 2379 (39.8%) completed both the FIT and FHQ and 95 (1.6%) completed the FHQ only. Addition of the FHQ to FIT-based screening resulted in one extra case of AN detected after 16 additional colonoscopies, resulting in a yield of 19.6 (95% CI, 16.4–23.5) for the combined strategy versus 19.5 (95% CI, 16.3–23.3) for the FIT-only strategy ( p  = 1.0). Conclusions The addition of an FHQ to one round of FIT screening did not increase the detection of AN compared with FIT only (ClinicalTrials.gov NCT02698462).