Cohort profile: a nationwide study in Dutch CHEK2 c.1100delC families using the infrastructure of the HEreditary Breast and Ovarian cancer study Netherlands - Hebon-CHEK2.

PURPOSE: CHEK2 c.1100delC is associated with an increased breast cancer risk in women. While this variant is prevalent in the Netherlands (1% in the general population), knowledge of aetiology and prognosis of breast cancer and other tumours in CHEK2 c.1100delC carriers is lacking. The nationwide HEreditary Breast and Ovarian cancer study the Netherlands (Hebon) cohort aims to answer study questions in families with an increased risk of breast cancer and ovarian cancer. While initially focusing on BRCA1/2-variant families, Hebon gradually expanded to include pathogenic variants in other genes associated with breast and/or ovarian cancer over time. This provides an excellent setting to establish a cohort to ultimately study the impact of CHEK2 c.1100delC on cancer risk prediction and surveillance, breast cancer treatment and prognosis. PARTICIPANTS: We invited all heterozygous and homozygous CHEK2 c.1100delC indexes and tested female relatives. 1802 women were included, of whom 1374 were heterozygotes and 938 were breast cancer cases. Pedigrees were collected from all clinical genetic departments. Furthermore, participants completed a detailed questionnaire on hormonal and lifestyle factors, family history, cancer diagnosis and treatment. FINDINGS TO DATE: Mean age at study inclusion was 53 years. Linkage with the Netherlands Cancer Registry showed a younger age at diagnosis in homozygotes (mean age 41.7 years) and heterozygotes (47.9 years) than non-carriers (51.2 years). Furthermore, carriers were more often diagnosed with grade 2, oestrogen receptor-positive breast cancer and more often developed contralateral breast cancer than non-carriers. Most women consumed alcohol regularly and about half never smoked. FUTURE PLANS: Further data linkages with the Netherlands Cancer Registry will allow prospective follow-up and breast cancer risk assessment in unaffected women at the time of genetic testing, risk of contralateral breast cancer and survival in patients with breast cancer. Also, linkage with the nationwide network and registry of histopathology and cytopathology in The Netherlands (PALGA) allows us to retrieve tumour samples to study tumourigenesis.

Cancer risks for other sites in addition to breast in CHEK2 c.1100delC families.

PURPOSE: Female CHEK2 c.1100delC heterozygotes are eligible for additional breast surveillance because of an increased breast cancer risk. Increased risks for other cancers have been reported. We studied whether CHEK2 c.1100delC is associated with an increased risk for other cancers within these families. METHODS: Including 10,780 individuals from 609 families, we calculated standardized incidence rates (SIRs) and absolute excess risk (AER, per 10,000 person-years) by comparing first-reported cancer derived from the pedigrees with general Dutch population rates from 1970 onward. Attained-age analyses were performed for sites in which significant increased risks were found. Considering the study design, we primarily focused on cancer risk in women. RESULTS: We found significant increased risks of colorectal cancer (CRC; SIR = 1.43, 95% CI = 1.14-1.76; AER = 1.43) and hematological cancers (SIR = 1.32; 95% CI = 1.02-1.67; AER = 0.87). CRC was significantly more frequent from age 45 onward. CONCLUSION: A significantly increased risk of CRC, and hematological cancers in women was found, starting at a younger age than expected. Currently, colorectal surveillance starts at age 45 in high-risk individuals. Our results suggest that some CHEK2 c.1100delC families might benefit from this surveillance as well; however, further research is needed to determine who may profit from this additional colorectal surveillance.

The benefit of adding polygenic risk scores, lifestyle factors, and breast density to family history and genetic status for breast cancer risk and surveillance classification of unaffected women from germline CHEK2 c.1100delC families.

To determine the changes in surveillance category by adding a polygenic risk score based on 311 breast cancer (BC)-associated variants (PRS311), questionnaire-based risk factors and breast density on personalized BC risk in unaffected women from Dutch CHEK2 c.1100delC families. In total, 117 unaffected women (58 heterozygotes and 59 non-carriers) from CHEK2 families were included. Blood-derived DNA samples were genotyped with the GSAMDv3-array to determine PRS311. Lifetime BC risk was calculated in CanRisk, which uses data from the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). Women, were categorized into three surveillance groups. The surveillance advice was reclassified in 37.9 % of heterozygotes and 32.2 % of non-carriers after adding PRS311. Including questionnaire-based risk factors resulted in an additional change in 20.0 % of heterozygotes and 13.2 % of non-carriers; and a subanalysis showed that adding breast density on top shifted another 17.9 % of heterozygotes and 33.3 % of non-carriers. Overall, the majority of heterozygotes were reclassified to a less intensive surveillance, while non-carriers would require intensified surveillance. The addition of PRS311, questionnaire-based risk factors and breast density to family history resulted in a more personalized BC surveillance advice in CHEK2-families, which may lead to more efficient use of surveillance.

Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.

BACKGROUND: Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. AIM: To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. METHODS: Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. RESULTS: There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)]. CONCLUSION: Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Breast cancer genomes from CHEK2 c.1100delC mutation carriers lack somatic TP53 mutations and display a unique structural variant size distribution profile.

BACKGROUND: CHEK2 c.1100delC was the first moderate-risk breast cancer (BC) susceptibility allele discovered. Despite several genomic, transcriptomic and functional studies, however, it is still unclear how exactly CHEK2 c.1100delC promotes tumorigenesis. Since the mutational landscape of a tumor reflects the processes that have operated on its development, the aim of this study was to uncover the somatic genomic landscape of CHEK2-associated BC. METHODS: We sequenced primary BC (pBC) and normal genomes of 20 CHEK2 c.1100delC mutation carriers as well as their pBC transcriptomes. Including pre-existing cohorts, we exhaustively compared CHEK2 pBC genomes to those from BRCA1/2 mutation carriers, those that displayed homologous recombination deficiency (HRD) and ER- and ER+ pBCs, totaling to 574 pBC genomes. Findings were validated in 517 metastatic BC genomes subdivided into the same subgroups. Transcriptome data from 168 ER+ pBCs were used to derive a TP53-mutant gene expression signature and perform cluster analysis with CHEK2 BC transcriptomes. Finally, clinical outcome of CHEK2 c.1100delC carriers was compared with BC patients displaying somatic TP53 mutations in two well-described retrospective cohorts totaling to 942 independent pBC cases. RESULTS: BC genomes from CHEK2 mutation carriers were most similar to ER+ BC genomes and least similar to those of BRCA1/2 mutation carriers in terms of tumor mutational burden as well as mutational signatures. Moreover, CHEK2 BC genomes did not show any evidence of HRD. Somatic TP53 mutation frequency and the size distribution of structural variants (SVs), however, were different compared to ER+ BC. Interestingly, BC genomes with bi-allelic CHEK2 inactivation lacked somatic TP53 mutations and transcriptomic analysis indicated a shared biology with TP53 mutant BC. Moreover, CHEK2 BC genomes had an increased frequency of > 1 Mb deletions, inversions and tandem duplications with peaks at specific sizes. The high chromothripsis frequency among CHEK2 BC genomes appeared, however, not associated with this unique SV size distribution profile. CONCLUSIONS: CHEK2 BC genomes are most similar to ER+ BC genomes, but display unique features that may further unravel CHEK2-driven tumorigenesis. Increased insight into this mechanism could explain the shorter survival of CHEK2 mutation carriers that is likely driven by intrinsic tumor aggressiveness rather than endocrine resistance.

Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.

Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09-1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words).

Moderators of the effect of psychosocial interventions on fatigue in women with breast cancer and men with prostate cancer: Individual patient data meta-analyses.

OBJECTIVE: Psychosocial interventions can reduce cancer-related fatigue effectively. However, it is still unclear if intervention effects differ across subgroups of patients. These meta-analyses aimed at evaluating moderator effects of (a) sociodemographic characteristics, (b) clinical characteristics, (c) baseline levels of fatigue and other symptoms, and (d) intervention-related characteristics on the effect of psychosocial interventions on cancer-related fatigue in patients with non-metastatic breast and prostate cancer. METHODS: Data were retrieved from the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) consortium. Potential moderators were studied with meta-analyses of pooled individual patient data from 14 randomized controlled trials through linear mixed-effects models with interaction tests. The analyses were conducted separately in patients with breast (n = 1091) and prostate cancer (n = 1008). RESULTS: Statistically significant, small overall effects of psychosocial interventions on fatigue were found (breast cancer: ß = -0.19 [95% confidence interval (95%CI) = -0.30; -0.08]; prostate cancer: ß = -0.11 [95%CI = -0.21; -0.00]). In both patient groups, intervention effects did not differ significantly by sociodemographic or clinical characteristics, nor by baseline levels of fatigue or pain. For intervention-related moderators (only tested among women with breast cancer), statistically significant larger effects were found for cognitive behavioral therapy as intervention strategy (ß = -0.27 [95%CI = -0.40; -0.15]), fatigue-specific interventions (ß = -0.48 [95%CI = -0.79; -0.18]), and interventions that only targeted patients with clinically relevant fatigue (ß = -0.85 [95%CI = -1.40; -0.30]). CONCLUSIONS: Our findings did not provide evidence that any selected demographic or clinical characteristic, or baseline levels of fatigue or pain, moderated effects of psychosocial interventions on fatigue. A specific focus on decreasing fatigue seems beneficial for patients with breast cancer with clinically relevant fatigue.

Correction to: Behavioural changes, sharing behaviour and psychological responses after receiving direct-to-consumer genetic test results:a systematic review and meta-analysis.

The published online version contains mistake in the Abstract section. The percentages for 'any positive lifestyle change' and 'improved dietary practices' have unintentionally been incorrectly reported.

Behavioural changes, sharing behaviour and psychological responses after receiving direct-to-consumer genetic test results: a systematic review and meta-analysis.

It has been hypothesised that direct-to-consumer genetic tests (DTC-GTs) could stimulate health behaviour change. However, genetic testing may also lead to anxiety and distress or unnecessarily burden the health care system. The aim is to review and meta-analyse the effects of DTC-GT on (1) behaviour change, (2) psychological response and (3) medical consumption. A systematic literature search was performed in three databases, using "direct-to-consumer genetic testing" as a key search term. Random effects meta-analyses were performed when at least two comparable outcomes were available. After selection, 19 articles were included involving 11 unique studies. Seven studies involved actual consumers who paid the retail price, whereas four included participants who received free genetic testing as part of a research trial (non-actual consumers). In meta-analysis, 23% had a positive lifestyle change. More specifically, improved dietary and exercise practices were both reported by 12%, whereas 19% quit smoking. Seven percent of participants had subsequent preventive checks. Thirty-three percent shared their results with any health care professional and 50% with family and/or friends. Sub-analyses show that behaviour change was more prevalent among non-actual consumers, whereas sharing was more prevalent among actual consumers. Results on psychological responses showed that anxiety, distress and worry were low or absent and that the effect faded with time. DTC-GT has potential to be effective as a health intervention, but the right audience needs to be addressed with tailored follow-up. Research is needed to identify consumers who do and do not change behaviour or experience adverse psychological responses.