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Purpose: In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer.Experimental Design: To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer, or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer-predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome.Results: Four patients carried causative mutations in a known cancer-predisposing gene: TP53 and DICER1 (n = 3). In another 4 patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy (EP300-based Rubinstein–Taybi syndrome, ARID1A-based Coffin–Siris syndrome, ACTB-based Baraitser–Winter syndrome, and EZH2-based Weaver syndrome). In addition, we identified two genes, KDM3B and TYK2, which are possibly involved in genetic cancer predisposition.Conclusions: In our selected cohort of patients, pathogenic germline mutations causative or likely causative of the cancer phenotype were found in 8 patients, and two possible novel cancer-predisposing genes were identified. Therewith, our study shows the added value of sequencing beyond a cancer gene panel in selected patients, to recognize childhood cancer predisposition. Clin Cancer Res; 24(7); 1594–603. ©2018 AACR.

Supplementary Table S1 - Cancer gene panel Supplementary Table S2 - Patients with multiple malignancies Supplementary Table S3 - Tumor types of index patients Supplementary Table S4 - Candidate genes Supplementary Table S5 - Overview of clinical features and mutations found in category 1 (ID and/or congenital anomalies) Supplementary Table S6 - Overview of clinical features and mutations found in category 2 (cancer twice) Supplementary Table S7 - Overview of clinical features and mutations found in category 3 (family history) Supplementary Table S8 - Overview of clinical features and mutations found in category 4 (adult type of cancer) Supplementary Table S9 - Overview of clinical features and mutations found in category 5 (multiple reasons for inclusion) Supplementary Figure S1 - Detection of mosaic mutation in ARID1A Supplementary Figure S2 - Family tree of case #04 Supplementary Figure S3 - Family tree of case #05 Supplementary Figure S4 - Family tree of case #07 Supplementary Figure S5 - Family tree of case #10 Supplementary Figure S6 - Family tree of case #12 Supplementary Figure S7 - Family tree of case #17 Supplementary Figure S8 - Family tree of case #21 Supplementary Figure S9 - Family tree of case #22 Supplementary Figure S10 - Family tree of case #24 Supplementary Figure S11 - Family tree of case #27 Supplementary Figure S12 - Family tree of case #28 Supplementary Figure S13 - Family tree of case #29 Supplementary Figure S14 - Family tree of case #34 Supplementary Figure S15 - Family tree of case #36 Supplementary Figure S16 - Family tree of case #39

This file contains all mutations identified in all patients.

Uptake of irrigation scheduling tools by New Zealand (NZ) farmers has remained static for many years and some researchers consider the use of linear, tech-transfer approaches as the main reason for this. To understand the controls and drivers that influence the uptake of these tools and to evaluate the effectiveness of a co-innovation approach in improving their (tools) uptake, a team of biophysical (hydrologists) and social researchers undertook a pilot study in an irrigation scheme in the South Island of NZ. Co-innovation offers a multi-directional, multi-level, multi-actor approach, in which input from stakeholders is valued in every part of the process, from problem definition to solution adoption. In this study, we focused on the adaptive aspect of co-innovation that allows stakeholders to periodically review their actions and respond to it in a way that is inclusive others’ views and reflective of feedback received. The pilot study activities were analysed retrospectively to develop a systemic view to the implementation of a co-innovation-based multi-stakeholder hydrology project. While implementing a co-innovation approach, five chronologically-distinct yet overlapping phases emerged in the project: 1. concept development, where the hydrologists came up with the research idea and seed concept; 2. trust building, where researchers (hydrologists and social) interacted with key on-farm stakeholders in developing and implementing the research idea into a pilot field study; 3. knowledge synthesis, where researchers collected on-farm biophysical and behavioural data to record practice change; 4. extended outreach, where stakeholders, including researchers, devised pathways to sustain the lessons learned and practices changed, and disseminated the learnings to the wider irrigation community; and 5. project legacy, where the researchers, after the development of the seed concept into a practice change, evolved an exit strategy. Apart from core research activities, such as data collection on irrigation water use and changes in irrigation scheduling practices, each one of the five phases included actions that were unique to that phase as well as to achieving the wider pilot study goal of improving water use efficiency. This paper discusses the learnings from these phases, including insights, and key identifiers and indicators of pilot study progression during each phase, which may serve as an example to other biophysical studies that propose to employ co-innovation-based multi stakeholder approach.

A pilot study, using a co-innovation approach in identify opportunities to improve irrigation management, is underway in five farms in an irrigation scheme in New Zealand. Through a process of co-learning, a group of on-farm and off-farm stakeholders defined the problem of on-farm water use efficiency and co-developed solutions to enhance farmers’ ability, desire and capacity to adopt improved irrigation practices. To enable informed decision-making, participants were supplied with current soil water demand (measured on farm) and 2- to 15-day rainfall forecasts as a daily email update. We conducted several one-on-one formal/informal meetings and annual workshops with stakeholders to evaluate the farmers’ ability in integrating the updates into their current irrigation practices. Selected key findings were (i) on-farm irrigation decisions are influenced by on-farm and off-farm hydrological, climatic, infrastructural and regulatory factors, thus we need to develop a wider view to irrigation management, (ii) for successful uptake, it is important to understand the external stimuli that directly and indirectly conflict or align with proposed practice changes, (iii) introduction of stakeholders with conflicting perspectives needs to be carefully managed, (iv) with co-learning, project objectives continuously evolve in response to ongoing monitoring, review and reflection on the processes, thus it is important to build flexibility into the implementation pathway and (v) when scaling out from five farms to the wider irrigation scheme, opportunities such as collective learning and reflection at end-user focused workshops may become more challenging owing to stakeholder numbers, thus other co-learning opportunities need to be identified.

Constitutional mismatch repair deficiency (CMMR-D) syndrome is characterised by a significantly increased risk for developing cancer in childhood. It arises when both parents have a mutation in the same mismatch repair gene and pass it on to their child.An 8-year-old girl was diagnosed with CMMR-D syndrome after she developed a brain tumour at the age of 4 and a T-cell non-Hodgkin lymphoma at the age of 6. She had multiple hyperpigmented skin lesions and died of myelodysplastic syndrome at the age of 11.In children with cancer CMMR-D syndrome can be recognized particularly if there are multiple primary malignancies and skin hyperpigmentations and hypopigmentations. The parents of these children are at high risk for colorectal and endometrial cancer (Lynch syndrome), amongst others.