Opinions and experiences of recontacting patients: a survey of Australasian genetic health professionals.

The issue of recontacting past genetics patients is increasingly relevant, particularly with the introduction of next-generation sequencing. Improved testing can provide additional information on the pathogenicity and prevalence of genetic variants, often leading to a need to recontact patients. Some international genetics societies have position statements and recommendations to guide genetic health professionals (GHPs) navigating the legal, ethical and practical issues of recontacting. In the absence of a standardised Australasian protocol, we explored the experiences and opinions of Australasian GHPs regarding patient follow-up and recontacting practices. Forty-five respondents completed an online survey. Most respondents indicated that recontacting occurred on an ad hoc basis, but most genetic services relied on patients (or family) initiating recontact. Implementation of a routine recontacting system was widely dismissed by 73% of respondents, citing lack of resources, limited information on legal responsibility and setting unrealistic expectations as common barriers. If recontact was contemplated, e-communication was an acceptable first step. This study identified the need for integrated familial cancer registries to assist under-resourced genetic services to maintain up-to-date patient records. Developing a standard recontacting protocol with flexibility to account for patient individuality and circumstances might enable provision of equitable service within Australasia.

Lynch syndrome associated endometrial carcinomas in Western Australia: an analysis of universal screening by mismatch repair protein immunohistochemistry.

BACKGROUND: In 2016 universal screening with mismatch repair protein immunohistochemistry in all newly diagnosed endometrial carcinomas was introduced in Western Australia. OBJECTIVE: To compare the prevalence of Lynch syndrome associated endometrial carcinomas between 2016 and 2019 with a historical control (2015). Additionally, to compare the number of cases appropriately referred for genetic assessment. METHODS: A cross-sectional study of cases presented at the Western Australia gynecologic oncology tumor board was carried out. The primary outcome was the prevalence of Lynch syndrome associated endometrial carcinomas. A secondary outcome was the number of cases appropriately referred for genetic assessment. The following variables were extracted: date of birth; age at diagnosis; vital status; tumor mismatch repair protein expression status (retained or lost) and if lost, the specific mismatch repair protein deficiency; patients who were referred to a genetic clinic; and family history, if recorded. Data were collected from the clinical databases of the Familial Cancer Program at Genetic Services of Western Australia and WOMEN Center, to determine whether patients were appropriately referred for genetic evaluation and to ascertain the results of genetic testing. RESULTS: Between 2016 and 2019, there were 1040 new endometrial carcinomas. Tumors of 883 (85%) patients underwent mismatch repair protein immunohistochemistry compared with 117 of 199 patients (59%) in 2015 (χ2 73.14, p<0.001). Of 883 tumors tested, 242 (27%) showed loss of mismatch repair protein expression. In 2015, 30 (26%) tumors of 117 tested showed loss of mismatch repair protein expression. During the 4 years of universal screening, 13 (1.5%) of 883 patients screened were diagnosed with Lynch syndrome compared with 2 (1.7%) of 117 in 2015 (Fisher's exact test 0.04, p=0.69). In 2015, 11 (37%) of 30 patients with loss of mismatch repair protein expression were not referred for genetic assessment compared with 36 (17%) of 209 patients in the universal screening group (χ2 6.28, p=0.02). No cases of Lynch syndrome were diagnosed in patients aged over 70 years. CONCLUSIONS: Universal immunohistochemical screening did not increase the proportion of Lynch syndrome associated endometrial carcinomas identified, although the study was underpowered to detect small differences. There was an improvement in appropriate referrals for genetic assessment.

Incidence of germline BRCA1/2 mutations in women with tubo-ovarian high-grade serous carcinomas with and without serous tubal intra-epithelial carcinomas.

OBJECTIVE: To compare the germline BRCA1 and BRCA2 mutation (gBRCA) status in women with high-grade serous tubo-ovarian and primary peritoneal carcinoma with and without serous tubal intra-epithelial carcinomas (serous tubal intra-epithelial carcinoma-positive vs serous tubal intra-epithelial carcinoma-negative). MATERIALS AND METHODS: A retrospective study was performed of patients in Western Australia diagnosed with high-grade serous tubo-ovarian and primary peritoneal carcinoma and referred for genetic counseling and gBRCA testing from July 1, 2014 to June 30, 2017. Histopathology reports were reviewed to ascertain whether serous tubal intra-epithelial carcinoma was present. Personal or family gBRCA status, family history, age at diagnosis, mode of treatment (neoadjuvant chemotherapy vs primary surgery), and stage were also recorded. RESULTS: A total of 269 women with high-grade serous tubo-ovarian and primary peritoneal carcinoma were referred for genetic counseling and testing. 114 patients were excluded because the serous tubal intra-epithelial carcinoma status was not assessable or because patients did not attend for genetic assessment. 155 patients (55 serous tubal intra-epithelial carcinoma-positive and 100 serous tubal intra-epithelial carcinoma-negative) underwent genetic testing. gBRCA mutations were found in 27.8% of serous tubal intra-epithelial carcinoma-positive patients compared with 14.0% of serous tubal intra-epithelial carcinoma-negative patients (p=0.094). Of those found to have a gBRCA mutation, 89.7% reported a positive personal or family history of BRCA-related cancers. CONCLUSIONS: The gBRCA mutation detection rate in serous tubal intra-epithelial carcinoma-positive patients was nearly double that of serous tubal intra-epithelial carcinoma-negative patients. Factors such as a positive family history of BRCA-related cancers were seen at a higher proportion in the mutation positive women.

Enabling Global Clinical Collaborations on Identifiable Patient Data: The Minerva Initiative.

The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies. This includes the application of cutting-edge machine learning methods to image data. As with most digital tools employed in health care, there are ethical and data governance challenges associated with using identifiable personal image data. There are also risks with failing to deliver on the patient benefits of these new technologies, the biggest of which is posed by data siloing. The Minerva Initiative has been designed to enable the public good of deep phenotyping while mitigating these ethical risks. Its open structure, enabling collaboration and data sharing between individuals, clinicians, researchers and private enterprise, is key for delivering precision public health.

Uptake of testing for germline BRCA mutations in patients with non-mucinous epithelial ovarian cancers in Western Australia: a comparison of different genetic counseling methods.

INTRODUCTION: Patients with non-mucinous epithelial tubo-ovarian cancers should be referred for genetic testing because approximately 15% will carry an inherited mutation in the BRCA1 or BRCA2 cancer susceptibility genes. However, referral rates for genetic testing remain low. For patients who carry a BRCA mutation, failure to refer for genetic testing results in missed opportunities for therapy and prevention of future cancers in the patient and at-risk relatives. In Western Australia between July 2013 and June 2015, 40.6% of patients with non-mucinous epithelial tubo-ovarian cancers discussed at a statewide gynecologic oncology tumor board were referred for genetic testing. Our objective was to investigate the proportion of patients with non-mucinous epithelial tubo-ovarian cancers in Western Australia referred for BRCA1/2 testing from July 2015 to December 2017, following the introduction of mainstreaming and tele-counseling. A secondary aim was to compare the uptake of genetic testing between different genetic counseling modalities. METHODS: Retrospective case series. All patients with high-grade non-mucinous epithelial tubo-ovarian cancers discussed at the weekly Western Australian gynecologic oncology tumor board meeting, between July 1, 2015 and December 31, 2017, and those referred for BRCA mutation testing, were ascertained. RESULTS: A total of 343 women were eligible for referral; 63 patients were excluded, leaving 280 patients for analysis. 220/280 patients were referred for genetic testing (78.6%). There were no differences in uptake of genetic testing by mode of genetic counseling. DISCUSSION: A significant increase in referrals of eligible patients for genetic testing was observed in 2015-2017 compared with 2013-2014. Although there were no differences in uptake of genetic testing by mode of counseling, mainstreaming and tele-counseling provide alternative options for patients that may lead to higher uptake of genetic testing.

Investigating barriers to genetic counseling and germline mutation testing in women with suspected hereditary breast and ovarian cancer syndrome and Lynch syndrome.

OBJECTIVE: The aim of the current study was to explore barriers to genetic counseling and testing in women with gynecological cancers deemed at significant risk of carrying a germline mutation. METHODS: A qualitative study using semi-structured interviews and inductively analysed thematically. Eight patients with ovarian or endometrial cancer participated in individual semi-structured telephone interviews that assessed motivation for genetic counseling and testing, perceived benefits and barriers, timing of the approach, perceptions of the referral process to genetic services and locus of control in relation to cancer and health. RESULTS: Analysis of the interview transcripts revealed five themes relating to perceptions of genetic counseling and testing: Lack of importance; Level of information received; Timing of referral processes; Fear and anxiety; Resistance to and perceptions of counseling. CONCLUSIONS: Participants had a limited understanding of hereditary cancer syndromes and did not appreciate the benefits of genetic testing. A consistent approach at the time of referral to genetic services is needed to ensure that the level and format of information is appropriate for patients. PRACTICE IMPLICATIONS: The rationale for genetic testing needs to be better explained to patients and the timing of referral should be based both on treatment priorities and patient preferences.

Improved Diagnosis and Care for Rare Diseases through Implementation of Precision Public Health Framework.

Public health relies on technologies to produce and analyse data, as well as effectively develop and implement policies and practices. An example is the public health practice of epidemiology, which relies on computational technology to monitor the health status of populations, identify disadvantaged or at risk population groups and thereby inform health policy and priority setting. Critical to achieving health improvements for the underserved population of people living with rare diseases is early diagnosis and best care. In the rare diseases field, the vast majority of diseases are caused by destructive but previously difficult to identify protein-coding gene mutations. The reduction in cost of genetic testing and advances in the clinical use of genome sequencing, data science and imaging are converging to provide more precise understandings of the 'person-time-place' triad. That is: who is affected (people); when the disease is occurring (time); and where the disease is occurring (place). Consequently we are witnessing a paradigm shift in public health policy and practice towards 'precision public health'.Patient and stakeholder engagement has informed the need for a national public health policy framework for rare diseases. The engagement approach in different countries has produced highly comparable outcomes and objectives. Knowledge and experience sharing across the international rare diseases networks and partnerships has informed the development of the Western Australian Rare Diseases Strategic Framework 2015-2018 (RD Framework) and Australian government health briefings on the need for a National plan.The RD Framework is guiding the translation of genomic and other technologies into the Western Australian health system, leading to greater precision in diagnostic pathways and care, and is an example of how a precision public health framework can improve health outcomes for the rare diseases population.Five vignettes are used to illustrate how policy decisions provide the scaffolding for translation of new genomics knowledge, and catalyze transformative change in delivery of clinical services. The vignettes presented here are from an Australian perspective and are not intended to be comprehensive, but rather to provide insights into how a new and emerging 'precision public health' paradigm can improve the experiences of patients living with rare diseases, their caregivers and families.The conclusion is that genomic public health is informed by the individual and family needs, and the population health imperatives of an early and accurate diagnosis; which is the portal to best practice care. Knowledge sharing is critical for public health policy development and improving the lives of people living with rare diseases.

Initiating an undiagnosed diseases program in the Western Australian public health system.

BACKGROUND: New approaches are required to address the needs of complex undiagnosed diseases patients. These approaches include clinical genomic diagnostic pipelines, utilizing intra- and multi-disciplinary platforms, as well as specialty-specific genomic clinics. Both are advancing diagnostic rates. However, complementary cross-disciplinary approaches are also critical to address those patients with multisystem disorders who traverse the bounds of multiple specialties and remain undiagnosed despite existing intra-specialty and genomic-focused approaches. The diagnostic possibilities of undiagnosed diseases include genetic and non-genetic conditions. The focus on genetic diseases addresses some of these disorders, however a cross-disciplinary approach is needed that also simultaneously addresses other disorder types. Herein, we describe the initiation and summary outcomes of a public health system approach for complex undiagnosed patients - the Undiagnosed Diseases Program-Western Australia (UDP-WA). RESULTS: Briefly the UDP-WA is: i) one of a complementary suite of approaches that is being delivered within health service, and with community engagement, to address the needs of those with severe undiagnosed diseases; ii) delivered within a public health system to support equitable access to health care, including for those from remote and regional areas; iii) providing diagnoses and improved patient care; iv) delivering a platform for in-service and real time genomic and phenomic education for clinicians that traverses a diverse range of specialties; v) retaining and recapturing clinical expertise; vi) supporting the education of junior and more senior medical staff; vii) designed to integrate with clinical translational research; and viii) is supporting greater connectedness for patients, families and medical staff. CONCLUSION: The UDP-WA has been initiated in the public health system to complement existing clinical genomic approaches; it has been targeted to those with a specific diagnostic need, and initiated by redirecting existing clinical and financial resources. The UDP-WA supports the provision of equitable and sustainable diagnostics and simultaneously supports capacity building in clinical care and translational research, for those with undiagnosed, typically rare, conditions.

3-Dimensional Facial Analysis-Facing Precision Public Health.

Precision public health is a new field driven by technological advances that enable more precise descriptions and analyses of individuals and population groups, with a view to improving the overall health of populations. This promises to lead to more precise clinical and public health practices, across the continuum of prevention, screening, diagnosis, and treatment. A phenotype is the set of observable characteristics of an individual resulting from the interaction of a genotype with the environment. Precision (deep) phenotyping applies innovative technologies to exhaustively and more precisely examine the discrete components of a phenotype and goes beyond the information usually included in medical charts. This form of phenotyping is a critical component of more precise diagnostic capability and 3-dimensional facial analysis (3DFA) is a key technological enabler in this domain. In this paper, we examine the potential of 3DFA as a public health tool, by viewing it against the 10 essential public health services of the "public health wheel," developed by the US Centers for Disease Control. This provides an illustrative framework to gage current and emergent applications of genomic technologies for implementing precision public health.

A Retrospective Exploration of the Impact of the 'Angelina Jolie Effect' on the Single State-Wide Familial Cancer Program in Perth, Western Australia.

Global media has the power to influence the ways the public engage with health services. On May 14th 2013, Angelina Jolie published an article in the New York Times magazine, outlining her decision to undergo BRCA mutation testing due to a family history of cancer; then proceed with a mastectomy. The article evoked significant interest from the media and the public. During the months that followed, the Familial Cancer Program (FCP) at Genetic Services of Western Australia (GSWA) experienced a significant increase in referrals and enquiries. Resources were overstretched and it became clear we needed to adjust work practices to manage the escalating numbers. New strategies were devised to cope with the influx of enquiries, albeit without the benefit of additional resources. We conducted an audit of referrals to the FCP made between January 2012 and December 2014. This included a comparison of the months prior to and following the New York Times article. The aim of the audit was to quantify the impact of the "Angelina Jolie effect" on referrals to the FCP. Whilst the increased awareness of the role of genetic services in risk assessment and testing for familial breast and ovarian cancer was considered positive, pre-referral risk assessment at the primary health level to evaluate the appropriateness of their patients for referral could have been helpful. Potentially, many inappropriate referrals to FCP may have been avoided with primary health evaluation thus lessening the burden on our service and preventing unnecessary worry in well women who possessed minimal family history or risk factors. It is important to understand the factors driving the uptake of risk reduction activities, particularly if engagement with a genetics service is considered part of that pathway. Continued education about cancer risk due to family history, individual features and awareness surrounding genetic testing criteria, costs and availability is required for both the public and health professionals.

The rare and undiagnosed diseases diagnostic service - application of massively parallel sequencing in a state-wide clinical service.

BACKGROUND: The Rare and Undiagnosed Diseases Diagnostic Service (RUDDS) refers to a genomic diagnostic platform operating within the Western Australian Government clinical services delivered through Genetic Services of Western Australia (GSWA). GSWA has provided a state-wide service for clinical genetic care for 28 years and it serves a population of 2.5 million people across a geographical area of 2.5milion Km(2). Within this context, GSWA has established a clinically integrated genomic diagnostic platform in partnership with other public health system managers and service providers, including but not limited to the Office of Population Health Genomics, Diagnostic Genomics (PathWest Laboratories) and with executive level support from the Department of Health. Herein we describe report presents the components of this service that are most relevant to the heterogeneity of paediatric clinical genetic care. RESULTS: Briefly the platform : i) offers multiple options including non-genetic testing; monogenic and genomic (targeted in silico filtered and whole exome) analysis; and matchmaking; ii) is delivered in a patient-centric manner that is resonant with the patient journey, it has multiple points for entry, exit and re-entry to allow people access to information they can use, when they want to receive it; iii) is synchronous with precision phenotyping methods; iv) captures new knowledge, including multiple expert review; v) is integrated with current translational genomic research activities and best practice; and vi) is designed for flexibility for interactive generation of, and integration with, clinical research for diagnostics, community engagement, policy and models of care. CONCLUSION: The RUDDS has been established as part of routine clinical genetic services and is thus sustainable, equitably managed and seeks to translate new knowledge into efficient diagnostics and improved health for the whole community.

Impact of Clinical Genetics Attendance at a Gynecologic Oncology Tumor Board on Referrals for Genetic Counseling and BRCA Mutation Testing.

OBJECTIVES: The objectives of this work were to determine the proportion of eligible patients with ovarian cancer discussed at a gynecologic oncology tumor board who were referred for counseling and BRCA mutation testing; to compare referral rates before genetics attendance at the tumor board to referral rates after genetics attendance; and to ascertain the proportions of women with germline BRCA mutations. MATERIALS AND METHODS: Eligible cases were identified from the minutes of the weekly Western Australian gynecologic oncology tumor board from July 1, 2013 to June 30, 2015.Patients with ovarian cancer who met eligibility criteria for genetics referral were identified and checked against the records of the genetic services database to ascertain whether a referral was received. Outcomes including attendance for counseling and results of mutation testing were analyzed. RESULTS: Two hundred sixty-one patients were eligible for referral during the 24-month study period. One hundred six patients (40.6%) were referred for counseling and germline mutation testing. Of the eligible patients, 26.7% were referred in the 12 months before genetics attendance at the tumor board compared to 51.7% of the eligible patients in the 12 months after genetics attendance (P ≤ 0.0001). Ninety-seven patients were offered BRCA mutation testing, and 73 underwent testing with 65 results reported to date. Twenty-two patients (33.8 %) tested positive for a germline BRCA mutation. CONCLUSIONS: Patients with ovarian cancer had a high rate of BRCA mutations. Attendance of a genetics service at a tumor board was associated with an improved rate of referral of patients for genetic counseling and BRCA mutation testing.

A germline MTOR mutation in Aboriginal Australian siblings with intellectual disability, dysmorphism, macrocephaly, and small thoraces.

We report on three Aboriginal Australian siblings with a unique phenotype which overlaps with known megalencephaly syndromes and RASopathies, including Costello syndrome. A gain-of-function mutation in MTOR was identified and represents the first reported human condition due to a germline, familial MTOR mutation. We describe the findings in this family to highlight that (i) the path to determination of pathogenicity was confounded by the lack of genomic reference data for Australian Aboriginals and that (ii) the disease biology, functional analyses in this family, and studies on the tuberous sclerosis complex support consideration of an mTOR inhibitor as a therapeutic agent.

Population-based screening for Lynch syndrome in Western Australia.

We showed earlier that routine screening for microsatellite instability (MSI) and loss of mismatch repair (MMR) protein expression in colorectal cancer (CRC) led to the identification of previously unrecognized cases of Lynch syndrome (LS). We report here the results of screening for LS in Western Australia (WA) during 1994-2012. Immunohistochemistry (IHC) for loss of MMR protein expression was performed in routine pathology laboratories, while MSI was detected in a reference molecular pathology laboratory. Information on germline mutations in MMR genes was obtained from the state's single familial cancer registry. Prior to the introduction of routine laboratory-based screening, an average of 2-3 cases of LS were diagnosed each year amongst WA CRC patients. Following the implementation of IHC and/or MSI screening for all younger (<60 years) CRC patients, this has increased to an average of 8 LS cases diagnosed annually. Based on our experience in WA, we propose three key elements for successful population-based screening of LS. First, for all younger CRC patients, reflex IHC testing should be carried out in accredited pathology services with ongoing quality control. Second, a state- or region-wide reference laboratory for MSI testing should be established to confirm abnormal or suspicious IHC test results and to exclude sporadic cases by carrying out BRAF mutation or MLH1 methylation testing. Finally, a state or regional LS coordinator is essential to ensure that all appropriate cases identified by laboratory testing are referred to and attend a Familial Cancer Clinic for follow-up and germline testing.

A state-wide population-based program for detection of lynch syndrome based upon immunohistochemical and molecular testing of colorectal tumours.

We have previously established in a large retrospective study that testing for microsatellite instability (MSI) in colorectal cancer (CRC) from patients aged <60 years was an effective first screen to identify individuals with Lynch syndrome (LS). From these findings, MSI and/or immunohistochemical (IHC) screening was recommended for all newly diagnosed CRC patients aged <60 years in Western Australia, regardless of family history of cancer. In the current study we evaluated the utility of routine MSI/IHC screening by diagnostic pathology laboratories for the detection of previously undiagnosed individuals and families with LS. From January 2009 to December 2010, 270 tumours were tested for MSI and for expression of MLH1, PMS2, MSH2 and MSH6 using IHC. Cases showing MSI and/or loss of expression were also tested for the BRAF V600E hotspot mutation. Seventy cases were found to have MSI, of which 25 were excluded from further investigation as possible LS cases due to presence of the BRAF V600E mutation. The remaining 45 "red flag" cases were eligible for germline testing based on their MSI, IHC and BRAF status. From 31 cases tested to date, 15 germline mutations have been found. Thirteen were from individuals not previously recognized as LS and two were untested members from known LS families. Extrapolation of the mutation incidence (15/31, 48%) to all red flag cases (n = 45) suggests that approximately 22 mutation carriers exist in this cohort. This value approximates the number of CRC cases due to LS that could be expected to arise in the Western Australian population over a two-year period (n = 24), assuming that 1% of all CRCs are due to LS. Although further improvements in workflow can be made, our preliminary findings following the implementation of state-wide routine MSI and IHC testing in Western Australia indicate that the majority of LS cases are being identified.

Challenges in the diagnosis and management of Lynch Syndrome in an Indigenous family living in a remote West Australian community.

CONTEXT: Lynch syndrome (LS), also referred to as hereditary non-polyposis colorectal cancer, is a familial cancer syndrome characterised by young age of onset of colorectal and other extra-colonic cancers. Most studies suggest that LS accounts for approximately 1% of all colorectal cancers (CRC). The identification of persons with a mutation for this syndrome is of major clinical importance because regular and life-long surveillance has been shown to improve their survival through early cancer detection. However, the identification of LS among CRC patients is a major challenge because there are no specific distinguishing clinical features. Clinical criteria based on family history of cancer and age of cancer diagnosis have been proposed. For various reasons, these are not well utilised and clinicians often fail to refer high-risk CRC patients for genetic assessment of LS. The low rate of referrals to the single, state-wide familial cancer program in Western Australia led to calls for a more sensitive and specific means of detecting LS cases. Virtually all tumours from LS patients are characterised by the molecular features of microsatellite instability (MSI) and loss of expression of mismatch repair proteins detected by immunohistochemistry (IHC). It was recently established that routine MSI and IHC testing in CRC patients aged under 60 years was an effective screening tool to identify previously unrecognized LS cases. This approach has now become routine practice in Western Australia and has led to the identification of more than 20 new LS families, including the Indigenous family described in this report. ISSUES: Population-based screening programs can identify individuals who may not be aware of their at-risk status, who may have little prior knowledge of their medical condition and who may have limited access to tertiary health services. This report describes some challenges met when following up a positive screening result for LS in an individual residing in a remote community more than 2000 km from the state's only Family Cancer Clinic. The challenges included finding the patient, arranging genetic counselling and testing, informing him of the result and providing advice regarding life-long surveillance. Also discussed are issues relating to management of the extended kindred in terms of cultural sensitivities, intra-familial communication and involvement of the local health providers, as well as the provision of genetic counselling, testing and surveillance services for patients living in remote regions. Prior to this study, there were no known Indigenous families with LS in Australia. LESSONS LEARNED: The likelihood of finding hereditary cancer syndromes in Indigenous families living in remote communities is low. However, advances in modern diagnostic screening technologies will result in the identification of an increased number of at-risk individuals, some of whom will be from minority groups or from remote communities. Despite geographical isolation and cultural differences, hereditary cancer syndromes can be managed in individuals and families living in rural and remote areas. The key issues identified from this case are flexibility with standard clinical genetic protocols and the presence of a local medical practitioner who takes an active interest in delivery of the genetic testing and surveillance strategies.

A child with an STK11 mutation and Sotos syndrome-like features: can STK11 mutations produce a Sotos syndrome phenocopy?

In accordance with interrelationships between tumour predisposition and somatic overgrowth, the authors present a boy with a familial serine threonine kinase 11 (STK11) mutation and Sotos syndrome-like features. The authors suggest that, analogous to phosphatase and tensin homolog mutations, STK11 mutations may predispose to somatic overgrowth. In a minority of instances, this may result in a Sotos syndrome phenocopy. If substantiated, this observation may yield insights into both the molecular causes of tumour predisposition and overgrowth syndromes.

Population-based detection of Lynch syndrome in young colorectal cancer patients using microsatellite instability as the initial test.

Approximately 1-2% of colorectal cancers (CRC) arise because of germline mutations in DNA mismatch repair genes, referred to as Lynch syndrome. These tumours show microsatellite instability (MSI) and loss of expression of mismatch repair proteins. Pre-symptomatic identification of mutation carriers has been demonstrated to improve survival; however, there is concern that many are not being identified using current practices. We evaluated population-based MSI screening of CRC in young patients as a means of ascertaining mutation carriers. CRC diagnosed in patients aged <60 years were identified from pathology records. No prior information was available on family history of cancer. PCR techniques were used to determine MSI in the BAT-26 mononucleotide repeat and mutation in the BRAF oncogene. Loss of MLH1, MSH2, MSH6 and PMS2 protein expression was evaluated in MSI+ tumours by immunohistochemistry. MSI+ tumours were found in 105/1,344 (7.8%) patients, of which 7 were excluded as possible Lynch syndrome because of BRAF mutation. Of the 98 "red flag" cases that were followed up, 25 were already known as mutation carriers or members of mutation carrier families. Germline test results were obtained for 35 patients and revealed that 22 showed no apparent mutation, 11 showed likely pathogenic mutations and 2 had unclassified variants. The proportion of MSI+ cases in different age groups that were estimated to be mutation carriers was 89% (<30 years), 83% (30-39), 68% (40-49) and 17% (50-59). We recommend MSI as the initial test for population-based screening of Lynch syndrome in younger CRC patients, regardless of family history.

Heterogeneous staining for mismatch repair proteins during population-based prescreening for hereditary nonpolyposis colorectal cancer.

The aim of this study was to determine the frequency of microsatellite instability (MSI(+)) in tumors from a population-based series of young colorectal cancer patients and its correlation with the loss of expression of mismatch repair (MMR) proteins. The BAT-26 mononucleotide repeat was used to screen for MSI(+) in all colorectal cancers diagnosed in Western Australia throughout a 5-year period in patients <60 years of age. MSI(+) was found in 75 of 1003 (7.5%) cases, of which six contained a concomitant mutation in BRAF and were therefore excluded from further investigations as possible hereditary nonpolyposis colorectal cancer. Immunohistochemistry was used to evaluate expression of the four major MMR proteins (MLH1, MSH2, MSH6, and PMS2) in the remaining 69 MSI(+) tumors. Complete loss of MLH1 and PMS2 expression or of MSH2 and MSH6 expression was found in 35 (51%) and 17 (25%) cases, respectively, whereas other patterns of complete loss were observed in eight cases (12%). Eight tumors (12%) were initially recorded as showing normal expression, but on review seven were reclassified as having abnormal staining because of heterogeneous patterns of MMR loss. Three of these seven cases had previously been found to have germline mutations. Because of possible misinterpretation of heterogeneous immunohistochemistry staining for MMR protein loss, MSI testing is recommended as the initial screen for population-based detection of hereditary nonpolyposis colorectal cancer.