As genomic profiling of constitutional and tumour-derived DNA becomes increasingly critical in ca... more As genomic profiling of constitutional and tumour-derived DNA becomes increasingly critical in cancer risk estimation, prognostication and treatment, there is a growing need for clinicians involved in cancer care to up-skill in Cancer Genetics. In the Republic of Ireland (ROI), this is particularly crucial, given a paucity of vocationally trained Clinical Geneticists per capita compared to other European countries. We aimed to assess the self-reported confidence of postgraduate medical/surgical trainees in ROI in requesting, interpreting, and managing genomic data in patients with cancer, and to assess their selfreported experience, and demand for future training in this area. A cross-sectional survey of postgraduate trainees in four specialties (Medical and Radiation Oncology, Surgery, and Obstetrics and Gynaecology (O&G)), training in ROI, was undertaken. A bespoke electronic questionnaire was designed to capture data regarding preceding experience, and confidence across several h...
Cancer in adolescents and young adults (AYAs) deserves special consideration for several reasons.... more Cancer in adolescents and young adults (AYAs) deserves special consideration for several reasons. AYA cancers encompass paediatric malignancies that present at an older age than expected, or early-onset of cancers that are typically observed in adults. However, disease diagnosed in the AYA population is distinct to those same cancers which are diagnosed in a paediatric or older adult setting. Worse disease-free and overall survival outcomes are observed in the AYA setting, and the incidence of AYA cancers is increasing. Knowledge of an individual’s underlying cancer predisposition can influence their clinical care and may facilitate early tumour surveillance strategies and cascade testing of at-risk relatives. This information can further influence reproductive decision making. In this review we discuss the risk factors contributing to AYA breast cancer, such as heritable predisposition, environmental, and lifestyle factors. We also describe a number of risk models which incorporate...
PTEN is a tumour suppressor gene involved in regulating cell division. Pathogenic germline varian... more PTEN is a tumour suppressor gene involved in regulating cell division. Pathogenic germline variants in PTEN predispose to benign and malignant growths of numerous organs, including of the breast. In the following report, we describe the first documented case of a fibroadenoma developing in ectopic breast tissue of the vulva in a patient with a germline pathogenic variant in PTEN. This highlights the risk of hyperplasia developing in any breast tissue, including rare ectopic sites, particularly in patients with underlying germline variants in cancer susceptibility genes.
Improving cancer survival rates globally requires improvements in disease detection and monitorin... more Improving cancer survival rates globally requires improvements in disease detection and monitoring, with the aim of improving early diagnosis and prediction of disease relapse. Traditional means of detecting and monitoring cancers rely largely on imaging and, where possible, blood-based protein biomarkers, many of which are non-specific. Treatments are being improved by identification of inherited and acquired genomic aberrations in tumors, some of which can be targeted by newly developed therapeutic interventions. Treatment of gynecological malignancy is progressively moving toward personalized therapy, as exemplified by application of PARP-inhibition for patients with BRCA-deficient tubo-ovarian cancers, or checkpoint inhibition in patients with mismatch repair-deficient disease. However, the more recent discovery of a group of biomarkers described under the umbrella term of “liquid biopsy” promises significant improvement in our ability to detect and monitor cancers. The term “li...
The recent publication of UK guidelines for the management of hereditary colorectal cancer1 immed... more The recent publication of UK guidelines for the management of hereditary colorectal cancer1 immediately preceded the COVID-19 pandemic. We commend the response by the British Society of Gastroenterology (BSG) relating to GI endoscopy activity amidst this pandemic.2 Such urgent measures are required to curtail the rate and breadth of coronavirus transmission throughout the country, and we are of the belief that the adherence to these guidelines during the early stages of this global pandemic was crucial in saving lives, and further guidance relating to the ‘recovery’ phase will be crucial in delivering diagnostic and cancer preventing endoscopic interventions. Though the emergency endoscopy COVID-19 guidance expressed clear and justified recommendations for the suspension of these services in non-urgent or routine screening populations, the management of patients deemed as being ‘high risk’ and subsequently prioritised for colonoscopy during this time is not currently well defined. For example, specific guidance for surveillance of individuals with conditions such as Lynch syndrome appeared vague in some statements …
Pathogenic variants in the BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancer. ... more Pathogenic variants in the BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancer. Individuals with identified pathogenic variants in the BRCA1 or BRCA2 gene can benefit from cancer risk‐reducing strategies. In the recent years, there has been an increase in the demand of genetic services. In light of the ongoing COVID19 pandemic, alternatives to face‐to‐face consultations have had to be considered and adopted, including telemedicine. Informed consent is necessary for genetic testing. Studies have suggested that increased levels of cancer‐specific distress may impair the patient's ability to retain information, therefore, providing informed consent. This systematic review and meta‐analysis aimed to answer if telephone genetic counseling for BRCA1 and BRCA2 genetic testing is non‐inferior to in‐person genetic counseling for the outcomes of cancer‐specific distress and genetic knowledge. Databases of Medline, Embase, PsycINFO, CINAHL, SciELO, Web of Science, CENTRAL, ProQuest Dissertation & Theses Database, Clinicaltrials.gov, EU clinical trials register were accessed to identify any published or unpublished relevant literature. Random‐effects models were used for the meta‐analysis. Four studies were included in the qualitative synthesis of the results. Three studies were included in the quantitative synthesis of the results. Telephone genetic counseling was non‐inferior compared to in‐person genetic counseling for the outcomes of cancer‐specific distress and genetic knowledge. Sensitivity analysis corroborated the main results. Telephone genetic counseling for BRCA1/BRCA2 genetic testing may be an alternative model of delivering genetic services in front of the increased demand/or when required by social context. However, the paucity of the evidence prevents from drawing strong conclusions regarding the generalizability of these results. Further research is needed to strengthen the conclusions.
Background: International best-practice guidelines recommend completion thyroidectomy and radioio... more Background: International best-practice guidelines recommend completion thyroidectomy and radioiodine remnant ablation (RRA) for patients with differentiated thyroid cancer (DTC) > 4 cm or with specific risk factors. Patients with DTC < 1 cm without risk factors are recommended for lobectomy alone. Indications for aggressive surgery and RRA are less clearly defined for tumours measuring 1-4 cm. A personalised approach to decision-making is recommended. Objectives: This study assesses therapeutic approaches to DTC as compared to the current British Thyroid Association (BTA) clinical practice guidelines. We ascertained the effect of equivocal guidance in the 1-4 cm tumour cohort on contemporary practice patterns. Methods: Data were obtained from a prospectively maintained thyroid cancer database of patients treated for DTC in a tertiary referral centre at the University Hospital Galway. Consecutive patients attending a dedicated thyroid cancer clinic between August 2014 and August 2017 were included. Clinicopathological characteristics and management strategies were assessed. Results: Ninety-four percent (n = 168/178) of patients were surgically managed in adherence with guidelines. A minority (n = 10) received surgery not aligned with guidelines. Ninety-seven percent (n = 172/178) of RRA treatment decisions were in accordance with guidelines. The BTA guidelines recommended a personalised decision-making approach for 18.0% (n = 32) and 44.9% (n = 80) of surgery and RRA treatment decisions, respectively. The more aggressive, treatment-driven approach was typically favoured by the multidisciplinary team, with 97% (n = 31/32) undergoing completion thyroidectomy and 100% (n = 80) proceeding to RRA. Conclusions: Management of DTC at our institution closely adheres to contemporary clinical practice guidelines. The finding of more aggressive management in those requiring a personalised decision-making approach highlights the requirement for improved risk stratification in this cohort to rationalise management strategies.
BackgroundInternational best-practice guidelines recommend completion thyroidectomy and radioiodi... more BackgroundInternational best-practice guidelines recommend completion thyroidectomy and radioiodine remnant ablation (RRA) for patients with differentiated thyroid cancer (DTC) > 4 cm or with specific risk factors. Patients with DTC < 1 cm without risk factors are recommended for lobectomy alone. Indications for aggressive surgery and RRA are less clearly defined for tumours measuring 1–4 cm. A personalised approach to decision-making is recommended.ObjectivesThis study assesses therapeutic approaches to DTC as compared to the current British Thyroid Association (BTA) clinical practice guidelines. We ascertained the effect of equivocal guidance in the 1–4 cm tumour cohort on contemporary practice patterns.MethodsData were obtained from a prospectively maintained thyroid cancer database of patients treated for DTC in a tertiary referral centre at the University Hospital Galway. Consecutive patients attending a dedicated thyroid cancer clinic between August 2014 and August 2017 were included. Clinicopathological characteristics and management strategies were assessed.ResultsNinety-four percent (n = 168/178) of patients were surgically managed in adherence with guidelines. A minority (n = 10) received surgery not aligned with guidelines. Ninety-seven percent (n = 172/178) of RRA treatment decisions were in accordance with guidelines. The BTA guidelines recommended a personalised decision-making approach for 18.0% (n = 32) and 44.9% (n = 80) of surgery and RRA treatment decisions, respectively. The more aggressive, treatment-driven approach was typically favoured by the multidisciplinary team, with 97% (n = 31/32) undergoing completion thyroidectomy and 100% (n = 80) proceeding to RRA.ConclusionsManagement of DTC at our institution closely adheres to contemporary clinical practice guidelines. The finding of more aggressive management in those requiring a personalised decision-making approach highlights the requirement for improved risk stratification in this cohort to rationalise management strategies.
Background Breast cancer is genetically heterogeneous, and parellel multi-gene sequencing is the ... more Background Breast cancer is genetically heterogeneous, and parellel multi-gene sequencing is the most cost- and time-efficient manner to investigate breast cancer predisposition. Numerous multi-gene panels (MGPs) are commercially available, but many include genes with weak/unproven associaton with breast cancer, or with predisposition to cancer of other types. This study investigates the utility of a custom-designed multi-gene panel in an Irish cohort with breast cancer. Methods A custom panel comprising 83 genes offered by 19 clinical “breast cancer predisposition” MGPs was designed and applied to germline DNA from 91 patients with breast cancer and 77 unaffected ethnicially matched controls. Variants were identified and classified using a custom pipeline. Results Nineteen loss-of-function (LOF) and 334 missense variants were identified. After removing common and/or benign variants, 15 LOF and 30 missense variants were analysed. Variants in known breast cancer susceptibility genes were identified, including in BRCA1 and ATM in cases, and in NF1 and CHEK2 in controls . Most variants identified were in genes associated with predisposition to cancers other than breast cancer ( BRIP1 , RAD50 , MUTYH , and mismatch repair genes), or in genes with unknown or unproven association with cancer. Conclusion Using multi-gene panels enables rapid, cost-effective identification of individuals with high-risk cancer predisposition syndromes. However, this approach also leads to an increased amount of uncertain results. Clinical management of individuals with particular genetic variants in the absence of a matching phenotype/family history is challenging. Further population and functional evidence is required to fully elucidate the clinical relevance of variants in genes of uncertain significance.
Red-automatically eligible for genetic referral 2. Yellowmay benefit from referral 3. Greendo not... more Red-automatically eligible for genetic referral 2. Yellowmay benefit from referral 3. Greendo not require referral Results There were 160 patients diagnosed in the period 01/ 01/2017-31/12/2017. Of these, 6 were excluded because of a pre-cancerous, rather than cancer, diagnosis: aplastic
BACKGROUND Molecular aberrations in cancer may represent therapeutic targets, and, if arising fro... more BACKGROUND Molecular aberrations in cancer may represent therapeutic targets, and, if arising from the germline, may impact further cancer risk management in patients and their blood relatives. Annually, 600-700 patients are referred for consideration of experimental drug trials in the Drug Development Unit (DDU) in our institution. A proportion of patients may merit germline genetic testing because of suspicious personal/family history or findings of tumour-based testing. We aimed to assess the impact of different multidisciplinary interventions on family history taking and referral rates from DDU to Cancer Genetics Unit (CGU). METHODS Over 42 months, three interventions were undertaken at different intervals: (1) embedding a genetics provider in the DDU review clinic, (2) 'traffic light' system flagging cancers with a heritable component and (3) virtual multidisciplinary meeting (MDM). Comparative analyses between intervals were undertaken, including referral rates to CGU, investigations and patient outcomes. Family history taking in a sample of 20 patients managed in each interval was assessed by a retrospective chart review. RESULTS Frequency of family history taking and referral to CGU, increased with each intervention, particularly, the virtual MDM (40% vs 85%). Referral rates increased over the study period, from 0.1 referral/week (5/year, 0.36% total referrals) to 1.2/week (projected 63/year, 3.81%). Forty-four (52%) patients referred required germline testing; in three of whom, variants were identified. Non-attendance rates were low (6, 7%). CONCLUSION Patients in the DDU are unique, with long cancer histories and often short estimated life expectancy. Multidisciplinary working between CGU and DDU facilitates germline testing of those patients who may otherwise miss the opportunity.
Genetics is the backbone of Neurology, where a number of disorders have a genetic aetiology and a... more Genetics is the backbone of Neurology, where a number of disorders have a genetic aetiology and are complex, requiring a dedicated Neurogenetics clinic. Genetics in the Republic of Ireland is under-resourced, with the lowest number of consultants per million of population in Europe. In November 2014, we established the monthly adult Neurogenetics clinic in Ireland, staffed by 2 consultants and 2 registrars from each speciality. We see patients with complex rare neurological conditions that may potentially have an underlying genetic basis, in the presence or absence of a family history. We performed a retrospective cohort analysis, reviewing symptoms and work-up data. Twenty-seven patients attended a pilot clinic over 12 months. Conditions encountered included Parkin-related PD, leucodystrophy, ataxia, fronto-temporal lobar degeneration, spinocerebellar ataxia type 6 (SCA6) and ataxia-telangiectasia. Identification of pathogenic mutations directed screening, treatment and facilitated onward genetic counselling (n = 10, 33%). A number of novel mutations were identified in MAPT gene (“missing tau mutation” McCarthy et al., Brain, 2015), SLCA1 gene and GRN (progranulin). Phenotypic features not previously reported were seen; e.g. writer’s cramp in SCA6; paroxysmal myoclonus in the glucose transporter protein type 1 (GLUT1) deficiency. Breast cancer screening for ATM mutations carriers and referral to international experts in two undiagnosed patients were arranged. The establishment of a Neurogenetics clinic has addressed a gap in service and allowed identification of rare and atypical diagnoses.
e12541 Abstract Background: The KRAS-variant is a functional, microRNA binding site variant that ... more e12541 Abstract Background: The KRAS-variant is a functional, microRNA binding site variant that predicts increased cancer risk as well as response to cancer therapies. Here we evaluate the impact of estrogen exposure on breast cancer (BC) cell transformation, as well as BC risk and tumor biology in women with the KRAS-variant. We further study the association of this variant with multiple primary breast cancer (MPBC). Methods: The impact of estrogen withdrawal on transformation in isogenic breast epithelial cell lines with or without the KRAS-variant was studied. Women with BC (n= 1712) and KRAS-variant unaffected controls (n= 80) were recruited, and hormonal exposures, KRAS-variant status, and pathology were compared. Presentation characteristics of MPBC were also studied. Results: Isogenic lines with the KRAS-variant had unique biology, and acute estrogen withdrawal led to oncogenic transformation. Consistent with our biologic findings, KRAS-variant BC patients were significantly more likely to have oo...
3571 Background: Lynch Syndrome (LS) accounts for 2-4% of all colorectal cancers (CRC) and is cau... more 3571 Background: Lynch Syndrome (LS) accounts for 2-4% of all colorectal cancers (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Increasing literature supports routine screening for LS using immunohistochemistry (IHC) to detect loss of MMR protein expression on tumour samples. We reviewed practices at 3 Irish cancer centres. The number of MMR deficient (dMMR) tumours detected was evaluated, and the subsequent number of genetic referrals and LS diagnoses determined. Methods: Colorectal databases at 3 Irish academic centres were reviewed from January 2005 - 2013. Centre 1 performs IHC upon physician request, centre 2 implemented reflex IHC (rIHC) in November 2008, and centre 3 has been performing rIHC since 2005. All new diagnoses of colorectal adenocarcinoma with available histology were included. Pathology reports were reviewed and genetic referrals analysed. Results: A total of 4,021 new CRC were diagnosed in 3,929 patients across 3 centres. The results are presented in the ...
As genomic profiling of constitutional and tumour-derived DNA becomes increasingly critical in ca... more As genomic profiling of constitutional and tumour-derived DNA becomes increasingly critical in cancer risk estimation, prognostication and treatment, there is a growing need for clinicians involved in cancer care to up-skill in Cancer Genetics. In the Republic of Ireland (ROI), this is particularly crucial, given a paucity of vocationally trained Clinical Geneticists per capita compared to other European countries. We aimed to assess the self-reported confidence of postgraduate medical/surgical trainees in ROI in requesting, interpreting, and managing genomic data in patients with cancer, and to assess their selfreported experience, and demand for future training in this area. A cross-sectional survey of postgraduate trainees in four specialties (Medical and Radiation Oncology, Surgery, and Obstetrics and Gynaecology (O&G)), training in ROI, was undertaken. A bespoke electronic questionnaire was designed to capture data regarding preceding experience, and confidence across several h...
Cancer in adolescents and young adults (AYAs) deserves special consideration for several reasons.... more Cancer in adolescents and young adults (AYAs) deserves special consideration for several reasons. AYA cancers encompass paediatric malignancies that present at an older age than expected, or early-onset of cancers that are typically observed in adults. However, disease diagnosed in the AYA population is distinct to those same cancers which are diagnosed in a paediatric or older adult setting. Worse disease-free and overall survival outcomes are observed in the AYA setting, and the incidence of AYA cancers is increasing. Knowledge of an individual’s underlying cancer predisposition can influence their clinical care and may facilitate early tumour surveillance strategies and cascade testing of at-risk relatives. This information can further influence reproductive decision making. In this review we discuss the risk factors contributing to AYA breast cancer, such as heritable predisposition, environmental, and lifestyle factors. We also describe a number of risk models which incorporate...
PTEN is a tumour suppressor gene involved in regulating cell division. Pathogenic germline varian... more PTEN is a tumour suppressor gene involved in regulating cell division. Pathogenic germline variants in PTEN predispose to benign and malignant growths of numerous organs, including of the breast. In the following report, we describe the first documented case of a fibroadenoma developing in ectopic breast tissue of the vulva in a patient with a germline pathogenic variant in PTEN. This highlights the risk of hyperplasia developing in any breast tissue, including rare ectopic sites, particularly in patients with underlying germline variants in cancer susceptibility genes.
Improving cancer survival rates globally requires improvements in disease detection and monitorin... more Improving cancer survival rates globally requires improvements in disease detection and monitoring, with the aim of improving early diagnosis and prediction of disease relapse. Traditional means of detecting and monitoring cancers rely largely on imaging and, where possible, blood-based protein biomarkers, many of which are non-specific. Treatments are being improved by identification of inherited and acquired genomic aberrations in tumors, some of which can be targeted by newly developed therapeutic interventions. Treatment of gynecological malignancy is progressively moving toward personalized therapy, as exemplified by application of PARP-inhibition for patients with BRCA-deficient tubo-ovarian cancers, or checkpoint inhibition in patients with mismatch repair-deficient disease. However, the more recent discovery of a group of biomarkers described under the umbrella term of “liquid biopsy” promises significant improvement in our ability to detect and monitor cancers. The term “li...
The recent publication of UK guidelines for the management of hereditary colorectal cancer1 immed... more The recent publication of UK guidelines for the management of hereditary colorectal cancer1 immediately preceded the COVID-19 pandemic. We commend the response by the British Society of Gastroenterology (BSG) relating to GI endoscopy activity amidst this pandemic.2 Such urgent measures are required to curtail the rate and breadth of coronavirus transmission throughout the country, and we are of the belief that the adherence to these guidelines during the early stages of this global pandemic was crucial in saving lives, and further guidance relating to the ‘recovery’ phase will be crucial in delivering diagnostic and cancer preventing endoscopic interventions. Though the emergency endoscopy COVID-19 guidance expressed clear and justified recommendations for the suspension of these services in non-urgent or routine screening populations, the management of patients deemed as being ‘high risk’ and subsequently prioritised for colonoscopy during this time is not currently well defined. For example, specific guidance for surveillance of individuals with conditions such as Lynch syndrome appeared vague in some statements …
Pathogenic variants in the BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancer. ... more Pathogenic variants in the BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancer. Individuals with identified pathogenic variants in the BRCA1 or BRCA2 gene can benefit from cancer risk‐reducing strategies. In the recent years, there has been an increase in the demand of genetic services. In light of the ongoing COVID19 pandemic, alternatives to face‐to‐face consultations have had to be considered and adopted, including telemedicine. Informed consent is necessary for genetic testing. Studies have suggested that increased levels of cancer‐specific distress may impair the patient's ability to retain information, therefore, providing informed consent. This systematic review and meta‐analysis aimed to answer if telephone genetic counseling for BRCA1 and BRCA2 genetic testing is non‐inferior to in‐person genetic counseling for the outcomes of cancer‐specific distress and genetic knowledge. Databases of Medline, Embase, PsycINFO, CINAHL, SciELO, Web of Science, CENTRAL, ProQuest Dissertation & Theses Database, Clinicaltrials.gov, EU clinical trials register were accessed to identify any published or unpublished relevant literature. Random‐effects models were used for the meta‐analysis. Four studies were included in the qualitative synthesis of the results. Three studies were included in the quantitative synthesis of the results. Telephone genetic counseling was non‐inferior compared to in‐person genetic counseling for the outcomes of cancer‐specific distress and genetic knowledge. Sensitivity analysis corroborated the main results. Telephone genetic counseling for BRCA1/BRCA2 genetic testing may be an alternative model of delivering genetic services in front of the increased demand/or when required by social context. However, the paucity of the evidence prevents from drawing strong conclusions regarding the generalizability of these results. Further research is needed to strengthen the conclusions.
Background: International best-practice guidelines recommend completion thyroidectomy and radioio... more Background: International best-practice guidelines recommend completion thyroidectomy and radioiodine remnant ablation (RRA) for patients with differentiated thyroid cancer (DTC) > 4 cm or with specific risk factors. Patients with DTC < 1 cm without risk factors are recommended for lobectomy alone. Indications for aggressive surgery and RRA are less clearly defined for tumours measuring 1-4 cm. A personalised approach to decision-making is recommended. Objectives: This study assesses therapeutic approaches to DTC as compared to the current British Thyroid Association (BTA) clinical practice guidelines. We ascertained the effect of equivocal guidance in the 1-4 cm tumour cohort on contemporary practice patterns. Methods: Data were obtained from a prospectively maintained thyroid cancer database of patients treated for DTC in a tertiary referral centre at the University Hospital Galway. Consecutive patients attending a dedicated thyroid cancer clinic between August 2014 and August 2017 were included. Clinicopathological characteristics and management strategies were assessed. Results: Ninety-four percent (n = 168/178) of patients were surgically managed in adherence with guidelines. A minority (n = 10) received surgery not aligned with guidelines. Ninety-seven percent (n = 172/178) of RRA treatment decisions were in accordance with guidelines. The BTA guidelines recommended a personalised decision-making approach for 18.0% (n = 32) and 44.9% (n = 80) of surgery and RRA treatment decisions, respectively. The more aggressive, treatment-driven approach was typically favoured by the multidisciplinary team, with 97% (n = 31/32) undergoing completion thyroidectomy and 100% (n = 80) proceeding to RRA. Conclusions: Management of DTC at our institution closely adheres to contemporary clinical practice guidelines. The finding of more aggressive management in those requiring a personalised decision-making approach highlights the requirement for improved risk stratification in this cohort to rationalise management strategies.
BackgroundInternational best-practice guidelines recommend completion thyroidectomy and radioiodi... more BackgroundInternational best-practice guidelines recommend completion thyroidectomy and radioiodine remnant ablation (RRA) for patients with differentiated thyroid cancer (DTC) > 4 cm or with specific risk factors. Patients with DTC < 1 cm without risk factors are recommended for lobectomy alone. Indications for aggressive surgery and RRA are less clearly defined for tumours measuring 1–4 cm. A personalised approach to decision-making is recommended.ObjectivesThis study assesses therapeutic approaches to DTC as compared to the current British Thyroid Association (BTA) clinical practice guidelines. We ascertained the effect of equivocal guidance in the 1–4 cm tumour cohort on contemporary practice patterns.MethodsData were obtained from a prospectively maintained thyroid cancer database of patients treated for DTC in a tertiary referral centre at the University Hospital Galway. Consecutive patients attending a dedicated thyroid cancer clinic between August 2014 and August 2017 were included. Clinicopathological characteristics and management strategies were assessed.ResultsNinety-four percent (n = 168/178) of patients were surgically managed in adherence with guidelines. A minority (n = 10) received surgery not aligned with guidelines. Ninety-seven percent (n = 172/178) of RRA treatment decisions were in accordance with guidelines. The BTA guidelines recommended a personalised decision-making approach for 18.0% (n = 32) and 44.9% (n = 80) of surgery and RRA treatment decisions, respectively. The more aggressive, treatment-driven approach was typically favoured by the multidisciplinary team, with 97% (n = 31/32) undergoing completion thyroidectomy and 100% (n = 80) proceeding to RRA.ConclusionsManagement of DTC at our institution closely adheres to contemporary clinical practice guidelines. The finding of more aggressive management in those requiring a personalised decision-making approach highlights the requirement for improved risk stratification in this cohort to rationalise management strategies.
Background Breast cancer is genetically heterogeneous, and parellel multi-gene sequencing is the ... more Background Breast cancer is genetically heterogeneous, and parellel multi-gene sequencing is the most cost- and time-efficient manner to investigate breast cancer predisposition. Numerous multi-gene panels (MGPs) are commercially available, but many include genes with weak/unproven associaton with breast cancer, or with predisposition to cancer of other types. This study investigates the utility of a custom-designed multi-gene panel in an Irish cohort with breast cancer. Methods A custom panel comprising 83 genes offered by 19 clinical “breast cancer predisposition” MGPs was designed and applied to germline DNA from 91 patients with breast cancer and 77 unaffected ethnicially matched controls. Variants were identified and classified using a custom pipeline. Results Nineteen loss-of-function (LOF) and 334 missense variants were identified. After removing common and/or benign variants, 15 LOF and 30 missense variants were analysed. Variants in known breast cancer susceptibility genes were identified, including in BRCA1 and ATM in cases, and in NF1 and CHEK2 in controls . Most variants identified were in genes associated with predisposition to cancers other than breast cancer ( BRIP1 , RAD50 , MUTYH , and mismatch repair genes), or in genes with unknown or unproven association with cancer. Conclusion Using multi-gene panels enables rapid, cost-effective identification of individuals with high-risk cancer predisposition syndromes. However, this approach also leads to an increased amount of uncertain results. Clinical management of individuals with particular genetic variants in the absence of a matching phenotype/family history is challenging. Further population and functional evidence is required to fully elucidate the clinical relevance of variants in genes of uncertain significance.
Red-automatically eligible for genetic referral 2. Yellowmay benefit from referral 3. Greendo not... more Red-automatically eligible for genetic referral 2. Yellowmay benefit from referral 3. Greendo not require referral Results There were 160 patients diagnosed in the period 01/ 01/2017-31/12/2017. Of these, 6 were excluded because of a pre-cancerous, rather than cancer, diagnosis: aplastic
BACKGROUND Molecular aberrations in cancer may represent therapeutic targets, and, if arising fro... more BACKGROUND Molecular aberrations in cancer may represent therapeutic targets, and, if arising from the germline, may impact further cancer risk management in patients and their blood relatives. Annually, 600-700 patients are referred for consideration of experimental drug trials in the Drug Development Unit (DDU) in our institution. A proportion of patients may merit germline genetic testing because of suspicious personal/family history or findings of tumour-based testing. We aimed to assess the impact of different multidisciplinary interventions on family history taking and referral rates from DDU to Cancer Genetics Unit (CGU). METHODS Over 42 months, three interventions were undertaken at different intervals: (1) embedding a genetics provider in the DDU review clinic, (2) 'traffic light' system flagging cancers with a heritable component and (3) virtual multidisciplinary meeting (MDM). Comparative analyses between intervals were undertaken, including referral rates to CGU, investigations and patient outcomes. Family history taking in a sample of 20 patients managed in each interval was assessed by a retrospective chart review. RESULTS Frequency of family history taking and referral to CGU, increased with each intervention, particularly, the virtual MDM (40% vs 85%). Referral rates increased over the study period, from 0.1 referral/week (5/year, 0.36% total referrals) to 1.2/week (projected 63/year, 3.81%). Forty-four (52%) patients referred required germline testing; in three of whom, variants were identified. Non-attendance rates were low (6, 7%). CONCLUSION Patients in the DDU are unique, with long cancer histories and often short estimated life expectancy. Multidisciplinary working between CGU and DDU facilitates germline testing of those patients who may otherwise miss the opportunity.
Genetics is the backbone of Neurology, where a number of disorders have a genetic aetiology and a... more Genetics is the backbone of Neurology, where a number of disorders have a genetic aetiology and are complex, requiring a dedicated Neurogenetics clinic. Genetics in the Republic of Ireland is under-resourced, with the lowest number of consultants per million of population in Europe. In November 2014, we established the monthly adult Neurogenetics clinic in Ireland, staffed by 2 consultants and 2 registrars from each speciality. We see patients with complex rare neurological conditions that may potentially have an underlying genetic basis, in the presence or absence of a family history. We performed a retrospective cohort analysis, reviewing symptoms and work-up data. Twenty-seven patients attended a pilot clinic over 12 months. Conditions encountered included Parkin-related PD, leucodystrophy, ataxia, fronto-temporal lobar degeneration, spinocerebellar ataxia type 6 (SCA6) and ataxia-telangiectasia. Identification of pathogenic mutations directed screening, treatment and facilitated onward genetic counselling (n = 10, 33%). A number of novel mutations were identified in MAPT gene (“missing tau mutation” McCarthy et al., Brain, 2015), SLCA1 gene and GRN (progranulin). Phenotypic features not previously reported were seen; e.g. writer’s cramp in SCA6; paroxysmal myoclonus in the glucose transporter protein type 1 (GLUT1) deficiency. Breast cancer screening for ATM mutations carriers and referral to international experts in two undiagnosed patients were arranged. The establishment of a Neurogenetics clinic has addressed a gap in service and allowed identification of rare and atypical diagnoses.
e12541 Abstract Background: The KRAS-variant is a functional, microRNA binding site variant that ... more e12541 Abstract Background: The KRAS-variant is a functional, microRNA binding site variant that predicts increased cancer risk as well as response to cancer therapies. Here we evaluate the impact of estrogen exposure on breast cancer (BC) cell transformation, as well as BC risk and tumor biology in women with the KRAS-variant. We further study the association of this variant with multiple primary breast cancer (MPBC). Methods: The impact of estrogen withdrawal on transformation in isogenic breast epithelial cell lines with or without the KRAS-variant was studied. Women with BC (n= 1712) and KRAS-variant unaffected controls (n= 80) were recruited, and hormonal exposures, KRAS-variant status, and pathology were compared. Presentation characteristics of MPBC were also studied. Results: Isogenic lines with the KRAS-variant had unique biology, and acute estrogen withdrawal led to oncogenic transformation. Consistent with our biologic findings, KRAS-variant BC patients were significantly more likely to have oo...
3571 Background: Lynch Syndrome (LS) accounts for 2-4% of all colorectal cancers (CRC) and is cau... more 3571 Background: Lynch Syndrome (LS) accounts for 2-4% of all colorectal cancers (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Increasing literature supports routine screening for LS using immunohistochemistry (IHC) to detect loss of MMR protein expression on tumour samples. We reviewed practices at 3 Irish cancer centres. The number of MMR deficient (dMMR) tumours detected was evaluated, and the subsequent number of genetic referrals and LS diagnoses determined. Methods: Colorectal databases at 3 Irish academic centres were reviewed from January 2005 - 2013. Centre 1 performs IHC upon physician request, centre 2 implemented reflex IHC (rIHC) in November 2008, and centre 3 has been performing rIHC since 2005. All new diagnoses of colorectal adenocarcinoma with available histology were included. Pathology reports were reviewed and genetic referrals analysed. Results: A total of 4,021 new CRC were diagnosed in 3,929 patients across 3 centres. The results are presented in the ...
Uploads
Papers by Terri McVeigh