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Monika Fazekas-Lavu,1 Andrew Parker,2 Allan D Spigelman,3,4 Rodney J Scott,5 Richard J Epstein,6 Michael Jensen,7 Katherine Samaras1,8 1Department of Endocrinology, 2Department of Pathology, St Vincent’s Hospital, Darlinghurst, NSW, Australia; 3Hereditary Cancer Clinic, St Vincent’s Cancer Genetics Service, Darlinghurst, NSW, Australia; 4University of NSW, St Vincent’s Clinical School, Darlinghurst, NSW, Australia; 5Division of Molecular Medicine, Pathology North, John Hunter Hospital and The Hunter Medical Research Institute, Newcastle, NSW, Australia; 6Department of Oncology, 7Department of Oncological Surgery/General Surgery, St Vincent’s Hospital, Darlinghurst, NSW, Australia; 8Diabetes and Metabolism Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia Abstract: Lynch syndrome describes a familial cancer syndrome comprising germline mutations in one of four DNA mismatch repair genes, MLH1, MSH2, MSH6, and PMS2 and is characterized by colorectal, endometrial, and other epithelial malignancies. Thyroid cancer is not usually considered to be part of the constellation of Lynch syndrome cancers nor have Lynch syndrome tumor gene mutations been reported in thyroid malignancies. This study reports a woman with Lynch syndrome (colonic cancer and a DNA mismatch repair mutation in the MSH2 gene) with a synchronous papillary thyroid cancer. Six years later, she developed metachronous breast cancer. Metastatic bone disease developed after 3 years, and the disease burden was due to both breast and thyroid diseases. Despite multiple interventions for both metastatic breast and thyroid diseases, the patient’s metastatic burden progressed and she died of leptomeningeal metastatic disease. Two prior case reports suggested thyroid cancer may be an extraintestinal malignancy of the Lynch syndrome cancer group. Hence, this study examined the genetic relationship between the patient’s known Lynch syndrome and her thyroid cancer. The thyroid cancer tissue showed normal expression of MSH2, suggesting that the tumor was not due to the oncogenic mutation of Lynch syndrome, and molecular analysis confirmed BRAF V600E mutation. Although in this case the thyroid cancer was sporadic, it raises the importance of considering cancer genetics in familial cancer syndromes when other cancers do not fit the criteria of the syndrome. Careful documentation of other malignancies in patients with thyroid cancer and their families would assist in better understanding of any potential association. Appropriate genetic testing will clarify whether a common pathogenic mechanism links seemingly unrelated cancers. Keywords: cancer genetics, familial cancer syndromes, thyroid and hereditary non-polyposis colorectal cancer

Background: Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in MUTYH or NTHL1 exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. The aim was to determine if adenomas from biallelic cases demonstrated these mutational signatures at diagnostic levels., Methods: Whole-exome sequencing of FFPE tissue and matched blood-derived DNA was performed on 9 adenomas and 15 CRCs from 13 biallelic MUTYH cases, on 7 adenomas and 2 CRCs from 5 biallelic NTHL1 cases and on 27 adenomas and 26 CRCs from 46 non-hereditary (sporadic) participants. All samples were assessed for COSMIC v3.2 SBS mutational signatures., Results: In biallelic MUTYH cases, SBS18+SBS36 signature proportions in adenomas (mean±standard deviation, 65.6%±29.6%) were not significantly different to those observed in CRCs (76.2%±20.5%, p-value =0.37), but were significantly higher compared with non-hereditary adenomas (7.6%±7.0%, p-value =3.4×10 -4 ). Similarly, in biallelic NTHL1 cases, SBS30 signature proportions in adenomas (74.5%±9.4%) were similar to those in CRCs (78.8%±2.4%) but significantly higher compared with non-hereditary adenomas (2.8%±3.6%, p-value =5.1×10 -7 ). Additionally, a compound heterozygote with the c.1187G>A p.(Gly396Asp) pathogenic variant and the c.533G>C p.(Gly178Ala) variant of unknown significance (VUS) in MUTYH demonstrated high levels of SBS18+SBS36 in four adenomas and one CRC, providing evidence for reclassification of the VUS to pathogenic., Conclusions: SBS18+SBS36 and SBS30 were enriched in adenomas at comparable proportions observed in CRCs from biallelic MUTYH and biallelic NTHL1 cases, respectively. Therefore, testing adenomas may improve the identification of biallelic cases and facilitate variant classification, ultimately enabling opportunities for CRC prevention., Competing Interests: Robert C. Grant received a scholarship from Pfizer and provided consulting or advisory roles for Astrazeneca, Tempus, Eisai, Incyte, Knight Therapeutics, Guardant Health, and Ipsen. All other authors have no relevant financial or non-financial interests to disclose.

Background: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants., Methods: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual., Findings: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0)., Interpretation: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings., Funding: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer., Competing Interests: Declaration of interests HL holds patents on intact PSA assays and is named on a patent for a statistical method to detect prostate cancer licensed to Arctic Partners and commercialised by OPKO Health, and has stock in Arctic Partners and OPKO Health and receives royalties from sales of the 4Kscore test. RAE has received speaker honoraria from Genitourinary-American Society of Clinical Oncology, The University of Chicago, European Society for Medical Oncology (paid by Bayer and Ipsen), and The Royal Marsden NHS Foundation Trust (with support from Janssen), and is a member of the AstraZeneca UK Limited Prostate Dx Advisory Panel external expert committee. No organisation had any role in the decision to publish or in the writing of the manuscript. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The Australian Pancreatic Cancer Screening Program (APCSP) offers endoscopic ultrasound surveillance for individuals at increased risk of pancreatic ductal adenocarcinoma (PDAC) with all participants requiring assessment by a Familial Cancer Service before or after study enrolment., Methods: Individuals aged 40-80 years (or 10 years younger than the earliest PDAC diagnosis) were eligible for APCSP study entry if they had 1) ≥ two blood relatives with PDAC (at least one of first-degree association); 2) a clinical or genetic diagnosis of Hereditary Pancreatitis or Peutz-Jeghers syndrome irrespective of PDAC family history; or 3) a known PDAC predisposition germline pathogenic variant (BRCA2, PALB2, CDKN2A, or Lynch syndrome) with ≥one PDAC-affected first- or second-degree relative. Retrospective medical record review was conducted for APCSP participants enrolled at the participating Australian hospitals from January 2011 to December 2019. We audited the genetic investigations offered by multiple Familial Cancer Services who assessed APCSP participants according to national guidelines, local clinical protocol and/or the availability of external research-funded testing, and the subsequent findings. Descriptive statistical analysis was performed using Microsoft Excel., Results: Of 189 kindreds (285 participants), 50 kindreds (71 participants) had a known germline pathogenic variant at enrolment (BRCA2 n = 35, PALB2 n = 6, CDKN2A n = 3, STK11 n = 3, PRSS1 n = 2, MLH1 n = 1). Forty-eight of 136 (35%) kindreds with no known germline pathogenic variant were offered mutation analysis; 89% was clinic-funded, with increasing self-funded testing since 2016. The relatively low rates of genetic testing performed reflects initial strict criteria for clinic-funded genetic testing. New germline pathogenic variants were detected in five kindreds (10.4%) after study enrolment (BRCA2 n = 3 kindreds, PALB2 n = 1, CDKN2A n = 1). Of note, only eight kindreds were reassessed by a Familial Cancer Service since enrolment, with a further 21 kindreds identified as being suitable for reassessment., Conclusion: Germline pathogenic variants associated with PDAC were seen in 29.1% of our high-risk cohort (55/189 kindreds; 82/285 participants). Importantly, 10.4% of kindreds offered genetic testing were newly identified as having germline pathogenic variants, with majority being BRCA2. As genetic testing standards evolve rapidly in PDAC, 5-yearly reassessment of high-risk individuals by Familial Cancer Services is warranted., (© 2021. The Author(s).)

Background: Guidelines for referral to cancer genetics service for women diagnosed with triple negative breast cancer have changed over time. This study was conducted to assess the changing referral patterns and outcomes for women diagnosed with triple negative breast cancer across three regional cancer centres during the years 2014-2018., Methods: Following ethical approval, a retrospective electronic medical record review was performed to identify those women diagnosed with triple negative breast cancer, and whether they were referred to a genetics service and if so, the outcome of that genetics assessment and/or genetic testing., Results: There were 2441 women with newly diagnosed breast cancer seen at our cancer services during the years 2014-2018, of whom 237 women were diagnosed with triple negative breast cancer. Based on age of diagnosis criteria alone, 13% (31/237) of our cohort fulfilled criteria for genetic testing, with 81% (25/31) being referred to a cancer genetics service. Of this group 68% (21/31) were referred to genetics services within our regions and went on to have genetic testing with 10 pathogenic variants identified; 5x BRCA1, 4x BRCA2 and × 1 ATM:c.7271 T > G., Conclusions: Referral pathways for women diagnosed with TNBC to cancer genetics services are performing well across our cancer centres. We identified a group of women who did not meet eligibility criteria for referral at their time of diagnosis, but would now be eligible, as guidelines have changed. The use of cross-discipline retrospective data reviews is a useful tool to identify patients who could benefit from being re-contacted over time for an updated cancer genetics assessment.

Background: Lynch syndrome is caused by germline mutations in the mismatch repair genes and is characterised by a familial accumulation of colorectal and other cancers. Earlier identification of Lynch syndrome patients enables surveillance and might reduce the risk of cancer. It is important to explore whether today's clinical care discovers patients with Lynch syndrome suitable for surveillance in time. This study aimed to describe what led to a diagnosis of Lynch syndrome in the cohort referred to the Hereditary Gastrointestinal Cancer Unit, Karolinska University Hospital, Solna, Sweden for gastrointestinal surveillance., Methods: This was a descriptive study. Data from 1975 to 2018 were collected and compiled as a database. Age at diagnosis was calculated from the date when a pathogenic MMR gene mutation was confirmed, from the period June 1994-September 2018. Data were collected from patient protocols prospectively during patient consultations and medical records retrospectively. Criteria for inclusion were registration at the outpatient clinic and a confirmed mismatch repair gene mutation., Results: A total of 305 patients were eligible for inclusion. Three major reasons for diagnosis were identified: 1. Predictive testing of a previously known mutation in the family (62%, mean age 37), 2. A family history of Lynch associated tumours (9%, mean age 37), 3. A diagnosis of cancer (29%, mean age 51). The proportion diagnosed due to cancer has not changed over time., Conclusion: A high proportion of patients (29%) were identified with Lynch syndrome after they had been diagnosed with an associated cancer, which suggests that there is significant room for improvement in the diagnosis of patients with Lynch syndrome before cancer develops.

Background: Cancer surveillance is important in the management of Lynch syndrome. In New South Wales, management guidelines for Lynch syndrome are published on the eviQ website. Benefits of cancer surveillance are maximized through adherence to guidelines. This has yet to be investigated in Sydney. Hence, this study aimed to determine the adherence rate of patients to these guidelines, assess their knowledge of the guidelines and determine potential factors hindering regular colonoscopies in these patients., Methods: A cross-sectional study was conducted among Lynch syndrome patients from the St Vincent's Hospital Cancer Genetics Unit, Sydney. Patients who appropriately fulfilled our inclusion criteria were mailed a questionnaire. The questionnaire was mailed twice to increase the response rate. Demographic and medical information were collected from patient medical records. Patient responses were analysed to determine adherence to the guidelines., Results: Sixty-two individuals were invited to participate in this study. Among them, 47 responded (76%) with two being excluded, due to potential confounding factors. Thirty (67%) had their colonoscopies at recommended intervals, while 15 (33%) had delays. Within these two groups, many were ultimately deemed non-adherent to the guidelines due to over-screening with other tests. In total, 31 (69%) participants were considered over-screening for cancer, leaving only seven (16%) participants fully adherent to the guidelines. Only three (7%) had knowledge of the eviQ guidelines., Conclusions: Adherence to the eviQ guidelines was poor. The majority of participants were being over-screened for cancer. Knowledge of the guidelines needs to be improved., (© 2020 Royal Australasian College of Surgeons.)

Background: Pancreatic cancer (PC) is an aggressive disease with a dismal 5-year survival rate. Surveillance of high-risk individuals is hoped to improve survival outcomes by detection of precursor lesions or early-stage malignancy., Methods: Since 2011, a national high-risk cohort recruited through St Vincent's Hospital, Sydney, has undergone prospective PC screening incorporating annual endoscopic ultrasound, formal genetic counselling and mutation analysis as appropriate. PancPRO, a Bayesian PC risk assessment model, was used to estimate 5-year and lifetime PC risks for familial pancreatic cancer (FPC) participants and this was compared to their perceived chance of pancreatic and other cancers. Genetic counselling guidelines were developed to improve consistency. Follow-up questionnaires were used to assess the role of genetic counselling and testing., Results: We describe the Australian PC screening program design and recruitment strategy and the results of the first 102 individuals who have completed at least one-year of follow-up. Seventy-nine participants met the FPC criteria (≥ two first-degree relatives affected), 22 individuals had both a BRCA2 pathogenic variant and a close relative with PC and one had a clinical diagnosis of Peutz-Jeghers syndrome. Participants reported a high perceived chance of developing PC regardless of their genetic testing status. PancPRO reported FPC participants' mean 5-year and lifetime PC risks as 1.81% (range 0.2-3.2%) and 10.17% (range 2.4-14.4%), respectively. Participants' perceived PC chance did not correlate with their PancPRO 5-year (r = - 0.17, p  = 0.128) and lifetime PC risks (r = 0.19, p  = 0.091). Two-thirds felt that current genetic testing would help them, and 91% of tested participants were glad to have undergone genetic testing. Overall, 79% of participants found genetic counselling to be helpful, and 88% reported they would recommend counselling to their relatives., Conclusions: Participants reported multiple benefits of genetic counselling and testing but continue to seek greater clarification about their individual PC risk. Extension of PancPRO is required to enable personalised PC risk assessment for all high-risk sub-groups. More detailed discussion of PC risk for BRCA2 pathogenic variant carriers, providing a written summary in all cases and a plan for genetics review were identified as areas for improvement., Competing Interests: Competing interestsThe authors declare they have no competing interests., (© The Author(s). 2019.)

Background: To determine the proportion of patients with colorectal cancer and abnormal immunohistochemistry testing of tumour tissue who were referred to a cancer genetic clinic for genetic counselling and possible germline testing of a blood sample for Lynch syndrome., Methods: This is a retrospective cohort study of patients with colorectal cancer and abnormal immunohistochemistry tumour tissue testing from St Vincent's Hospital (between November 2007 and December 2016). Patient list was compared against a state-wide database TrakGene to ascertain the overall referral rate for these patients., Results: Of 216 patients, the total referral rate was 33.8% (n = 73), of which 27.8% (n = 60) were referred to St Vincent's Hospital's Cancer Genetics Service, 6% (n = 13) were referred externally and the remaining 66.2% (n = 143) were not referred. Binomial regression analysis performed displayed that age influenced likelihood of referral, where patients were 7.7% more likely to be referred for every decreasing year in age (P = 0.0004). Some clinicians were 4.3 times more likely to refer patients compared to others (P = 0.002)., Conclusion: Suboptimal patient uptake for cancer genetics evaluation was found. Identifying barriers to patient referral should lead to changes that increase patient referrals. This will ensure that patients receive adequate education, counselling and management of Lynch syndrome. It would also allow for the identification of further at-risk relatives for whom preventative strategies can be employed. In addition, identification of relatives not at risk by genetic testing will liberate them from unnecessary colonoscopies. Discussion with the clinicians involved has since allowed for copies of the immunohistochemistry results to be forwarded by the Pathology Department to the Cancer Genetics Unit for checking and follow up with the clinician to ensure that their patients are aware of the result and have been offered referral for cancer genetic evaluation. This process is subject to ongoing audit., (© 2019 Royal Australasian College of Surgeons.)

Aim: The role of germline testing in prostate cancer is evolving and knowledge of an individual's genetic profile may be used to guide not only an assessment of their familial risk but also have prognostic and therapeutic implications. Although international guidelines have incorporated recommendations for germline testing in prostate cancer, there is little Australian data to guide referrals. The aim of this study is to review the frequency of relevant pathogenic mutations in an Australian center, their associated clinical factors and clinical impact., Methods: We conducted a single-center retrospective review of men with prostate cancer that undertook prospective germline testing using a targeted next generation sequencing panel., Results: Results for 100 men were analyzed. Median age at diagnosis was 62 years (range 43-84); 92% had metastatic disease at referral. A pathogenic mutation was confirmed in 9%, a likely pathogenic variant in 2% and a variant of uncertain significance in 15%. Age ≤60 years was associated with an increased risk for a pathogenic germline variant (P = 0.0096). Two of the nine (22%) with pathogenic variants went on to receive targeted treatment., Conclusions: In this single center study, the incidence of germline mutations in genes associated with DNA-repair was consistent with rates seen previously published international series of men with metastatic disease. A pathogenic variant was only seen in one patient >60 years of age and no man referred solely on the basis of age or high-risk localized disease had a relevant finding., (© 2019 John Wiley & Sons Australia, Ltd.)

While familial adenomatous polyposis accounts for approximately 1% of all colorectal cancer, the genetic cause underlying the development of multiple colonic adenomas remains unsolved in many patients. Adenomatous polyposis syndromes can be divided into: familial adenomatous polyposis, MUTYH-associated polyposis, polymerase proofreading associated polyposis and the recently described NTHL1-associated polyposis (NAP). NAP is characterised by recessive inheritance, attenuated adenomatous polyposis, colonic cancer(s) and possible extracolonic malignancies. To date, 11 cases have been reported as having germline homozygous or compound heterozygous mutations in the base excision repair gene NTHL1. Here we present a further case of a 65-year-old male with a history of adenomatous polyposis and bladder cancer, who has a previously described homozygous nonsense variant in the NTHL1 gene. This case is consistent with the emerging phenotype previously described of multiple colorectal adenomas and at least one primary tumour, adding to the small but growing body of literature about NAP.

We report the case of a female found to have mosaicism for mutation in the STK11 gene, with the mutant allele expressed in her gametes, evident by her affected offspring, and in her gastrointestinal tract demonstrated on an excised polyp analysed for diagnosis. Mosaicism for Peutz-Jeghers syndrome (PJS) has been reported in a small number of cases previously but a clinical presentation such as this has not previously been described. This finding of mosaicism was several years after initial investigations failed to identify the same STK11 mutation in this woman whose son was diagnosed with PJS at a young age. This case highlights the importance of considering mosaicism as an explanation for apparent de novo cases of PJS syndrome. It also has implications for genetic counselling, predictive testing and cancer screening.

Causative germline mutations in mismatch repair (MMR) genes can only be identified in ~50% of families with a clinical diagnosis of the inherited colorectal cancer (CRC) syndrome hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome (LS). Identification of these patients are critical as they are at substantially increased risk of developing multiple primary tumors, mainly colorectal and endometrial cancer (EC), occurring at a young age. This demonstrates the need to develop new and/or more thorough mutation detection approaches. Next-generation sequencing (NGS) was used to screen 22 genes involved in the DNA MMR pathway in constitutional DNA from 14 HNPCC and 12 sporadic EC patients, plus 2 positive controls. Several softwares were used for analysis and functional annotation. We identified 5 exonic indel variants, 42 exonic nonsynonymous single-nucleotide variants (SNVs) and 1 intronic variant of significance. Three of these variants were class 5 (pathogenic) or class 4 (likely pathogenic), 5 were class 3 (uncertain clinical relevance) and 40 were classified as variants of unknown clinical significance. In conclusion, we have identified two LS families from the sporadic EC patients, one without a family history of cancer, supporting the notion for universal MMR screening of EC patients. In addition, we have detected three novel class 3 variants in EC cases. We have, in addition discovered a polygenic interaction which is the most likely cause of cancer development in a HNPCC patient that could explain previous inconsistent results reported on an intronic EXO1 variant., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Since the identification of BRCA1 there has only ever been described two bi-allelic mutation carriers, one of whom was subsequently shown to be a mono-allelic carrier. The second patient diagnosed with two BRCA1 mutations appears to be accurate but there remain some questions about the missense variant identified in that patient. In this report we have identified a woman who is a bi-allelic mutation carrier of BRCA1 and provide an explanation as to why this patient has a phenotype very similar to that of any mono-allelic mutation carrier. The splice variant identified in this patient appears to be associated with the up-regulation of a BRCA1 splice variant that rescues the lethality of being a double mutant. The consequences of the findings of this report may have implications for mutation interpretation and that could serve as a model for not only BRCA1 but also for other autosomal dominant disorders that are considered as being embryonically lethal.

Familial Adenomatous Polyposis (FAP) is the second most common inherited predisposition to colorectal cancer (CRC) associated with the development of hundreds to thousands of adenomas in the colon and rectum. Mutations in APC are found in ~ 80% polyposis patients with FAP. In the remaining 20% no genetic diagnosis can be provided suggesting other genes or mechanisms that render APC inactive may be responsible. Copy number variants (CNVs) remain to be investigated in FAP and may account for disease in a proportion of polyposis patients. A cohort of 56 polyposis patients and 40 controls were screened for CNVs using the 2.7M microarray (Affymetrix) with data analysed using ChAS (Affymetrix). A total of 142 CNVs were identified unique to the polyposis cohort suggesting their involvement in CRC risk. We specifically identified CNVs in four unrelated polyposis patients among CRC susceptibility genes APC, DCC, MLH1 and CTNNB1 which are likely to have contributed to disease development in these patients. A recurrent deletion was observed at position 18p11.32 in 9% of the patients screened that was of particular interest. Further investigation is necessary to fully understand the role of these variants in CRC risk given the high prevalence among the patients screened.

Background: Inherited predisposition to pancreatic cancer contributes significantly to its incidence and presents an opportunity for the development of early detection strategies. The genetic basis of predisposition remains unexplained in a high proportion of patients with familial PC (FPC)., Methods: Clinicopathologic features were assessed in a cohort of 766 patients who had been diagnosed with pancreatic ductal adenocarcinoma (PC). Patients were classified with FPC if they had ≥1 affected first-degree relatives; otherwise, they were classified with sporadic PC (SPC)., Results: The prevalence of FPC in this cohort was 8.9%. In FPC families with an affected parent-child pair, 71% in the subsequent generation were 12.3 years younger at diagnosis. Patients with FPC had more first-degree relatives who had an extrapancreatic malignancy (EPM) (42.6% vs 21.2; P<.0001), particularly melanoma and endometrial cancer, but not a personal history of EPM. Patients with SPC were more likely to be active smokers, have higher cumulative tobacco exposure, and have fewer multifocal precursor lesions, but these were not associated with differences in survival. Long-standing diabetes mellitus (>2 years) was associated with poor survival in both groups., Conclusions: FPC represents 9% of PC, and the risk of malignancy in kindred does not appear to be confined to the pancreas. Patients with FPC have more precursor lesions and include fewer active smokers, but other clinicopathologic factors and outcome are similar to those in patients with SPC. Furthermore, some FPC kindreds may exhibit anticipation. A better understanding of the clinical features of PC will facilitate efforts to uncover novel susceptibility genes and the development of early detection strategies., (© 2014 American Cancer Society.)

To evaluate trends and associations surrounding patient referral to cancer genetics services in NSW. The specific aims of the questionnaire used to collect information were to: (1) quantify the types of cancers being referred, (2) identify the source of referral for the patients, (3) categorise the referral as being either sought by the patient or suggested by the doctor, (4) quantify how often family history was asked, (5) determine who first raised the topic of family history, (6) identify any discouragement faced by patients, (7) clarify the cancer status of patients referred. A comparative patient-reported study was carried out using a questionnaire as the data collection tool in structured short interviews. The questions were aimed at eliciting the patient's understanding of why they were referred to the clinic, whether family history was discussed at the time of referral and who raised the issue via a series of YES/NO and open response questions. Data were collected from March 2012 to August 2012 from two different clinics, St Vincent's Hereditary Cancer Clinic, Sydney and the Hunter Family Cancer Service, Newcastle-both in New South Wales, Australia. Written consent was obtained. The study found that specialists were responsible for the majority of the 150 referrals and were more likely to be proactive in referring, as opposed to GPs (Phi and Cramer's V test). Patients reported that at the time of referral their family history was not asked in 13.5 % of cases, despite being significant. In the 131 cases where family history was discussed, it was the patient on approximately 2 in 5 occasions that brought up the topic. The most common types of cancer seen were breast cancer and colorectal. At both services GP referrals were more common then specialist referrals. On three occasions patients sought referral after being notified that the bloods they had collected by their GP for genetic testing were held by the laboratory due to failure to follow protocol. Six patients reported being discouraged to attend when seeking a referral. At the time of referral 58.7 % of patients were considered to be without cancer. Overall, 20 % of patients requested their referral to the cancer genetics clinics. The discussion of family history in the context of familial cancer is key to accurate risk assessment and management advice. Further education of doctors is required as evidenced by the number of patients where family history was not asked and in those patients who had bloods collected by their GP without counselling.

We report a familial adenomatous polyposis patient with a known truncating mutation on exon 15 of the APC gene who developed an invasive follicular thyroid cancer in addition to multiple intra-cranial and spinal desmoids. This combination of manifestations has not previously been recorded in the literature.

Purpose: To explore the referral pathways of patients with newly diagnosed colorectal cancer to surgeons., Method: Australian surgeons from three states completed a questionnaire and their records were audited., Results: Thirty-three surgeons provided data on 530 patients seen in the preceding 12 months. The median time between colonoscopy and first surgical consult was 10 days, with 19% of patients waiting more than 28 days. After adjustment for clustering, no surgeon factors were associated with the number of days between colonoscopy and surgery. A report back to the general practitioner (GP) was found in 78% of patients' records. This feedback varied between surgeons but none of the specific surgeon characteristics examined could explain this., Conclusion: Surgeons usually communicated with GP regardless of whether they were the referral source. However, communication with GP varied considerably among surgeons, with no evidence of a report to the GP in one-fifth of cases.

Purpose: Videoconferencing is increasingly used to deliver family cancer services for hereditary breast and ovarian cancer to outreach areas. This study compared the effectiveness and acceptability of genetic counseling for hereditary breast and ovarian cancer through videoconferencing (hereafter referred to as "telegenetics")., Methods: One hundred six women seen by telegenetics and 89 women seen face-to-face completed self-administered questionnaires before, and 1 month after, genetic counseling. Telegenetics consultations involved a genetic clinician via telegenetics in addition to a local genetic counselor present with the patient., Results: No significant differences were found between telegenetics and face-to-face genetic counseling in terms of knowledge gained (P = 0.55), satisfaction with the genetic counseling service (P = 0.76), cancer-specific anxiety (P = 0.13), generalized anxiety (P = 0.42), depression (P = 0.96), perceived empathy of the genetic clinician (P = 0.13), and perceived empathy of the genetic counselor (P = 0.12). Telegenetics performed significantly better than face-to-face counseling in meeting patients' expectations (P = 0.009) and promoting perceived personal control (P = 0.031)., Conclusion: Telegenetics seems to be an acceptable and effective method of delivering genetic counseling services for hereditary breast and ovarian cancer to underserved areas.

Background: Despite the well recognized protective effect of cruciferous vegetables against various cancers, including human colorectal cancers, little is known about how this effect is conferred. It is thought that some phytochemicals found only in these vegetables confer the protection. These compounds include the glucosinolates, of which indole-3-carbinol is one. They are known to induce carcinogen-metabolizing (phase II) enzymes, including the glutathione S-transferase (GST) family. Other effects in humans are not well documented. We wished to assess the effect of indole-3-carbinol on GST enzymes., Methods: We carried out a placebo-controlled human volunteer study. All patients were given 400 mg daily of indole-3-carbinol for three months, followed by placebo. Serum samples were tested for the GSTM1 genotype by polymerase chain reaction. Serum GST levels were assessed using enzyme-linked immunosorbent assay and Western Blot methodologies., Results: Forty-nine volunteers completed the study. GSTM1 genotypes were obtained for all but two volunteers. A slightly greater proportion of volunteers were GSTM1-positive, in keeping with the general population. GST was detected in all patients. Total GST level was not affected by indole-3-carbinol dosing compared with placebo. Although not statistically significant, the GSTM1 genotype affected the serum GST level response to indole-3-carbinol., Conclusion: Indole-3-carbinol does not alter total serum GST levels during prolonged dosing.

Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by germline mutations in DNA mismatch repair genes; however, variation in disease expression suggests that there are potential modifying factors. Polymorphisms of the HFE gene, which cause the iron overload disorder hereditary haemochromatosis, have been proposed as potential risk factors for the development of colorectal cancer (CRC). To understand the relationship between HNPCC disease phenotype and polymorphisms of the HFE gene, a total of 362 individuals from Australia and Poland with confirmed causative MMR gene mutations were genotyped for the HFE C282Y and H63D polymorphisms. A significantly increased risk of developing CRC was observed for H63D homozygotes when compared with combined wild-type homozygotes and heterozygotes (hazard ratio = 2.93, p = 0.007). Evidence for earlier CRC onset was also observed in H63D homozygotes with a median age of onset 6 years earlier than wild type or heterozygous participants (44 vs. 50 years of age). This effect was significant by all tests used (log-rank test p = 0.026, Wilcoxon p = 0.044, Tarone-Ware p = 0.035). No association was identified for heterozygosity of either polymorphism and limitations on power-prevented investigation of C282Y homozygosity or compound C282Y/H63D heterozygosity. In the Australian sample only, women had a significantly reduced risk of developing CRC when compared with men (hazard ratio = 0.58, p = 0.012) independent of HFE genotype for either single nucleotide polymorphisms. In conclusion, homozygosity for the HFE H63D polymorphism seems to be a genetic modifier of disease expression in HNPCC. Understanding the mechanisms by which HFE interrelates with colorectal malignancies could lead to reduction of disease risk in HNPCC.

Background & Aims: Most patients with familial adenomatous polyposis (FAP) develop duodenal adenomas; duodenal cancer is a major cause of mortality in this patient group. We reviewed cases of duodenal cancer in patients with FAP to identify factors that determine long-term cancer risk., Methods: Twenty FAP patients (12 male) were identified from a registry database search. Data from registry and medical notes and endoscopic and histopathologic reports were evaluated., Results: Of the cancers that developed in these patients, 11 were ampullary and 9 were duodenal. The median age at cancer diagnosis was 53 years. Seventeen patients died (median age at death, 57 y; median survival from diagnosis, 11 mo); the cause of death was metastatic or duodenal/ampullary cancer in 14 patients. Fifteen patients presented symptomatically (including 3 interval cancers while on surveillance). Two were diagnosed at surveillance and 3 were diagnosed during surgery performed for endoscopic features of advanced benign disease. Duodenal cancers were associated with a significantly lower mean colonic polyp count than ampullary cancers (496 +/- 282 vs 1322 +/- 735; P = .025); there appeared to be familial clustering of this cancer. When endoscopic data were available (n = 11 of 20), all ampullary cancers arose from ampullas greater than 1 cm. The Spigelman stage did not predict risk of ampullary cancer but did predict duodenal cancer (median stage 2 vs stage 4 for duodenal cancer)., Conclusions: Once cancer arises in patients with FAP, prognosis is poor, so cancer prevention should be the main goal. Surveillance intervals should reflect both Spigelman staging and ampullary disease.