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Background Bilateral-Risk-Reducing-Mastectomy-(BRRM) is well described in BRCA1/2 pathogenic variant carriers. However, little is known about the relative uptake, time trends or factors influencing uptake in those at increased breast cancer risk not known to be carriers. The aim of this study is to assess these factors in both groups. Methods BRRM uptake was assessed from entry to the Manchester Family History Clinic or from date of personal BRCA1/2 test. Follow up was censored at BRRM, breast cancer diagnosis, death or January 01, 2020. Cumulative incidence and cause specific and competing risk regression analyses were used to assess the significance of factors associated with BRRM. Results Of 7195 women at ≥25% lifetime breast cancer risk followed for up to 32 years, 451 (6.2%) underwent pre-symptomatic BRRM. Of those eligible in different risk groups the 20-year uptake of BRRM was 47.7%-(95%CI = 42.4–53.2%) in 479 BRCA1/2 carriers; 9.0% (95%CI = 7.26–11.24%) in 1261 women at ≥40% lifetime risk (non-BRCA), 4.8%-(95%CI = 3.98–5.73%) in 3561 women at 30–39% risk and 2.9%-(95%CI = 2.09–4.09%) in 1783 women at 25–29% lifetime risk. In cause-specific Cox regression analysis death of a sister with breast cancer50; OR = 0.26,95%CI = 0.17–0.41). Uptake continued to rise to 20 years from initial risk assessment. Conclusion We have identified several additional factors that correlate with BRRM uptake and demonstrate continued increases over time. These factors will help to tailor counselling and support for women., Highlights • BRRM continues even 20 years post original breast cancer risk assessment. • Potential triggers include death of mother/sister, children and a breast biopsy. • Uptake is clearly informed by lifetime risk of BC and higher in younger the women.

Poly(ADP-ribose) polymerase (PARP) inhibitors improve survival in BRCA-mutant high-grade serous ovarian carcinoma. As a result, germline and somatic BRCA1/2 testing has become standard practice in women diagnosed with ovarian cancer. We outline changes in testing and detection rates of germline BRCA1/2 pathogenic variants (PVs) in cases of non-mucinous epithelial ovarian cancer diagnosed during three eras, spanning 12 years, within the North West of England, and compare the uptake of cascade testing in families identified by oncology-led mainstreaming versus regional genetics clinics. Eras included: Period 1 (20% risk threshold for testing): between January 2007 and May 2013; Period 2 (10% risk threshold for testing): between June 2013 and October 2017 and; Period 3 (mainstream testing): between November 2017 and November 2019. A total of 1081 women underwent germline BRCA1/2 testing between January 2007 and November 2019 and 222 (20.5%) were found to have a PV. The monthly testing rate increased by 3.3-fold and 2.5-fold between Periods 1–2 and Periods 2–3, respectively. A similar incidence of germline BRCA1/2 PVs were detected in Period 2 (17.2%) and Period 3 (18.5%). Uptake of cascade testing from first-degree relatives was significantly lower in those women undergoing mainstream testing compared with those tested in regional genetics clinics (31.6% versus 47.3%, P = 0.038). Mainstream testing allows timely detection of germline BRCA1/2 status to select patients for PARP inhibitors, but shortfalls in the uptake of cascade testing in first-degree relatives requires optimisation to broaden benefits within families.

BACKGROUNDIdentification of germ-line mutations in pancreatic ductal adenocarcinoma (PDAC) could impact on patient/family.AIMTo assess the referral pathways for genetic consultations in PDAC.METHODSElectronic records of PDAC patients were reviewed retrospectively. Patients eligible for genetic consultation referral were identified following the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) criteria. RESULTSFour-hundred patients were eligible. Of 113 patients (28.3%) meeting EUROPAC criteria, 8.8% were referred for genetic opinion. Germ-line mutations were identified in 0.75% of the whole population.CONCLUSION Earlier referrals and increased awareness may be able to overcome the low rate of successful genetic appointments.

BackgroundTesting cancers for mismatch repair deficiency (dMMR) by immunohistochemistry (IHC) is a quick and inexpensive means of triaging individuals for germline Lynch syndrome testing. The aim of this study was to evaluate tumour dMMR and the prevalence of Lynch syndrome in patients referred to the Manchester Centre for Genomic Medicine, which serves a population of 5.6 million.MethodsTumour testing used IHC for MMR proteins with targeted BRAF and MLH1 promotor methylation testing followed by germline mutation and somatic testing as appropriate.ResultsIn total, 3694 index tumours were tested by IHC (2204 colorectal cancers (CRCs), 739 endometrial cancers (ECs) and 761 other), of which 672/3694 (18.2%) had protein loss, including 348 (9.4%) with MLH1 loss. MLH1 loss was significantly higher for 739 ECs (15%) vs 2204 CRCs (10%) (p=0.0003) and was explained entirely by higher rates of somatic MLH1 promoter hypermethylation (87% vs 41%, pMLH1 hypermethylation or BRAF c.1799T>A had constitutional MLH1 pathogenic variants. Of 456 patients with tumours showing loss of MSH2/MSH6, 216 (47.3%) had germline pathogenic variants in either gene. Isolated PMS2 loss was most suggestive of a germline MMR variant in 19/26 (73%). Of those with no germline pathogenic variant, somatic testing identified likely causal variants in 34/48 (71%) with MLH1 loss and in MSH2/MSH6 in 40/47 (85%) with MSH2/MSH6 loss.ConclusionsReflex testing of EC/CRC leads to uncertain diagnoses in many individuals with dMMR following IHC but without germline pathogenic variants or MLH1 hypermethylation. Tumour mutation testing is effective at decreasing this by identifying somatic dMMR in >75% of cases.

BackgroundHereditary causes of ovarian cancer include Lynch syndrome, which is due to inherited pathogenic variants affecting one of the four mismatch repair genes involved in DNA repair. The aim of this study was to evaluate tumour mismatch repair deficiency and prevalence of Lynch syndrome in high-risk women referred to the Manchester Centre for Genomic Medicine with ovarian cancer over the past 20 years.MethodsWomen with ovarian cancer diagnosed before the age of 35 years and/or with a suggestive personal or family history of Lynch syndrome cancers underwent tumour testing with immunohistochemistry for mismatch repair deficiency and, where indicated, MLH1 promoter methylation testing followed by constitutional testing for Lynch syndrome.ResultsIn total, 261 ovarian cancers were tested and 27 (10.3%; 95% CI 6.9% to 14.7%) showed mismatch repair deficiency by immunohistochemistry. Three of 7 with MLH1 loss showed MLH1 promoter hypermethylation, and 18 of the remaining 24 underwent constitutional testing for Lynch syndrome. A further 15 women with mismatch repair proficient tumours underwent constitutional testing because of a strong family history of Lynch syndrome cancers. Pathogenic variants were identified in 9/33 (27%) women who underwent constitutional testing, aged 33–59 years (median 48 years), including one whose tumour was mismatch repair proficient. Most Lynch syndrome tumours were of endometrioid histological subtype.ConclusionsTumour mismatch repair deficiency identified by immunohistochemistry is a useful prescreen for constitutional testing in women with ovarian cancer with personal or family histories suggestive of Lynch syndrome.

Background: Whilst the requirement for thresholds for testing for mutations in BRCA1/2 is being questioned, they are likely to remain for individuals unaffected by a relevant cancer. It is still useful to provide pre-testing likelihoods, but models need to take into account tumour pathology.Methods: The Manchester scoring system (MSS) is a well utilised, simple, paper based model for assessing carrier probability that already incorporates pathology data. We have used mutation testing data from 4115 unrelated samples from affected non-Jewish individuals alongside tumour pathology to further refine the scoring system.Results: Adding additional points for high grade serous ovarian cancer

Women with Lynch syndrome (LS) have a significantly increased lifetime risk of endometrial cancer (40-60 %) and ovarian cancer (7-12 %). Currently there is little evidence to support the efficacy of screening for the early detection of these cancers. Another option is risk-reducing hysterectomy and/or bilateral salpingo-oophorectomy (BSO). Research on the impact of BSO in premenopausal women with a non-LS associated family history cancer has generally shown that women have a high level of satisfaction about their decision to undergo surgery. However, debilitating menopausal symptoms and sexual dysfunction are common post-surgical problems. We used a mixed methods study to explore the impact of risk-reducing gynaecological surgery in women with LS: 24 women were invited to take part; 15 (62.5 %) completed validated questionnaires and 12 (50 %) participated in semi-structured interviews. Our results suggest that risk reducing surgery does not lead to significant psychological distress and the women tend not to think or worry much about developing cancer. However, they tend to be distressed about the physical and somatic symptoms associated with menopause; their social well-being is somewhat affected, but sexual difficulties are minimal. The women reported being overwhelmingly satisfied with their decision to have surgery and with the quality of information they received prior to the operation. However, they felt underprepared for menopausal symptoms and received conflicting advice about whether or not to use HRT. Recommendations from the study include that professionals discuss the menopause, its side effects and HRT in detail prior to surgery.

Lynch syndrome (LS), previously known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominantly inherited condition. It is characterised by the development of colorectal cancer (CRC), endometrial cancer, and other cancers. This article will review the clinical and genetic aspects of LS. It will outline the diagnostic criteria for the condition and how to identify patients or families with LS. It will also review bowel and other screening recommendations, surgical options, and highlight some counselling issues.

This article examines how to develop confidence and competence in tailoring genetic/genomic information for different patients. The focus is on the issues that nurses working in a multicultural society need to be aware of, and include taking into account people's ethnicity, culture, religion and ethical perspectives, as well as their developmental stage.

SUMMARY Hereditary bowel cancer syndromes account for up to 5% of colorectal cancer (CRC) incidence. Presentation of CRC under the age of 50 years should alert clinicians to a possible underlying genetic predisposition. This article focuses on Lynch syndrome (hereditary nonpolyposis CRC). Regular bowel screening is effective in reducing the risk of CRC and improving overall survival in Lynch syndrome families. The issues surrounding the clinical diagnostic criteria and the shortcomings of the referral process are described, and it is questioned whether a universal strategy for diagnosis should be employed. This article summarizes the evidence for the benefit of bowel screening and suggests practical steps to help ensure compliance with screening recommendations. Finally, it is discussed how collaboration between geneticists, gastroenterologists and surgeons can inform surgical decision-making for the benefit of the patient.

Background Neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), familial adenomatous polyposis (FAP), von Hippel-Lindau syndrome (VHL), and Gorlin syndrome (GS) are single gene diseases that predispose to early onset tumours. Few studies have assessed the effect of these diseases on life expectancy. This study9s aim was to assess this effect, and to test the hypothesis that genetic registers increase survival. Method NF1, NF2, VHL, FAP, and GS patients were identified through the North West Regional Genetic Register Service and the North West Cancer Intelligence Service. Information on benign and malignant tumours, and deaths were obtained. Kaplan–Meier curves were used to show actuarial survival rates for each disease, compared to the local population, and in patients diagnosed pre/post the regional genetic register. Log rank (Mantel–Cox) tests were used to compare survival between groups. Results Life expectancies were significantly reduced for all diseases investigated compared with the local population (80.0 years) (p=0.05). GS had the longest life expectancy at 73.4 years, followed by NF1 at 71.5 years, NF2 at 69.0 years, FAP at 63.6 years, and VHL at 52.5 years. Patients diagnosed after establishment of the genetic register had an increase in survival compared to those diagnosed pre-1990: NF2 (14.7 years), FAP (13.9 years), VHL (16.3 years), and GS (11.2 years). Conclusion Life expectancy for all five diseases was less than normal, although in recent years this reached the level of the local population in GS. Although there have been improvements in all conditions which may in part be attributable to better targeted care through the genetic register service, more needs to be done to address the very poor life expectancy in VHL.

Prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) for later onset and/or reduced penetrance inherited cancer predispositions, e.g. familial adenomatous polyposis, hereditary non-polyposis colorectal cancer/Lynch syndrome and hereditary breast and ovarian cancer, raise a number of ethical issues. Some of these are the same as for conditions which present early in childhood, are fully penetrant and for which no/limited treatment options are possible; others relate to whether reduced penetrance and/or the availability of treatment mean that these are not serious (enough) conditions to warrant tests prior to/during pregnancy or to justify termination of pregnancy. However, attempts to reach a consensus on what counts as a serious (enough) condition in the context of PND and PGD have been unsuccessful. Such a definition may anyway be unhelpful if it cannot also take into account, for example, the woman's/couple's awareness and experience of the condition and the impact of the condition on affected individuals and their families. Individuals affected by, or at high risk of, later onset and/or reduced penetrance inherited cancer predispositions are generally supportive of access to PND and PGD for their own conditions, even if they would not consider using it themselves. Professionals working in clinical cancer genetics need to be prepared to discuss PND and PGD with this group of patients.

Introduction Lynch syndrome is known to cause an increased risk of malignancies, including bowel and endometrial cancers. However, the risk of breast cancer associated with mutations in the mismatch repair (MMR) genes that cause Lynch syndrome is still unclear. Materials and methods This study assesses the cumulative risk of breast cancer in 106 MLH1 and 118 MSH2 families. Families were referred on the basis of clinical criteria. Pedigree information was obtained, and tumour immunohistochemistry and microsatellite testing performed. Appropriate patients underwent sequencing and multiple ligation dependent probe amplification of all relevant exons of the MMR genes. Kaplan–Meier analysis of cumulative lifetime risk of breast cancer was made combining proven mutation carriers and their first-degree female relatives. Results After allocation of mutation status, the cumulative risk of breast cancer to 70 years in MLH1 carriers was 18.6% (95% CI 11.3 to 25.9)). This is significantly higher than the cumulative risk for MSH2 which was 11.2% (95% CI 1.4 to 21.0) to age 70 years (p=0.014). The UK population risk is 7.5%–8% at the age of 70 years. Prospective analysis identified six breast cancers in 1120 years of follow-up with an OR of 3.41 (95% CI 1.53 to 7.59). Discussions Female MLH1 carriers would appear to be at moderate risk of breast cancer and should be considered for breast screening at ages earlier than national screening programmes.

Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by congenital and developmental abnormalities, hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), and strong predisposition to acute myeloid leukemia (AML). In this article, we describe clinical and molecular findings in a boy with a severe FA phenotype who developed AML by the age of 2. Although he lacked a strong family history of cancer, he was subsequently shown to carry biallelic mutations in the FANCD1/BRCA2 gene. These included an IVS7 splice-site mutation, which is strongly associated with early AML in homozygous or compound heterozygous carrier status in FA-D1 patients. Myeloid leukemia cells from this patient have been maintained in culture for more than 1 year and have been designated as the SB1690CB cell line. Growth of SB1690CB is dependent on granulocyte macrophage colony stimulating factor or interleukin-3. This cell line has retained its MMC sensitivity and has undergone further spontaneous changes in the spectrum of cytogenetic aberrations compared with the primary leukemia. This is the second AML cell line derived from an FA-D1 patient and the first proof that malignant clones arising in FA patients can retain inherited MMC sensitivity. As FA-derived malignancies are normally not very responsive to treatment, this implies there are important mechanisms of acquiring correction of the cellular FA phenotype that would explain the poor chemoresponsiveness observed in FA-associated malignancies and might also play a role in the initiation and progression of cancer in the general population.

BACKGROUND: We have previously described a weighted index for determining the diagnostic significance of dento-osseous changes observed on dental panoramic radiographs (DPRs) in individuals at 50% risk of inheriting Familial Adenomatous Polyposis (FAP). A diagnostic test based on this index (Dental Panoramic Radiograph Score, DPRS) was shown to have a sensitivity of 69% and specificity of 100%. OBJECTIVES: To evaluate the validity of the diagnostic test in an independent sample of individuals at 50% risk of inheriting FAP. DESIGN: A retrospective assessment of DPRs in individuals at 50% risk of inheriting FAP. SUBJECTS AND METHODS: A final year dental student assessed blindly and independently, DPRs from an independent sample (n = 119) of affected (n = 26), unaffected (n = 78) and clinically low risk individuals (n = 15). This revealed a sensitivity and specificity of 62 and 97% respectively which is in close agreement with results of the previous study. The dental student's training in assessing DPRs was previously tested using radiographs from 81 individuals from our original study. Weighted Kappa statistics were used to test for agreement. A kappa score of 0.82 (95% confidence interval 0.70-0.93) indicated almost perfect agreement. MAIN OUTCOME: The DPRS is a reproducible and valid index for assessing the diagnostic significance of dentoosseous changes, in individuals at 50% risk of FAP, even in relatively inexperienced hands.

Presymptomatic genetic testing in childhood for adult onset conditions is generally discouraged as it does not directly benefit the child and removes their autonomy. In certain cancer prone conditions such as Familial Adenomatous Polyposis and Von Hippel Lindau disease there are risks of disease in childhood and benefit to children not inheriting a mutation in being able to forego unpleasant screening tests. Li-Fraumeni syndrome caused by constitutional TP53 mutations there are also implications in childhood with a risk of around 20% of a childhood malignancy. However, as yet no evidence based surveillance programme has been identified. We describe our experience of childhood testing for four children in two Li-Fraumeni families caused by TP53 mutations.

A weighted scoring system (Dental Panoramic Radiograph Score) taking into consideration the nature, extent, and site of osseous and dental changes on dental panoramic radiographs in familial adenomatous polyposis is described. The weighting takes into consideration the incidence of the anomaly in the general population. The reliability of the system was tested by application to 85 people known to be affected by clinical or mutation analysis, 30 people lacking mutation in the adenomatous polyposis gene, and 19 people shown to be at low risk (< 1%) by linkage analysis. Using the highest thresholds, a specificity of 100% and sensitivity of approximately 68% was obtained. If all positive findings were considered as significant, sensitivity was increased to approximately 82% but the specificity was reduced to approximately 88%. Significant DPRS findings were observed at a significantly higher frequency in patients aged over 20 compared to the patients aged 20 and under. Overall, approximately 68% of the affected subjects had significant changes, and approximately 18% had normal appearance on DPR, with the remainder having changes classified as minimal or equivocal.

One case of non-penetrance of the familial adenomatous polyposis (FAP) gene at 59 years of age and late onset of polyps on endoscopy and biopsy in this and two other families is described. Screening protocols should include dental screening as well as indirect ophthalmoscopy and endoscopy to detect minimal manifestations of the gene. In the absence of a specific DNA predictive test, bowel screening should continue well beyond 30 years of age.