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In the 33 years since the first diagnostic cancer predisposition gene (CPG) tests in the Manchester Centre for Genomic Medicine, there has been substantial changes in the identification of index cases and cascade testing for at-risk family members. National guidelines in England and Wales are usually determined from the National Institute of healthcare Evidence and these have impacted on the thresholds for testing BRCA1/2 in Hereditary Breast Ovarian Cancer (HBOC) and in determining that all cases of colorectal and endometrial cancer should undergo screening for Lynch syndrome. Gaps for testing other CPGs relevant to HBOC have been filled by the UK Cancer Genetics Group and CanGene-CanVar project (web ref. https://www.cangene-canvaruk.org/ ). We present time trends (1990-2020) of identification of index cases with germline CPG variants and numbers of subsequent cascade tests, for BRCA1, BRCA2, and the Lynch genes (MLH1, MSH2, MSH6 and PMS2). For BRCA1/2 there was a definite increase in the proportion of index cases with ovarian cancer only and pre-symptomatic index tests both doubling from 16 to 32% and 3.2 to > 8% respectively. A mean of 1.73-1.74 additional family tests were generated for each BRCA1/2 index case within 2 years. Overall close to one positive cascade test was generated per index case resulting in > 1000 risk reducing surgery operations. In Lynch syndrome slightly more cascade tests were performed in the first two years potentially reflecting the increased actionability in males with 42.2% of pre-symptomatic tests in males compared to 25.8% in BRCA1/2 (p < 0.0001)., (© 2024. The Author(s).)

Purpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC., Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53., Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83-66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58-23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52-29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2., Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC., (© 2021. The Author(s).)

DICER1 syndrome is a rare genetic disorder that predisposes to a wide spectrum of tumors. Developing surveillance protocols for this syndrome is challenging because uncertainty exists about the clinical efficacy of surveillance, and appraisal of potential benefits and harms vary. In addition, there is increasing evidence that germline DICER1 pathogenic variants are associated with lower penetrance for cancer than previously assumed. To address these issues and to harmonize DICER1 syndrome surveillance programs within Europe, the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) and Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom reviewed current surveillance strategies and evaluated additional relevant literature. Consensus was achieved for a new surveillance protocol and information leaflet that informs patients about potential symptoms of DICER1-associated tumors. The surveillance protocol comprises a minimum program and an extended version for consideration. The key recommendations of the minimum program are: annual clinical examination from birth to age 20 years, six-monthly chest X-ray and renal ultrasound from birth to age 6 years, and thyroid ultrasound every 3 years from age 8 to age 40 years. The surveillance program for consideration comprises additional surveillance procedures, and recommendations for DICER1 pathogenic variant carriers outside the ages of the surveillance interval. Patients have to be supported in choosing the surveillance program that best meets their needs. Prospective evaluation of the efficacy and patient perspectives of proposed surveillance recommendations is required to expand the evidence base for DICER1 surveillance protocols., (© 2021. The Author(s).)

To assess the need for adjustment in the likelihood of germline BRCA1/2 mutations in women with HER2+ breast cancers. We analysed primary mutation screens on women with breast cancer with unequivocal HER2 overexpression and assessed the likelihood of BRCA1/BRCA2 mutations by age, oestrogen receptor status and Manchester score. Of 1111 primary BRCA screens with confirmed HER2 status only 4/161 (2.5%) of women with HER2 amplification had a BRCA1 mutation identified and 5/161 (3.1%) a BRCA2 mutation. The pathology adjusted Manchester score between 10 and 19% and 20%+ thresholds resulted in a detection rate of only 6.5 and 15% respectively. BOADICEA examples appeared to make even less downward adjustment. There is a very low detection rate of BRCA1 and BRCA2 mutations in women with HER2 amplified breast cancers. The Manchester score and BOADICEA do not make sufficient downward adjustment for HER2 amplification. For unaffected women, assessment of breast cancer risk and BRCA1/2 probability should take into account the pathology of the most relevant close relative. Unaffected women undergoing mutation testing for BRCA1/2 should be advised that there is limited reassurance from a negative test result if their close relative had a HER2+ breast cancer.

BRCA1 and BRCA2 mutation carriers have an increased risk of contralateral breast cancer after primary breast cancer. Risk reduction strategies are discussed after assessment of risk factors for developing contralateral breast cancer. We assessed potential risk factors that could be of use in clinical practice, including the novel use of single nucleotide polymorphisms (SNP) testing. 506 BRCA1 and 505 BRCA2 mutation carriers with a diagnosis of breast cancer were observed for up to 30 years. The risk of a contralateral breast cancer is approximately 2-3% per year, remaining constant for at least 20 years. This was similar in both BRCA1 and BRCA2 carriers. Initial breast cancer before age 40-years was a significant risk factor, which was more pronounced in BRCA1 patients. The effect of risk-reducing oophorectomy on contralateral breast cancer risk may be overestimated because of bias. No significant association was found between overall breast cancer risk SNP score and contralateral breast cancer development. Young mutation carriers, particularly those with BRCA1 mutations, who develop breast cancer have a significantly higher risk of developing contralateral breast cancer, remaining constant for over 20 years. Contralateral risk-reducing mastectomy should be considered in this group, in particular as there is a survival benefit. Caution is advised when counselling women considering risk-reducing oophorectomy as, after accounting for statistical bias, the associated risk reduction was found to be non-significant, and potentially smaller than has been previously reported. SNP testing did not add any further discriminatory information when assessing contralateral breast cancer risk.

Accurate individualized breast cancer risk assessment is essential to provide risk-benefit analysis prior to initiating interventions designed to lower breast cancer risk and start surveillance. We have previously shown that a manual adaptation of Claus tables was as accurate as the Tyrer-Cuzick model and more accurate at predicting breast cancer than the Gail, Claus model and Ford models. Here we reassess the manual model with longer follow up and higher numbers of cancers. Calibration of the manual model was assessed using data from 8,824 women attending the family history evaluation and screening programme in Manchester UK, with a mean follow up of 9.71 years. After exclusion of 40 prevalent cancers, 406 incident breast cancers occurred, and 385.1 were predicted (O/E = 1.05, 95 % CI 0.95-1.16) using the manual model. Predictions were close to that of observed cancers in all risk categories and in all age groups, including women in their forties (O/E = 0.99, 95 % CI 0.83-1.16). Manual risk prediction with use of adjusted Claus tables and curves with modest adjustment for hormonal and reproductive factors was a well-calibrated approach to breast cancer risk estimation in a UK family history clinic.

Urological tumours are the third most frequent malignancy in Lynch syndrome after colonic and endometrial cancer. Upper urinary tract tumours are well recognised in Lynch syndrome, but the association with prostate and bladder cancer is controversial. We determined the incidence and cumulative and relative risks of prostate and bladder cancer in a cohort of Lynch syndrome families. Male Lynch syndrome mutation carriers and their genetically untested male first degree relatives (FDR) were identified from the Manchester Regional Lynch syndrome database (n = 821). Time to the development of urological cancer was identified for each urological site (renal pelvis, ureter, bladder and prostate). Cumulative and relative risks were calculated, with results classified by mutation carrier status and specific causative genetic mutations. Eight prostate cancers were identified, only one occurring before the age of 60. Analysis of person-years at risk of prostate cancer by Lynch syndrome mutation carrier status suggests a correlation between MSH2 mutation carriers and a tenfold increased risk of prostate cancer (RR 10.41; 95 % CI 2.80, 26.65). No such association was found with bladder cancer (RR 1.88; 95 % CI 0.21, 6.79). The association of upper urinary tract tumours with MSH2 and MLH1 mutations was confirmed. We have carried out the largest study of male Lynch syndrome mutation carriers to establish the risks of urological malignancy. A tenfold increased risk of prostate cancer is supported in MSH2 with mutation carriers having roughly double the risk of prostate cancer to FDRs. A trial of PSA testing in MSH2 carriers from 40 to 50 years may be justifiable.

The risks of cancers other than breast and ovarian amongst BRCA1 and BRCA2 mutation carriers are based on relatively few family based studies with the risk of specific cancers tested in population based samples of cancers from founder populations. We assessed risks of "other cancers" in 268 BRCA1 families and 222 BRCA2 families using a person years at risk analysis from 1975 to 2005. Cancer confirmations were overall higher than in previous family based studies at 64%. There was no overall increase in risk for BRCA1 carriers although oesophagus had a significant increased RR of 2.9 (95% CI 1.1-6.0) and stomach at 2.4 (95% CI 1.2-4.3), these were based mainly on unconfirmed cases. For BRCA2 increased risks for cancers of the pancreas (RR 4.1, 95% CI 1.9-7.8) and prostate (RR 6.3, 95% CI 4.3-9.0) and uveal melanoma (RR 99.4, 95% CI 11.1-359.8) were confirmed. Possible new associations with oesophagus (RR 4.1, 95% CI 1.9-7.8) and stomach (RR 2.7, 95% CI 1.3-4.8) were detected but these findings should be treated with caution due to lower confirmation rates. In contrast to previous research a higher risk of prostate cancer was found in males with mutations in the BRCA2 OCCR region. The present study strengthens the known links between BRCA2 and pancreatic and prostate cancer, but throws further doubt onto any association with BRCA1. New associations with upper gastro-intestinal malignancy need to be treated with caution and confirmed by large prospective studies.

Recent candidate gene and genome wide association studies have revealed novel loci associated with an increased risk of breast cancer. We evaluated the effect of these breast cancer associated variants on ovarian cancer risk in individuals with familial ovarian cancer both with and without BRCA1 or BRCA2 mutations. A total of 158 unrelated white British women (54 BRCA1/2 mutation positive and 104 BRCA1/2 mutation negative) with familial ovarian cancer were genotyped for FGFR2, TNRC9/TOX3 and CASP8 variants. The p.Asp302His CASP8 variant was associated with reduced ovarian cancer risk in the familial BRCA1/2 mutation negative ovarian cancer cases (P = 0.016). The synonymous TNRC9/TOX3 (Ser51) variant was present at a significantly lower frequency than in patients with familial BRCA1/2 positive breast cancer (P = 0.0002). Our results indicate that variants in CASP8 and TNRC9/TOX3 alter the risk of disease in individuals affected with familial ovarian cancer.

Inactivation or loss of the tumour suppressor Ras associated domain family 1 isoform A (RASSF1A) allele has been described in breast cancer. Recently, a missense polymorphism predicting p.A331S in RASSF1A was associated with an increased risk of breast cancer and early-onset breast cancer in BRCA1 and BRCA2 mutation carriers. We genotyped p.A331S RASSF1A in 854 independent, familial, white breast cancer patients (645 BRCA mutation negative, 119 BRCA1 and 90 BRCA2 positive) and compared the genotype in 331 healthy women. The RASSF1A p.A331S variant was not more common in the familial breast cancer cases than in the controls (P = 0.27). Subset analysis demonstrated no association in the BRCA1 (P = 0.26), BRCA2 (P = 0.16) or BRCA negative (P = 0.30) samples. Hence, the RASSF1A p.A331S polymorphism is not confirmed as a significant germline contributor to familial breast cancer susceptibility.

64 families with a history of male breast cancer aged 60 or less or with a family history of male and female breast cancer were screened for the presence of BRCA1 and BRCA2 mutations. Seventeen pathogenic BRCA2 and four BRCA1 mutations were identified (34%) in samples from an affected family member. All but one of the mutations segregated with disease where samples were available and pedigree structure permitted. Despite high sensitivity of mutation testing only 64% of families fulfilling BCLC criteria had an identifiable pathogenic mutation. It is possible that at least some of these families may have mutations in other genes, although we found no involvement of CHEK2 1100delC.

Evaluation of familial colorectal cancer referral can assist in the planning of future cancer surveillance. The aim of the study is to assess colorectal cancer referral pattern to our regional genetics service. Hospital computer records and/or department referral books were used to identify cases referred to the regional genetic service during a 10-year period (1992-2001 inclusive). All files were reviewed along with associated demographic data, risk assessments, referral details, results from mutation testing and screening recommendations. In terms of result, a total of 1100 family files were reviewed (Familial Adenomatous Polyposis families were in a separate register). The number of referrals showed a 10-fold increase over the 10 years. 171 (15.6%) of families met the Amsterdam criteria II were classified as high-risk, 589 (53.5%) families were classified as moderate-risk and 337 (31.0%) as average or low risk. 22.9% families were referred with inaccurate cancer history. Sixty-one families have been identified with mismatch repair mutations. 56.8% of referred individuals were recommended to have regular colonoscopy ranging from 18 monthly to 5 yearly depending on their risks. In conclusion, there has been a 10-fold increase in individuals with suspected hereditary bowel cancer referred to the North West Regional Genetics Service in the last ten years. Genetic assessment may reduce the number of low-risk individuals and those who were found not to be mutation carriers from having unnecessary colonoscopic screening. Thus genetic risk assessment should precede the initiation of regular endoscopic screening.

33 families with a history of male breast cancer aged 60 or less or with a family history of male and female breast cancer were screened for the presence of BRCA2 mutations. 12 pathogenic BRCA2 mutations were identified (36%) in samples from an affected family member. All mutations segregated with disease where it was possible to check. Of the 14 families fulfilling BCLC criteria, 9 (64%) had mutations whilst only 3/16 (19%) of male breast cancer patients with less significant female breast cancer family history having a mutation. All 3 families with ovarian cancer and 3 families with multiple male breast cancer cases had BRCA2 mutations. These data are a further guide to how to prioritise samples for BRCA2 mutation analysis.

The purpose of this study was to retrospectively compare the outcomes of treatment in 304 women with familial and sporadic breast cancer to clarify the options for the primary management of familial breast cancer. The majority of women were consecutively ascertained on the basis of either breast cancer diagnosed at age < 40 years or bilateral breast cancer. In addition, known BRCA1 mutation carriers were identified through the genetics services in participating centres. These patients were subdivided into those with a significant family history of breast cancer or known BRCA1 mutation (FH+) and those with no significant family history (FH-). There were no significant differences in age, surgical treatment or adjuvant treatment between the two groups, but there were significantly more women whose nodal status was unknown in the FH+ group. Ipsilateral recurrence occurred in 22.2% of FH+ patients compared with 24.1% of FH- patients (p = 0.774) who underwent breast conserving surgery. There was a striking excess of contralateral breast cancers in the FH+ group (35.9% v 16%, p = 0.0007), with a cumulative risk of contralateral cancer of 36% at 10 years. This was reflected in a non-significant trend toward worse relapse free survival in the FH+ group (p = 0.0563), but no difference was observed in overall survival between the two patient groups (p = 0.142). Similarly, for patients with known BRCA1 mutations, contralateral recurrence occurred more frequently, but other outcomes were not significantly different from the FH- group. Breast conserving treatment is not associated with an increased risk of local recurrence in women with familial breast cancer and the prognosis of these women appears to be similar to that of young women with apparently sporadic breast cancer. However, the risk of contralateral breast cancer is significant in the FH+ group and should be considered in planning primary treatment and follow up.