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Simple Summary: Females with PTEN Hamartoma Tumor Syndrome (PHTS) have very high hereditary breast cancer risks up to 76%. The aim of this European cohort study was to the describe the lifestyle in PHTS patients and to assess associations between physical activity, alcohol consumption, tobacco smoking, BMI and breast cancer in female adult PHTS patients. It was observed that of 125 patients who completed the questionnaire, 81% were ≥2 times/week physically active, 86% consumed on average <1 glass of alcohol/day, 78% never smoked and most patients were overweight or obese (72%). In total, 39 developed breast cancer (31%). No indications were found that associations between lifestyle and breast cancer in PHTS patients are different from the general population. These findings suggest that awareness about lifestyle among PHTS patients is important, as a healthier lifestyle could potentially decrease their breast cancer risk in a similar way as for the general population. Females with PTEN Hamartoma Tumor Syndrome (PHTS) have breast cancer risks up to 76%. This study assessed associations between breast cancer and lifestyle in European female adult PHTS patients. Data were collected via patient questionnaires (July 2020–March 2023) and genetic diagnoses from medical files. Associations between lifestyle and breast cancer were calculated using logistic regression corrected for age. Index patients with breast cancer before PHTS diagnosis (breast cancer index) were excluded for ascertainment bias correction. In total, 125 patients were included who completed the questionnaire at a mean age of 44 years (SD = 13). This included 21 breast cancer indexes (17%) and 39 females who developed breast cancer at 43 years (SD = 9). Breast cancer patients performed about 1.1 times less often 0–1 times/week physical activity than ≥2 times (ORtotal-adj = 0.9 (95%CI 0.3–2.6); consumed daily about 1.2–1.8 times more often ≥1 than 0–1 glasses of alcohol (ORtotal-adj = 1.2 (95%CI 0.4–4.0); ORnon-breastcancer-index-adj = 1.8 (95%CI 0.4–6.9); were about 1.04–1.3 times more often smokers than non-smokers (ORtotal-adj = 1.04 (95%CI 0.4–2.8); ORnon-breastcancer-index-adj = 1.3 (95%CI 0.4–4.2)); and overweight or obesity (72%) was about 1.02–1.3 times less common (ORtotal-adj = 0.98 (95%CI 0.4–2.6); ORnon-breastcancer-index-adj = 0.8 (95%CI 0.3–2.7)). Similar associations between lifestyle and breast cancer are suggested for PHTS and the general population. Despite not being statistically significant, results are clinically relevant and suggest that awareness of the effects of lifestyle on patients' breast cancer risk is important. [ABSTRACT FROM AUTHOR]

Background: In South-Eastern Norway, genetic testing for BRCA1 and BRCA2 is offered to breast cancer patients by their treating surgeon or oncologist. Genetic counselling from a geneticist or a genetic counsellor is offered only to those who test positive for a pathogenic variant or have a family history of cancer. This practice is termed "mainstreamed genetic testing". The aim of this study was to learn about patients' experience of this healthcare service. Methods: Qualitative in-depth interviews were conducted with 22 breast cancer patients who had been diagnosed during the first half of 2016 or 2017 at one regional and one university hospital and who had been offered testing by their treating physician. A six-phase thematic approach was used to analyse the data. Results: The participants had varied experiences of how and when testing was offered. Three main themes emerged from the analysis: 1. informational and communicational needs and challenges during a chaotic time, 2. the value of genetic testing and 3. the importance of standardised routines for mainstreamed genetic testing. Conclusions: Despite the shock of their diagnosis and the varying experiences they had in respect of how and when testing was offered, all of the participants emphasised that genetic testing had been an important part of their diagnosis and treatment. Our results indicate that there is a need for continuous collaboration between geneticists, surgeons, oncologists and laboratory specialists in order to establish simple and robust routines so as to ensure that all eligible breast cancer patients are offered testing at a point when the test result can have an impact on treatment. [ABSTRACT FROM AUTHOR]

Studies have shown that a significant number of eligible breast cancer patients are not offered genetic testing or referral to genetic counseling. To increase access to genetic testing in South Eastern Norway, testing has since 2014 been offered directly to breast cancer patients by surgeons and oncologists. This practice is termed "mainstreamed genetic testing". The aim of this study was to investigate to what extent patients in South Eastern Norway are offered testing. Three hundred and sixty one patients diagnosed in 2016 and 2017 at one regional and one university hospital in South Eastern Norway were included. Data on whether the patients fulfilled the criteria, whether they had been offered testing and if they were tested were collected. In total, 26.6% (96/361) fulfilled the criteria for testing. Seventy five percent (69/92) of these were offered testing, and 71.7% (66/92) were tested. At the university hospital, 90.2% (37/41) of eligible patients were offered testing, and at the regional hospital 62.7% (32/51). Fifty two percent (12/23) of eligible patient not offered testing were younger than 50 years at time of diagnosis. As many as 95.4% (125/131) of all patients who were offered testing, wanted to be tested. The majority of patients who fulfilled the criteria were offered testing, supporting the practice of mainstreamed genetic testing. There were nevertheless differences in rates of testing between the hospitals that affected all groups of patients, indicating that genetic testing may not be equally accessible to all patients. We suggest that efforts should be made to increase awareness and improve routines for genetic testing of breast cancer patients in Norway. [ABSTRACT FROM AUTHOR]

Prostate cancer is one of the most common and heritable human cancers. Our aim was to find germline biomarkers that can predict disease outcome. We previously detected predisposing signals at 2q37, the location of the prostate specific ANO7 gene. To investigate, in detail, the associations between the ANO7 gene and PrCa risk and disease aggressiveness, ANO7 was sequenced in castration resistant tumors together with samples from unselected PrCa patients and unaffected males. Two pathogenic variants were discovered and genotyped in 1769 patients and 1711 unaffected males. Expression of ANO7 vs. PrCa aggressiveness was investigated. Different databases along with Swedish and Norwegian cohorts were used for validation. Case–control and aggressive vs. nonaggressive association analyses were performed against risk and/or cancer aggressiveness. The ANO7 mRNA level and patient survival were analyzed using expression data from databases. Variant rs77559646 showed both risk (OR 1.40; p = 0.009, 95% CI 1.09–1.78) and association with aggressive PrCa (Genotype test p = 0.04). It was found to be an eQTL for ANO7 (Linear model p‐values for Finnish patients p = 0.009; Camcap prostate tumor p = 2.53E‐06; Stockholm prostate tumor cohort p = 1.53E‐13). rs148609049 was not associated with risk, but was related to shorter survival (HR 1.56; 95% CI 1.03–2.36). High ANO7 expression was independently linked to poor survival (HR 18.4; 95% CI 1.43–237). ANO7 genotypes correlate with expression and biochemical relapse, suggesting that ANO7 is a potential PrCa susceptibility gene and that its elevated expression correlates with disease severity and outcome. What's new? The discovery of germline biomarkers to predict outcome in prostate cancer could greatly aid disease management. One such marker of particular interest in this regard is the prostate‐specific gene ANO7, which previous studies have associated with high‐grade prostate cancer. Here, specific germline ANO7 genotypes were associated with increased prostate cancer risk. In patients, ANO7 expression correlated with disease severity, with elevated expression associated with decreased overall survival. The data suggest that ANO7 is a susceptibility marker in prostate cancer and, with further characterization, could be used to inform patient selection strategies and therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort.Methods: PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV.Results: 1634 participants had ⩾3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml-l, PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers.Conclusions: PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone. [ABSTRACT FROM AUTHOR]

Background: Founder mutations in the two breast cancer genes, BRCA1 and BRCA2, have been described in many populations, among these are Ashkenazi-Jewish, Polish, Norwegian and Icelandic. Founder mutation testing in patients with relevant ancestry has been a cost-efficient approach in such populations. Four Norwegian BRCA1 founder mutations were defined by haplotyping in 2001, and accounted for 68% of BRCA1 mutation carriers at the time. After 15 more years of genetic testing, updated knowledge on the mutation spectrum of both BRCA1 and BRCA2 in Norway is needed. In this study, we aim at describing the mutation spectrum and frequencies in the BRCA1/2 carrier population of the largest clinic of hereditary cancer in Norway. Methods: A total of 2430 BRCA1 carriers from 669 different families, and 1092 BRCA2 carriers from 312 different families were included in a quality of care study. All variants were evaluated regarding pathogenicity following ACMG/ENIGMA criteria. The variants were assessed in AlaMut and supplementary databases to determine whether they were known to be founder mutations in other populations. Results: There were 120 different BRCA1 and 87 different BRCA2 variants among the mutation carriers. Forty-six per cent of the registered BRCA1/2 families (454/981) had a previously reported Norwegian founder mutation. The majority of BRCA1/2 mutations (71%) were rare, each found in only one or two families. Fifteen per cent of BRCA1 families and 25% of BRCA2 families had one of these rare variants. The four well-known Norwegian BRCA1 founder mutations previously confirmed through haplotyping were still the four most frequent mutations in BRCA1 carriers, but the proportion of BRCA1 mutation carriers accounted for by these mutations had fallen from 68 to 52%, and hence the founder effect was weaker than previously described. Conclusions: The spectrum of BRCA1 and BRCA2 mutations in the carrier population at Norway's largest cancer genetics clinic is diverse, and with a weaker founder effect than previously described. As a consequence, retesting the families that previously have been tested with specific tests/founder mutation tests should be a prioritised strategy to find more mutation positive families and possibly prevent cancer in healthy relatives. [ABSTRACT FROM AUTHOR]

Background: Identification of BRCA mutations in breast cancer (BC) patients influences treatment and survival and may be of importance for their relatives. Testing is often restricted to women fulfilling high-risk criteria. However, there is limited knowledge of the sensitivity of such a strategy, and of the clinical aspects of BC caused by BRCA mutations in less selected BC cohorts. The aim of this report was to address these issues by evaluating the results of BRCA testing of BC patients in South-Eastern Norway.Methods: 1371 newly diagnosed BC patients were tested with sequencing and Multi Ligation Probe Amplification (MLPA). Prevalence of mutations was calculated, and BC characteristics among carriers and non-carriers compared. Sensitivity and specificity of common guidelines for BRCA testing to identify carriers was analyzed. Number of identified female mutation positive relatives was evaluated.Results: A pathogenic BRCA mutation was identified in 3.1%. Carriers differed from non-carriers in terms of age at diagnosis, family history, grade, ER/PR-status, triple negativity (TNBC) and Ki67, but not in HER2 and TNM status. One mutation positive female relative was identified per mutation positive BC patient. Using age of onset below 40 or TNBC as criteria for testing identified 32-34% of carriers. Common guidelines for testing identified 45-90%, and testing all below 60 years identified 90%. Thirty-seven percent of carriers had a family history of cancer that would have qualified for predictive BRCA testing. A Variant of Uncertain Significance (VUS) was identified in 4.9%.Conclusions: Mutation positive BC patients differed as a group from mutation negative. However, the commonly used guidelines for testing were insufficient to detect all mutation carriers in the BC cohort. Thirty-seven percent had a family history of cancer that would have qualified for predictive testing before they were diagnosed with BC. Based on our combined observations, we suggest it is time to discuss whether all BC patients should be offered BRCA testing, both to optimize treatment and improve survival for these women, but also to enable identification of healthy mutation carriers within their families. Health services need to be aware of referral possibility for healthy women with cancer in their family. [ABSTRACT FROM AUTHOR]

Germline mutations in the CDKN2A gene are associated with an increased risk of malignant melanoma and pancreatic cancer. In order to find out if the behavior pattern in families with a CDKN2A mutation is similar to what we previously have described in families with a BRCA1 mutation, we have studied the uptake of genetic services in probands and their relatives. We describe whether they attend genetic counseling when invited, whether they want a mutation test after being counseled and whether they adhere to recommendations for surveillance. 66 % (95/144) of first-degree relatives to mutation carriers contacted us within the study period. 98 % (126/128) of all relatives who came for genetic counseling decided on genetic testing for their family's mutation, and 93 % (66/71) of all mutation carriers wanted referral to yearly skin examinations. Female relatives had a significantly higher uptake of genetic services compared to males, similar to the findings in families with a BRCA1 mutation. Uptake of genetic services in general in families with a CDKN2A mutation is high. Females seem to have a higher interest in genetic testing than males, regardless of gene mutated. [ABSTRACT FROM AUTHOR]

Germline mutations in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. Molecular screening of these two genes in patients with a family history of breast or ovarian cancer has revealed pathogenic variants as well as genetic variants of unknown significance (VUS). These VUS may cause a challenge in the genetic counseling process regarding clinical management of the patient and the family. We investigated 32 variants previously detected in 33 samples from patients with a family history of breast or ovarian cancer. cDNA was analyzed for alternative transcripts and selected missense variants located in the BRCT domains of BRCA1 were assessed for their trans-activation ability. Although an extensive cDNA analysis was done, only three of the 32 variants appeared to affect the splice-process ( BRCA1 c.213-5T>A, BRCA1 c.5434C>G and BRCA2 c.68-7T>A). In addition, two variants located in the BRCT domains of BRCA1 (c.5075A>C p.Asp1692Ala and c.5513T>G p.Val1838Gly) were shown to abolish the BRCT domain trans-activation ability, whereas BRCA1 c.5125G>A p.Gly1709Arg exhibited equal trans-activation capability as the WT domain. These functional studies may offer further insights into the pathogenicity of certain identified variants; however, this assay is only applicable for a subset of missense variants. [ABSTRACT FROM AUTHOR]

Background: Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant syndrome caused by activating germline mutations in the RET ( REarranged during Transfection) proto-oncogene. MEN 2A has a strong (>95%) and age-dependent (5-25 years) clinical penetrance of medullary thyroid carcinoma (MTC). Several major studies have analyzed the predictive and prognostic factors for MEN 2A to find indicators that predict the optimal timing of prophylactic thyroidectomy. The aims of this study were to describe all known RET positive MEN 2A patients diagnosed in Norway and to evaluate the clinical course of MTC, as well as its predictive and prognostic factors. Methods: This nationwide retrospective cohort study included data for 65 (14 index and 51 screening patients) out of a total of 67 MEN 2A patients with the RET gene mutation who were diagnosed in Norway since 1974. Data were collected by reviewing patient files. The variables analyzed were genotype, phenotype, preoperative basal calcitonin, age at thyroid surgery, central lymph node dissection and nodal status at primary surgery, number of surgical procedures, and biochemical cure. Of the 65 patients, 60 had undergone thyroid surgery. The median follow-up period was 9.9 years. The patients were divided into pre- RET-and RET-era, which included patients who had thyroid surgery before January 1, 1994, and after, respectively. Results: In index and screening patients, MTC was found, respectively, in 100% and 45% of cases, central lymph node dissection at primary surgery was done for 64% and 52% of patients, and the median total number of surgical procedures was two (range 1-6) and one (range 1-4). At primary surgery, all patients ( n = 13) with lymph node metastases had preoperative basal calcitonin levels ≥68 pg/mL, and all patients ( n = 17) without central lymph node dissection and preoperative basal calcitonin <40 pg/mL were biochemically cured. Multivariate analysis showed that preoperative basal calcitonin was a significant predictive factor for MTC superior to age at thyroid surgery when analyzing the entire period ( p = 0.009) and the RET-era separately ( p = 0.021). Prognostic factors for biochemical cure were preoperative basal calcitonin, central lymph node dissection, and nodal status at primary surgery ( p = 0.037, p = 0.002, and p = 0.005) when analyzing the entire period, but only nodal status at primary surgery when the RET-era was considered separately ( p = 0.006). Conclusions: Preoperative basal calcitonin alone can serve as an indicator for optimal timing and the extent of thyroid surgery for MEN 2A patients that could be considered safe. The results are consistent with previously reported data. [ABSTRACT FROM AUTHOR]

Background: Common genetic variants have been shown to modify BRCA1 penetrance. The aim of this study was to validate these reports in a special cohort of Norwegian BRCA1 mutation carriers that were selected for their extreme age of onset of disease. Methods: The ten variants rs13387042, rs3803662, rs8170, rs9397435, rs700518, rs10046, rs3834129, rs1045485, rs2363956 and rs16942 were selected to be tested on samples from our biobank. We selected female BRCA1 mutation carriers having had a diagnosis of breast or ovarian cancer below 40 years of age (young cancer group, N = 40), and mutation carriers having had neither breast nor ovarian cancer above 60 years of age (i.e., old no cancer group, N = 38). Relative risks and odd ratios of belonging to the young cancer versus old no cancer groups were calculated as a function of having or not having the SNPs in question. Results: Five of the ten variants were found to be significantly associated with early onset cancer. Some of the variation between our results and those previously reported may be ascribed to stochastic effects in our limited number of patient studies, and/or genetic drift in linkage disequilibrium in the genetically isolated Norwegian population. This is in accordance with the understanding that the SNPs are markers in linkage disequilibrium with their respective disease-causing genetic variants, and that this may vary between different populations. Conclusions: The results confirmed associations previously reported, with the notion that the degree of association may differ between other populations, which must be considered when discussing the clinical use of the associations described. [ABSTRACT FROM AUTHOR]

Background: Common genetic variants have been shown to modify BRCA1 penetrance. The aim of this study was to validate these reports in a special cohort of Norwegian BRCA1 mutation carriers that were selected for their extreme age of onset of disease. Methods: The ten variants rs13387042, rs3803662, rs8170, rs9397435, rs700518, rs10046, rs3834129, rs1045485, rs2363956 and rs16942 were selected to be tested on samples from our biobank. We selected female BRCA1 mutation carriers having had a diagnosis of breast or ovarian cancer below 40 years of age (young cancer group, N = 40), and mutation carriers having had neither breast nor ovarian cancer above 60 years of age (i.e., old no cancer group, N = 38). Relative risks and odd ratios of belonging to the young cancer versus old no cancer groups were calculated as a function of having or not having the SNPs in question. Results: Five of the ten variants were found to be significantly associated with early onset cancer. Some of the variation between our results and those previously reported may be ascribed to stochastic effects in our limited number of patient studies, and/or genetic drift in linkage disequilibrium in the genetically isolated Norwegian population. This is in accordance with the understanding that the SNPs are markers in linkage disequilibrium with their respective disease-causing genetic variants, and that this may vary between different populations. Conclusions: The results confirmed associations previously reported, with the notion that the degree of association may differ between other populations, which must be considered when discussing the clinical use of the associations described. [ABSTRACT FROM AUTHOR]

Background: Using immunohistochemistry (IHC) to select cases for mismatch repair (MMR) genetic testing, we failed to identify a large kindred with the deleterious PMS2 mutation c.989-1G > T. The purpose of the study was to examine the sensitivity of IHC and microsatellite instability-analysis (MSI) to identify carriers of the mutation, and to estimate its penetrance and expressions. Methods: All carriers and obligate carriers of the mutation were identified. All cancer diagnoses were confirmed. IHC and MSI-analysis were performed on available tumours. Penetrances of cancers included in the Amsterdam and the Bethesda Criteria, for MSI-high tumours and MSI-high and low tumours were calculated by the Kaplan-Meier algorithm. Results Probability for co-segregation of the mutation and cancers by chance was 0.000004. Fifty-six carriers or obligate carriers were identified. There was normal staining for PMS2 in 15/18 (83.3%) of tumours included in the AMS1/AMS2/Bethesda criteria. MSI-analysis showed that 15/21 (71.4%) of tumours were MSI-high and 4/21 (19.0%) were MSI-low. Penetrance at 70 years was 30.6% for AMS1 cancers (colorectal cancers), 42.8% for AMS2 cancers, 47.2% for Bethesda cancers, 55.6% for MSI-high and MSI-low cancers and 52.2% for MSI-high cancers. Conclusions: The mutation met class 5 criteria for pathogenicity. IHC was insensitive in detecting tumours caused by the mutation. Penetrance of cancer was 56% at 70 years. Besides colorectal cancers, the most frequent expressions were carcinoma of the endometrium and breast in females and stomach and prostate in males. [ABSTRACT FROM AUTHOR]

We report prospectively observed risk for breast cancer in breast cancer kindreds without a demonstrable BRCA1/ 2 mutation. According to family history, the optimal available member(s) of each breast cancer kindred attending our clinic was tested for BRCA mutations. Women in families without a demonstrable BRCA mutation were subjected to annual mammography. BRCA mutations were demonstrated in 496/2,118 (23 %) breast cancer kindreds. In families without a demonstrable BRCA mutation, a total of 3,161 healthy women aged 25-59 years were prospectively followed for 24,808 observation years. Sixty-four cancers were observed, compared to 34.0 expected ( p < 0.01), arriving at a 7.9 % cumulative risk at age 60 compared to 4.0 % in the population [relative risk (RR) = 2.0]. Women with one mother or sister affected ≤50 years and with no other close relatives with breast cancer did not have increased risk (0 cancers observed and 0.6 expected at age 40, 11 cancers observed and 7.9 expected at age 60, p > 0.05). Excluding these, cumulative risk at 60 years was 8.8 % (RR = 2.2). The highest cumulative risk at 60 years was 11.4 %, found in families with two cases ≤55 years (RR = 2.8). In breast cancer kindreds without a demonstrable BRCA mutation, the risk for breast cancer in female first degree relatives was about twice the risk in the general population. Women with one early affected relative only did not have increased risk for early onset breast cancer, while those with more than one young affected relative had close to three times population risk. [ABSTRACT FROM AUTHOR]

We report the 5- and 10-year survival rate of women diagnosed with breast cancer in the context of an annual MRI-based surveillance program. In 2001, as part of a national initiative, women in Norway with a BRCA1 mutation were offered annual screening with breast MRI in addition to mammography. 802 women with a BRCA1 mutation were screened one or more times and followed for a mean of 4.2 years. As of December 2011, 68 of 802 women in the screening program were diagnosed with DCIS or invasive breast cancer (8.5 %), including eight prevalent, 50 incident screen-detected and eight interval cancers. Two latent cancers were detected at prophylactic mastectomy. Sixty-three of the cancers were invasive and five were in situ. The mean tumour size was 1.4 cm (range 0.2-4.5 cm), and 85 % of the patients were node-negative. Ten of the 68 patients died of cancer in the follow-up period. The 5-year breast cancer-specific survival for women with cancer was 75 % (95 % CI 56-86 %) and the 10-year survival was 69 % (95 % CI: 48-83 %). The 5-year survival for women with Stage 1 breast cancer was 82 % compared to 98 % in the population. The 5- and 10-year survival of women with a BRCA1-associated breast cancer detected in a national MRI-based screening program in BRCA1 mutation carriers Norway was less than anticipated. The benefit of annual MRI surveillance on reducing breast cancer mortality in BRCA1 mutation carriers remains to be proven. [ABSTRACT FROM AUTHOR]

Endometrial cancer is frequent in MMR-mutation carriers. Estimates of annual incidence rates have, however, been based on retrospective studies. The purpose of our study was to prospectively assess the incidence rates of endometrial cancer in women either having a mutation in one of the four MMR genes MLH1, MSH2, MSH6 or PMS2 (Mut+) or belonging to families meeting the revised Amsterdam criteria in which no MMR mutation was detected (Ams+). Eight out of 80 Mut+ (10%) contracted invasive endometrial cancer compared to 1/171 (0.6%) of the Ams+ ( P = 0.0006). The annual incidence rate after first control was 2.5% in Mut+ and 0.2% in Ams+. Two of the 8 Mut+ women (25%) had synchronous gynaecological tumours. The numbers included did not allow for firm conclusions, but the results are in keeping with the notion that the inherited colon-endometrial cancer syndrome may be restricted to carriers of MMR mutations. [ABSTRACT FROM AUTHOR]

Background: Chemoresistance is the main obstacle to cure in most malignant diseases. Anthracyclines are among the main drugs used for breast cancer therapy and in many other malignant conditions. Single parameter analysis or global gene expression profiles have failed to identify mechanisms causing in vivo resistance to anthracyclines. While we previously found TP53 mutations in the L2/L3 domains to be associated with drug resistance, some tumors harboring wild-type TP53 were also therapy resistant. The aim of this study was; 1) To explore alterations in the TP53 gene with respect to resistance to a regular dose epirubicin regimen (90 mg/m² every 3 week) in patients with primary, locally advanced breast cancer; 2) Identify critical mechanisms activating p53 in response to DNA damage in breast cancer; 3) Evaluate in vitro function of Chk2 and p14 proteins corresponding to identified mutations in the CHEK2 and p14(ARF) genes; and 4) Explore potential CHEK2 or p14(ARF) germline mutations with respect to family cancer incidence. Methods and Findings: Snap-frozen biopsies from 109 patients collected prior to epirubicin (as preoperative therapy were investigated for TP53, CHEK2 and p14(ARF) mutations by sequencing the coding region and p14(ARF) promoter methylations. TP53 mutastions were associated with chemoresistance, defined as progressive disease on therapy (p = 0.0358; p = 0.0136 for mutations affecting p53 loop domains L2/L3). Germline CHEK2 mutations (n = 3) were associated with therapy resistance (p = 0.0226). Combined, mutations affecting either CHEK2 or TP53 strongly predicted therapy resistance (p = 0.0101; TP53 mutations restricted to the L2/L3 domains: p = 0.0032). Two patients progressing on therapy harbored the CHEK2 mutation, Arg95Ter, completely abrogating Chk2 protein dimerization and kinase activity. One patient (Epi132) revealed family cancer occurrence resembling families harboring CHEK2 mutations in general, the other patient (epi203) was non-conclusive. No mutation or promoter hypermethylation in p14(ARF) were detected. Conclusion: This study is the first reporting an association between CHEK2 mutations and therapy resistance in human cancers and to document mutations in two genes acting direct up/down-stream to each other to cause therapy failure, emphasizing the need to investigate functional cascades in future studies. [ABSTRACT FROM AUTHOR]

Objective. In recent years persons at risk for colorectal cancers (CRC) have been subjected to follow-up with colonoscopy in many centres. There is, however, limited knowledge about the effect of such interventions. The objective of this study was to report the results of our observations during the past 15 years. Material and methods. Healthy persons were included in the study according to their family history of CRCs, and prospectively followed with colonoscopies. Results. Altogether, 1133 individuals were included and observed for a total of 3474 follow-up years from the first to the last colonoscopy initiated by our activity. Mismatch repair (MMR) mutations were detected in 6.5% of cases. A total of 1383 polyps were removed, 72% were less than 5 mm in diameter. Findings were scored as hyperplastic polyps (n=887), adenomas with mild to moderate dysplasia (n=460), adenomas with high-grade dysplasia (n=30) and cancers (n=6). Two cancers were observed after the first colonoscopy, compared with 2.6 expected by chance and more than 20 expected under the hypothesis of predominant inherited diseases in the families. Observed annual incidence rates for adenomas were similar in all groups, while in the mutation carriers there was a higher frequency of progression to severe dysplasia or infiltrating cancer. Conclusions. A simple explanation for the combined findings may be that all selected families had a similar tendency to produce adenomas, while mutation carriers more frequently demonstrated dysplasia/cancer in the adenomas. The low annual incidence rates for CRC indicated that the removal of adenomas may have prevented cancers. [ABSTRACT FROM AUTHOR]

BRCA1 associated tumours are found to express an oestrogen receptor negative “basal epithelial-like” phenotype. In contrast to ER negative tumours in general, such tumours rarely harbour amplification of the HER-2 gene. However, little is known about TOP2A gene amplification status in BRCA1-associated tumours. Such information may be of importance to therapy, as amplification of TOP2A has been associated with dose-dependent sensitivity to anthracycline therapy in breast cancer. We examined 40 breast carcinomas from BRCA1 mutation carriers and 40 sporadic breast carcinomas matched for age, tumour diameter and histological grade for HER-2 and TOP2A amplification status using fluorescence in situ hybridisation (FISH). Co-amplification of TOP2A and HER-2 was found in four of the mutation carriers and in three of the controls. While six tumours in the control group harboured HER-2 amplifications with normal TOP2A, this occurred in three of the BRCA1 associated tumours only. In contrast, three of the BRCA1-associated tumours but none of the controls harboured TOP2A amplification despite normal HER-2 status. Our findings have potential therapeutic implications. HER-2 assessment is routinely used to select breast cancer patients for trastuzumab but also dose-intensive anthracycline therapy. Our data suggest that BRCA1-associated breast cancers also need to be tested for TOP2A amplification. [ABSTRACT FROM AUTHOR]

Background: Although quality of life (QoL) and mental distress in women belonging to familial cancer families have been studied, little is known on these matters in women with absence of demonstrated mutations. The aim of this study was to examine QoL and cancer-related distress in such women. Methods: About 330 women at risk for familial cancers in the absence of demonstrated mutations were invited to the study. About 239 women (72%) (risk group) completed the Short Form 12 (SF-12) and the Impact of Event Scale (IES). The SF-12-findings were compared to the age-adjusted findings from the general female population (controls). Results: The risk group had significantly better physical QoL than controls, while no significant difference was found for mental QoL. Within the risk group the type of familial cancer did not make a significant difference in QoL, but to have a father with cancer or a deceased parent, was associated with increased risk of being a case with low QoL. Mental QoL showed moderate correlation with cancer-related distress. Conclusions: : Women belonging to familial cancer families in the absence of demonstrated mutations had at least as good QoL as controls in spite of living with a permanent cancer-related threat. [ABSTRACT FROM AUTHOR]

A total of 845 women from breast-ovarian cancer kindreds were enrolled in a clinical follow-up program for early disease diagnosis; 35 women were prospectively identified with cancer. In order to estimate the role of genetic factors for cancer predisposition in this well-defined set of patients, considered as representative for familial breast-ovarian cancer in the Norwegian population, the BRCA1 gene was investigated for germline mutations. The entire coding region of BRCA1 was analysed using a protein truncation test, direct sequencing and a screen for known large genomic deletions and insertions. Twenty one (60%) of the 35 patients were identified as carriers of 11 distinct BRCA1 mutations. Two previously described founder mutations, 1675delA and 1135insA, were found to account for more than half (11/21) of all BRCA1 cases and for almost one third (11/35) of all breast and ovarian cancers. Supported by a previous population-based analysis of these founder mutations in ovarian cancer, our findings suggest that a significant proportion of women at risk for developing inherited breast and ovarian cancer can be identified. This is particularly obvious in certain geographic regions where these founder mutations are prevalent. Women carrying the two founder mutations had a significantly older age of disease onset as compared to women with other BRCA1 mutations. This observation indicates that BRCA mutation penetrance estimates from populations with strong founder effects may be biased. One reason why some deleterious mutations are allowed to prevail in a population may be coupled to penetrance and the fact that they seldom induce disease in women in child-bearing ages. Eleven out of 12 (92%) breast cancers in BRCA1 mutation carriers were estrogen receptor negative, versus 4 out of 9 (44%) in mutation negative patients (p = 0.03). Histopathological characteristics of the prospectively detected cancers indicated an unfavourable prognosis in mutation carriers. [ABSTRACT FROM AUTHOR]

Based on results from our surveillance program for women at risk for inherited breast cancer, we have calculated cost per year earned. Norwegian National Insurance Service reimbursement fees were used in the calculations. The calculated costs are based on empirical figures for expanding already established medical genetic departments and diagnostic outpatient clinics to undertake the work described. Cost per year earned was estimated at Euro 753 using our current practice of identifying the high-risk women through a traditional cancer family clinic. A strategy of identifying the high-risk families through genetic testing of all incident breast and ovarian cancers for founder mutations in BRCA1, will increase the cost to Euro 832. Costs related more to genetic counseling and clinical follow-up than to laboratory procedures. This potential economic limiting factor coincides with a shortage of personnel trained in genetic counseling. The number of relatives counseled to identify one healthy female mutation carrier (i.e. the uptake of genetic testing) is more important to cost-effectiveness than family size. Costs will vary depending upon the penetrance of the mutations detected and the prevalence of founder mutations in the population examined. Prevalences of BRCA1 founder mutations in some high incidence areas of Norway may be sufficiently high to consider population screening. Unlike mutation screening of cancer genes, founder mutation analysis will not identify DNA variants of uncertain clinical significance. Identification of high-risk families through founder mutation analysis of BRCA1 ensures that families with maximum risks are given first access to the limited resources of the high-risk clinics. This may be the greatest contribution to increased cost effectiveness of such a strategy. The assumptions underlying the calculations are discussed. The conclusion is that inherited breast cancer may be managed effectively for the cost of Euro 750–1,600 per... [ABSTRACT FROM AUTHOR]

BACKGROUND: Surveillance programmes for women at increased genetic risk of breast cancer are being established worldwide but little is known of their efficacy in early detection of cancers and hence reduction in mortality. METHODS: Data were contributed from seven centres participating in the EU Demonstration Programme on Clinical Services for Familial Breast Cancer.  All breast tumours (n = 161) detected prospectively, from the time of enrolment of women in a screening programme, were recorded.  Analysis took account of age at diagnosis, whether tumours were screen-detected or not, their pathological stage and outcome by Kaplan—Meier survival plots. RESULTS: Mean age at diagnosis was 48.6 years. Overall, 75% of tumours were detected in the course of planned examinations.  For women under age 50 at diagnosis, this figure was 68%.  Eighteen percent were mammographically negative, (23% in patients under age 50).  At first ("prevalence") round and at follow-up screening, 16% and 22% of tumours respectively were carcinoma in situ (CIS) while 27% and 22% respectively had evidence of nodal or distant spread (CaN+).  Comparison of screen-detected and other tumours showed that the latter were more frequently mammogram-negative and CaN+.  Overall five-year survival was 89% and five-year event-free survival 86%.  Five-year event-free survival was 100% for CIS, 88% for invasive cancer without nodal or distant spread and 67% for CaN+. CONCLUSIONS: The majority of cancers arising in women at increased genetic risk of breast cancer can be detected by planned screening, even in those under age 50.  Surveillance should include regular expert clinical examination and teaching of "breast awareness" as well as mammography.  Attention to the logistics of screening programmes may improve still further the proportion of tumours that are screen-detected.  The... [ABSTRACT FROM AUTHOR]

The article presents the authors' views on a case report about a girl with Fanconi anaemia (FA), wherein she also exhibited breast and ovarian cancer. It notes that a patient with FA may be heterozygous if carrying different mutations, or homozygous if carrying the same mutation on both alleles. They agreed that when FA is caused by biallelic Germline breast cancer gene 2 mutations, both mutations may not necessarily be recognized as pathogenic with respect to breast and ovarian cancer.

Background: Pathogenic variants in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. Screening of these genes has become easily accessible in diagnostic laboratories. Sequencing and copy number analyses are used to detect pathogenic variants, but also lead to identification of variants of unknown clinical significance (VUS). If the effect of a VUS can be clarified, it has direct consequence for the clinical management of the patient and family members. A splicing assay is one of several tools that might help in the classification of VUS. We therefore established mRNA analyses for BRCA1 and BRCA2 in the diagnostic laboratory in 2015. We hereby report the results of mRNA analysis variants in BRCA1 and BRCA2 after three years. Methods: Variants predicted to alter splicing and variants within the canonical splice sites were selected for splicing analyses. Splicing assays were performed by reverse transcription-PCR of patient RNA. A biallalic expression analysis was carried out whenever possible. Results: Twenty-five variants in BRCA1 and BRCA2 were analyzed by splicing assays; nine showed altered transcripts and 16 showed normal splicing patterns. The two novel pathogenic variants in BRCA1 c.4484 + 3 A > C and c.5407–10G > A were characterized. Conclusions: We conclude that mRNA analyses are useful in characterization of variants that may affect splicing. The results can guide classification of variants from unknown clinical significance to pathogenic or benign in a diagnostic laboratory, and thus be of direct clinical importance. [ABSTRACT FROM AUTHOR]

This corrects the article DOI: 10.1038/bjc.2017.429. [ABSTRACT FROM AUTHOR]

Background Reported prevalence, penetrance and expression of deleterious mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2, may reflect differences in the clinical criteria used to select families for DNA testing. The authors have previously reported that clinical criteria are not sensitive enough to identify MMR mutation carriers among incident colorectal cancer cases. Objective To describe the sensitivity of the criteria when applied to families with a demonstrated MMR mutation. Methods Families with an aggregation of colorectal cancers were examined for deleterious MMR mutations according to the Mallorca guidelines. All families with a detected MMR mutation as of November 2009 were reclassified according to the Amsterdam and Bethesda criteria. Results Sixty-nine different DNA variants were identified in a total of 129 families. The original Amsterdam clinical criteria were met by 38%, 12%, 78% and 25% of families with mutations in MSH2, MSH6, MLH1 and PMS2, respectively. Corresponding numbers for the revised Amsterdam criteria were 62%, 48%, 87% and 38%. Similarly, each of the four clinical Bethesda criteria had low sensitivity for identifying MSH6 or PMS2 mutations. Conclusion Amsterdam criteria and each of the Bethesda criteria were inadequate for identifying MSH6 mutation-carrying kindreds. MSH6 mutations may be more common than currently assumed, and the penetrance/expression of MSH6 mutations, as derived from families meeting current clinical criteria, may be misleading. To increase detection rate of MMR mutation carriers, all cancers in the Lynch syndrome tumour spectrum should be subjected to immunohistochemical analysis and/or analysis for microsatellite instability. [ABSTRACT FROM AUTHOR]

Background: Women with a germline mutation in one of the MMR genes MLH1, MSH2 or MSH6 reportedly have 4-12% lifetime risk of ovarian cancer, but there is limited knowledge on survival. Prophylactic bilateral salpingo-oophorectomy (PBSO) has been suggested for preventing this condition. Aim: The purpose of this retrospective multicentre study was to describe survival in carriers of pathogenic mutations in one of the MMR genes, and who had contracted ovarian cancer. Methods: Women who had ovarian cancer, and who tested positive for or were obligate carriers of an MMR mutation, were included from 11 European centres for hereditary cancer. Most women had not attended for gynaecological screening. Crude and disease specific survival was calculated by the Kaplan-Meier algorithm. Results: Among the 144 women included, 81.5% had FIGO stage 1 or 2 at diagnosis. 10 year ovarian cancer specific survival independent of staging was 80.6%, compared to less than 40% that is reported both in population based series and in BRCA mutation carriers. Disease specific 30 year survival for ovarian cancer was 71.5%, and for all hereditary non-polyposis colon cancer (HNPCC)/Lynch syndrome related cancers including ovarian cancer it was 47.3%. Conclusions: In the series examined, infiltrating ovarian cancer in Lynch syndrome had a better prognosis than infiltrating ovarian cancer in BRCA1/2 mutation carriers or in the general population. Lifetime risk of ovarian cancer of about 10% and a risk of dying of ovarian cancer of 20% gave a lifetime risk of dying of ovarian cancer of about 2% in female MMR mutation carriers. [ABSTRACT FROM AUTHOR]

Presents the abstract of the article 'Use of Cytology to Diagnose Inherited Breast Cancer,' by Pål Møller, Gareth Evans, Elaine Anderson, Lovise M æ hle, Fiona Lalloo, Ketil R. Heimdal and C. Michael Steel.