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 (OR
= 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 (OR
= 1.2 (95%CI 0.4-4.0); OR
= 1.8 (95%CI 0.4-6.9); were about 1.04-1.3 times more often smokers than non-smokers (OR
= 1.04 (95%CI 0.4-2.8); OR
= 1.3 (95%CI 0.4-4.2)); and overweight or obesity (72%) was about 1.02-1.3 times less common (OR
= 0.98 (95%CI 0.4-2.6); OR
= 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 Ten BRCA mutations were demonstrated to be frequent in the Norwegian population. We present maps verifying the uneven distribution of prevalences according to municipality. We tested ...incident breast cancer cases treated in Mid-Norway from 1999 onwards for these mutations. Uptake of testing was 97% and 2.5% were demonstrated to be mutation carriers. Ten (77%) were outside families previously known to carry a mutation. Ten (77%) did not meet clinical criteria to be selected for mutation testing. We tested incident ovarian cancer cases in South-West Norway from 2001 onwards. Uptake of testing was 80% and 23% were mutation carriers. Twenty-one (88%) were outside families previously known. Twelve (67%) did not meet clinical criteria to be selected for testing. All patients with mutation collaborated actively to give our offer of predictive genetic testing to their relatives. No complaint on the activity was received.
Norway has one of the highest rates of death due to prostate cancer (PCa) in the world. To assess the contribution of both common and rare single nucleotide variants (SNPs) to the prostate cancer ...burden in Norway, we assessed the frequency of the established prostate cancer susceptibility allele, HOXB13 G84E, as well as a series of validated, common PCa risk SNPs in a Norwegian PCa population of 779 patients. The G84E allele was observed in 2.3% of patients compared to 0.7% of control individuals, OR = 3.8, P = 1 × 10‐4. While there was a trend toward an earlier age at diagnosis, overall the clinicopathologic features of PCa were not significantly different in G84E carriers and non‐carriers. Evaluation of 32 established common risk alleles revealed significant associations of risk alleles at 13 loci, including SNPs at 8q24, and near TET2, SLC22A3, NKX3‐1, CASC8, MYC, DAP2IP, MSMB, HNF1B, PPP1R14A, and KLK2/3. When the data for each SNP are combined into a genetic risk score (GRS), Norwegian men within the top decile of GRS have over 5‐fold greater risk to be diagnosed with PCa than men with GRS in the lowest decile. These results indicate that risk alleles of HOXB13 and common variant SNPs are important components of inherited PCa risk in the Norwegian population, although these factors appear to contribute little to the malignancy's aggressiveness.
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.
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.
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%.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
Background
Pathogenic germline variants in the mismatch repair (MMR) genes are associated with an increased risk of prostate cancer (PCa). Since 2010 we have recommended MMR carriers annual PSA ...testing from the age of 40. Prospective studies of the outcome of long‐term PSA screening are lacking. This study aimed to investigate the incidence and characteristics of PCa in Norwegian MMR carriers attending annual PSA screening (PSA threshold >3.0 ng/mL) to evaluate whether our recommendations should be continued.
Methods
This is a prospective observational study of 225 male MMR carriers who were recommended annual PSA screening by the Section of Inherited Cancer, Oslo University Hospital from 2010 and onwards. Incidence and tumor characteristics (age, PSA at diagnosis, Gleason score, TNM score) were described. IHC and MSI‐analyses were done on available tumors. Standardized incidence ratio (SIR) was calculated based on data from the Cancer Registry of Norway.
Results
Twenty‐two of 225 (9.8%) had been diagnosed with PCa, including 10/69 (14.5%) MSH2 carriers and 8/61 (13.1%) MSH6 carriers. Ten of 20 (50%) tumors had Gleason score ≥4 + 3 on biopsy and 6/11 (54.5%) had a pathological T3a/b stage. Eight of 17 (47.1%) tumors showed abnormal staining on IHC and 3/13 (23.1%) were MSI‐high. SIR was 9.54 (95% CI 5.98–14.45) for all MMR genes, 13.0 (95% CI 6.23–23.9) for MSH2 and 13.74 for MSH6 (95% CI 5.93–27.08).
Conclusions
Our results indicate that the MMR genes, and especially MSH2 and MSH6, are associated with a significant risk of PCa, and a high number of tumors show aggressive characteristics. While the impact of screening on patient outcomes remains to be more firmly established, the high SIR values we observe provide support for continued PSA screening of MSH2 and MSH6 carriers. Studies are needed to provide optimal recommendations for PSA‐threshold and to evaluate whether MLH1 and PMS2 carriers should not be recommended screening.
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.
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.
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.
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.
Genetic predisposition to prostate cancer includes multiple common variants with a low penetrance (single nucleotide polymorphisms)
and rare variants with higher penetrance. The mismatch repair (MMR) ...genes MLH1, MSH2, MSH6 , and PMS2 are associated with Lynch syndrome where colon and endometrial cancers are the predominant phenotypes. The purpose of our
study was to investigate whether germ-line mutations in these genes may be associated with prostate cancer. One hundred and
six male carriers or obligate carriers of MMR mutations were identified. Nine had contracted prostate cancer. Immunohistochemical
analysis was done on tumor tissue from eight of the nine tumors. Observed incidence, cumulative risk at 60 and 70 years of
age, age of onset, and Gleason score were compared with expected as assessed from population-based series. Absence of gene
product from the mutated MMR gene was found in seven of eight tumors. Expected number of prostate cancers was 1.52 compared
with 9 observed ( P < 0.01). Mean age of onset of prostate cancer was 60.4 years compared with 66.6 expected ( P = 0.006); the number of men with a Gleason score between 8 and 10 was significantly higher than expected ( P < 0.00001). Kaplan-Meier analysis suggested that cumulative risk by 70 years in MMR mutation carriers may be 30% (SE, 0.088)
compared with 8.0% in the general population. This is similar to the high risk associated with BRCA2 mutations. To our knowledge, this study is the first to indicate that the MMR genes may be among the rare genetic variants
that confer a high risk of prostate cancer when mutated. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2460–7)
Founder mutations in the two breast cancer genes,
and
, 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
founder mutations were defined by haplotyping in 2001, and accounted for 68% of
mutation carriers at the time. After 15 more years of genetic testing, updated knowledge on the mutation spectrum of both
and
in Norway is needed. In this study, we aim at describing the mutation spectrum and frequencies in the
carrier population of the largest clinic of hereditary cancer in Norway.
A total of 2430
carriers from 669 different families, and 1092
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.
There were 120 different
and 87 different
variants among the mutation carriers. Forty-six per cent of the registered
families (454/981) had a previously reported Norwegian founder mutation. The majority of
mutations (71%) were rare, each found in only one or two families. Fifteen per cent of
families and 25% of
families had one of these rare variants. The four well-known Norwegian
founder mutations previously confirmed through haplotyping were still the four most frequent mutations in
carriers, but the proportion of
mutation carriers accounted for by these mutations had fallen from 68 to 52%, and hence the founder effect was weaker than previously described.
The spectrum of
and
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.
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