Immune infiltration, aggressive pathology, and poor survival outcomes in RECQL helicase deficient breast cancers.

RECQL is essential for genomic stability. Here, we evaluated RECQL in 449 pure ductal carcinomas in situ (DCIS), 152 DCIS components of mixed DCIS/invasive breast cancer (IBC) tumors, 157 IBC components of mixed DCIS/IBC and 50 normal epithelial terminal ductal lobular units (TDLUs). In 726 IBCs, CD8+, FOXP3+, IL17+, PDL1+, PD1+ T-cell infiltration (TILs) were investigated in RECQL deficient and proficient cancers. Tumor mutation burden (TMB) was evaluated in five RECQL germ-line mutation carriers with IBC by genome sequencing. Compared with normal epithelial cells, a striking reduction in nuclear RECQL in DCIS was evident with aggressive pathology and poor survival. In RECQL deficient IBCs, CD8+, FOXP3+, IL17+ or PDL1+ TILs were linked with aggressive pathology and shorter survival. In germline RECQL mutation carriers, increased TMB was observed in 4/5 tumors. We conclude that RECQL loss is an early event in breast cancer and promote immune cell infiltration.

A Single nucleotide polymorphism in the ALDH2 gene modifies the risk of esophageal squamous cell carcinoma in BRCA2 p.K3326* carriers.

Esophageal squamous cell carcinoma (ESCC) has a very high incidence rate in northeastern Iran. Our team previously reported the BReast CAncer gene 2 (BRCA2) p.K3326* mutation as a moderately penetrant ESCC susceptibility variant in northern Iran (odds ratio (OR) = 3.64, 95% confidence interval (CI) = 1.74-7.59, P = 0.0003). Recently, it has been reported that aldehydes can induce BRCA2 haploinsufficiency in cells with a heterozygous pathogenic BRCA2 mutation and predispose them to carcinogenic effects. Based on this observation, we speculate that dysfunctional variants in Aldehyde Dehydrogenase 2 Family Member (ALDH2) may result in aldehyde-induced BRCA2 haploinsufficiency and increase cancer risk in BRCA2 mutation carriers. In support of this hypothesis, our team recently reported the breast cancer risk modifying effect of an ALDH2 common polymorphism, rs10744777, among Polish carriers of the BRCA2 p.K3326* mutation. In the current case-control study, we aimed to investigate the ESCC risk modifying effect of this ALDH2 polymorphism among BRCA2 p.K3326* mutation carriers. We assessed the interaction between the ALDH2 rs10744777 polymorphism and BRCA2 p.K3326* mutation in ESCC risk by genotyping this ALDH2 variant in the germline DNA of 746 ESCC cases and 1,373 controls from northern Iran who were previously genotyped for the BRCA2 p.K3326* mutation. Among a total of 464 individuals with TT genotype of the ALDH2 rs10744777 polymorphism, which is associated with lower ALDH2 expression, we found 9 of 164 cases versus 3 of 300 controls who carried the BRCA2 p.K3326* variant (OR = 5.66, 95% CI = 1.22-26.2, P = 0.018). This finding supports our hypothesis that the ALDH2-rs10744777 TT genotype may be a significant risk modifier of ESCC in individuals with a BRCA2 p.K3326* mutation.

Evaluating the Utility of ctDNA in Detecting Residual Cancer and Predicting Recurrence in Patients with Serous Ovarian Cancer.

Ovarian cancer has a high case fatality rate, but patients who have no visible residual disease after surgery have a relatively good prognosis. The presence of any cancer cells left in the peritoneal cavity after treatment may precipitate a cancer recurrence. In many cases, these cells are occult and are not visible to the surgeon. Analysis of circulating tumour DNA in the blood (ctDNA) may offer a sensitive method to predict the presence of occult (non-visible) residual disease after surgery and may help predict disease recurrence. We assessed 48 women diagnosed with serous ovarian cancer (47 high-grade and 1 low-grade) for visible residual disease and for ctDNA. Plasma, formalin-fixed paraffin-embedded (FFPE) tumour tissue and white blood cells were used to extract circulating free DNA (cfDNA), tumour DNA and germline DNA, respectively. We sequenced DNA samples for 59 breast and ovarian cancer driver genes. The plasma sample was collected after surgery and before initiating chemotherapy. We compared survival in women with no residual disease, with and without a positive plasma ctDNA test. We found tumour-specific variants (TSVs) in cancer cells from 47 patients, and these variants were sought in ctDNA in their post-surgery plasma. Fifteen (31.9%) of the 47 patients had visible residual disease; of these, all 15 had detectable ctDNA. Thirty-one patients (65.9%) had no visible residual disease; of these, 24 (77.4%) patients had detectable ctDNA. Of the patients with no visible residual disease, those patients with detectable ctDNA had higher mortality (20 of 27 died) than those without detectable ctDNA (3 of 7 died) (HR 2.32; 95% CI: 0.67-8.05), although this difference was not statistically significant (p = 0.18). ctDNA in post-surgical serum samples may predict the presence of microscopic residual disease and may be a predictor of recurrence among women with ovarian cancer. Larger studies are necessary to validate these findings.

The APOBEC3B c.783delG Truncating Mutation Is Not Associated with an Increased Risk of Breast Cancer in the Polish Population.

The APOBEC3B gene belongs to a cluster of DNA-editing enzymes on chromosome 22 and encodes an activation-induced cytidine deaminase. A large deletion of APOBEC3B was associated with increased breast cancer risk, but the evidence is inconclusive. To investigate whether or not APOBEC3B is a breast cancer susceptibility gene, we sequenced this gene in 617 Polish patients with hereditary breast cancer. We detected a single recurrent truncating mutation (c.783delG, p.Val262Phefs) in four of the 617 (0.65%) hereditary cases by sequencing. We then genotyped an additional 12,484 women with unselected breast cancer and 3740 cancer-free women for the c.783delG mutation. The APOBEC3B c.783delG allele was detected in 60 (0.48%) unselected cases and 19 (0.51%) controls (OR = 0.95, 95% CI 0.56-1.59, p = 0.94). The allele was present in 8 of 1968 (0.41%) familial breast cancer patients from unselected cases (OR = 0.80, 95% CI 0.35-1.83, p = 0.74). Clinical characteristics of breast tumors in carriers of the APOBEC3B mutation and non-carriers were similar. No cancer type was more frequent in the relatives of mutation carriers than in those of non-carriers. We conclude the APOBEC3B deleterious mutation p.Val262Phefs does not confer breast cancer risk. These data do not support the hypothesis that APOBEC3B is a breast cancer susceptibility gene.

What Is Known about Breast Cancer in Young Women?

Breast cancer (BC) is the second leading cause of cancer-related death in women under the age of 40 years worldwide. In addition, the incidence of breast cancer in young women (BCYW) has been rising. Young women are not the focus of screening programs and BC in younger women tends to be diagnosed in more advanced stages. Such patients have worse clinical outcomes and treatment complications compared to older patients. BCYW has been associated with distinct tumour biology that confers a worse prognosis, including poor tumour differentiation, increased Ki-67 expression, and more hormone-receptor negative tumours compared to women >50 years of age. Pathogenic variants in cancer predisposition genes such as BRCA1/2 are more common in early-onset BC compared to late-onset BC. Despite all these differences, BCYW remains poorly understood with a gap in research regarding the risk factors, diagnosis, prognosis, and treatment. Age-specific clinical characteristics or outcomes data for young women are lacking, and most of the standard treatments used in this subpopulation currently are derived from older patients. More age-specific clinical data and treatment options are required. In this review, we discuss the epidemiology, clinicopathologic characteristics, outcomes, treatments, and special considerations of breast cancer in young women. We also underline future directions and highlight areas that require more attention in future studies.

Variants in ATRIP are associated with breast cancer susceptibility in the Polish population and UK Biobank.

Several breast cancer susceptibility genes have been discovered, but more are likely to exist. To identify additional breast cancer susceptibility genes, we used the founder population of Poland and performed whole-exome sequencing on 510 women with familial breast cancer and 308 control subjects. We identified a rare mutation in ATRIP (GenBank: NM_130384.3: c.1152_1155del [p.Gly385Ter]) in two women with breast cancer. At the validation phase, we found this variant in 42/16,085 unselected Polish breast cancer-affected individuals and in 11/9,285 control subjects (OR = 2.14, 95% CI = 1.13-4.28, p = 0.02). By analyzing the sequence data of the UK Biobank study participants (450,000 individuals), we identified ATRIP loss-of-function variants among 13/15,643 breast cancer-affected individuals versus 40/157,943 control subjects (OR = 3.28, 95% CI = 1.76-6.14, p < 0.001). Immunohistochemistry and functional studies showed the ATRIP c.1152_1155del variant allele is weakly expressed compared to the wild-type allele, and truncated ATRIP fails to perform its normal function to prevent replicative stress. We showed that tumors of women with breast cancer who have a germline ATRIP mutation have loss of heterozygosity at the site of ATRIP mutation and genomic homologous recombination deficiency. ATRIP is a critical partner of ATR that binds to RPA coating single-stranded DNA at sites of stalled DNA replication forks. Proper activation of ATR-ATRIP elicits a DNA damage checkpoint crucial in regulating cellular responses to DNA replication stress. Based on our observations, we conclude ATRIP is a breast cancer susceptibility gene candidate linking DNA replication stress to breast cancer.

Genetic testing women with newly diagnosed breast cancer: What criteria are the most predictive of a positive test?

BACKGROUND: Knowledge of pathogenic variants in cancer-predisposing genes is important when making breast cancer treatment decisions, but genetic testing is not universal and criteria must be met to qualify for genetic testing. The objective of this study was to evaluate the pathogenic variant yield for nine cancer predisposition genes by testing criteria, singly and in combination. METHODS: Women diagnosed with breast cancer between June 2013 and May 2018 were recruited from four centers in Toronto, Canada. Participants completed a demographics and family history questionnaire and clinical characteristics were collected from medical charts. Genetic testing was done for BRCA1, BRCA2, PALB2, ATM, CHEK2, BRIP1, RAD51D, RECQL, and TP53. Pathogenic variant frequencies were calculated according to five criteria (age ≤ 50, triple-negative breast cancer, family history, bilateral breast cancer, or Jewish ethnicity). RESULTS: Of the 1006 women studied, 100 women (9.9%) were found to have a pathogenic variant in one of the nine genes tested. The highest prevalence of pathogenic variants was found in women with triple-negative breast cancer (23%). Of the 100 pathogenic variants detected, 78 were detected in women diagnosed at age 50 or less. A total of 96% of the mutations were identified with three criteria (age of diagnosis, family history, and triple-negative status). CONCLUSIONS: Genetic testing criteria for women with breast cancer should include women with triple-negative breast cancer, regardless of age. All women aged 50 years or below at time of breast cancer diagnosis should be offered genetic testing.

High Expression of RECQL Protein in ER-Positive Breast Tumours Is Associated With a Better Survival.

Background: RECQL (also known as RECQ1 and RECQL1) is a gene of recent interest in breast cancer and an association between high levels of RECQL protein in breast cancer tumour cells and good survival of patients has been reported. Methods: To validate this association, we measured the RECQL protein levels in tumours of 933 breast cancer patients using immunohistochemistry analysis and followed the patients for death from breast cancer. Results: Women with a level of RECQL protein above the 75th percentile had better 15-year disease-specific survival among ER-positive patients (62.5% vs. 48.7%, HR= 0.72, 95%CI= 0.52-0.98, p-value = 0.04), but not among ER- patients (48.9% vs. 48.0%, HR= 1.07, 95%CI= 0.67-1.69, p-value= 0.79). Among the ER-negative patients, high RECQL protein levels were associated with better survival among women who received tamoxifen treatment (67.0% vs. 51.5%, HR= 0.64, 95%CI= 0.41-0.99, p-value= 0.04). Conclusion: RECQL might be a new predictive marker for tamoxifen treatment among ER-positive patients.

An appraisal of genetic testing for prostate cancer susceptibility.

Most criteria for genetic testing for prostate cancer susceptibility require a prior diagnosis of prostate cancer, in particular cases with metastatic disease are selected. Advances in the field are expected to improve outcomes through tailored treatments for men with advanced prostate cancer with germline pathogenic variants, although these are not currently offered in the curative setting. A better understanding of the value of genetic testing for prostate cancer susceptibility in screening, for early detection and prevention is necessary. We review and summarize the literature describing germline pathogenic variants in genes associated with increased prostate cancer risk and aggressivity. Important questions include: what is our ability to screen for and prevent prostate cancer in a man with a germline pathogenic variant and how does knowledge of a germline pathogenic variant influence treatment of men with nonmetastatic disease, with hormone-resistant disease and with metastatic disease? The frequency of germline pathogenic variants in prostate cancer is well described, according to personal and family history of cancer and by stage and grade of disease. The role of these genes in aggressive prostate cancer is also discussed. It is timely to consider whether or not genetic testing should be offered to all men with prostate cancer. The goals of testing are to facilitate screening for early cancers in unaffected high-risk men and to prevent advanced disease in men with cancer.

Potential clinical utility of liquid biopsies in ovarian cancer.

BACKGROUND: Ovarian cancer (OC) is the most lethal gynecologic malignancy worldwide. One of the main challenges in the management of OC is the late clinical presentation of disease that results in poor survival. Conventional tissue biopsy methods and serological biomarkers such as CA-125 have limited clinical applications. Liquid biopsy is a novel sampling method that analyzes distinctive tumour components released into the peripheral circulation, including circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), cell-free RNA (cfRNA), tumour-educated platelets (TEPs) and exosomes. Increasing evidence suggests that liquid biopsy could enhance the clinical management of OC by improving early diagnosis, predicting prognosis, detecting recurrence, and monitoring response to treatment. Capturing the unique tumour genetic landscape can also guide treatment decisions and the selection of appropriate targeted therapies. Key advantages of liquid biopsy include its non-invasive nature and feasibility, which allow for serial sampling and longitudinal monitoring of dynamic tumour changes over time. In this review, we outline the evidence for the clinical utility of each liquid biopsy component and review the advantages and current limitations of applying liquid biopsy in managing ovarian cancer. We also highlight future directions considering the current challenges and explore areas where more studies are warranted to elucidate its emerging clinical potential.

Common Variant in ALDH2 Modifies the Risk of Breast Cancer Among Carriers of the p.K3326* Variant in BRCA2.

PURPOSE: The BRCA2 p.K3326* variant is considered a low-penetrance variant for breast cancer. Aldehydes that accumulate in cells under insufficient aldehyde oxidation were most recently shown to trigger carcinogenesis by promoting depletion of BRCA2 protein. Allele T of the common variant rs10744777 in the ALDH2 gene was associated with reduced expression of aldehyde dehydrogenase, the main enzyme in aldehyde oxidation. We hypothesized that this allele could modify breast cancer risk in women with the BRCA2 p.K3326* low-penetrance variant through reduced function of ALDH2, increased accumulation of cellular aldehydes, and depletion of BRCA2 protein. MATERIALS AND METHODS: We genotyped 11,873 Polish women diagnosed with breast cancer and 7,615 ethnically matched controls for these two variants. Next, we extended our analysis of rs10744777 to 231 carriers of pathogenic BRCA2 mutations. RESULTS: BRCA2 p.K3326* variant was associated with significant increase in breast cancer risk only in those who were homozygous for the T allele of the ALDH2 rs10744777 variant (odds ratio = 1.72; 95% CI, 1.19 to 2.48; P = .003). The BRCA2 p.K3326* variant did not increase the risk of breast cancer among those who were heterozygous or homozygous for the C allele of the ALDH2 rs10744777 variant (odds ratio = 1.05; 95% CI, 0.73 to 1.51; P = .81). In the carriers of high-risk BRCA2 mutations, the TT genotype of rs10744777 conferred a modest (18%) and not significant increase in breast cancer risk. CONCLUSION: Our results suggest that BRCA2 p.K3326* variant, which is low-penetrance by itself, confers increased breast cancer risk on the background of the TT genotype of the ALDH2 rs10744777 variant in the Polish population.

Genetic Testing for All: Overcoming Disparities in Ovarian Cancer Genetic Testing.

Nearly 3% of the population carries genetic variants that lead to conditions that include hereditary breast and ovarian cancer and Lynch syndrome. These pathogenic variants account for approximately 20% of ovarian cancer cases, and those with germline pathogenic variants have an odds ratio between 4 and 40 for developing ovarian cancer compared with noncarriers. Given the high prevalence of genetic variants, multiple organizations, including ASCO, recommend universal genetic counseling and testing for women diagnosed with epithelial ovarian cancer. Unfortunately, most individuals with a hereditary ovarian cancer syndrome are unaware of their underlying mutation, and racial and ethnic minority individuals as well as patients of low socioeconomic status experience disproportionate rates of underrecognition, leading to late and missed diagnoses. In this article, we review the current understanding of disparities in genetic testing for people with ovarian cancer, the role of population-based genetic testing, and innovative strategies to overcome the critical inequities present in current cancer genetic medicine. Underuse and disparities related to accessing recommended genetic services are complex and multifactorial, requiring improvements in processes related to provider identification, genetic counseling and testing referral, and patient uptake/adherence. Through the expansion of remote genetic counseling, offering online strategies for genetic testing, and reaching at-risk relatives through direct relative contact cascade testing and population-based genetic testing, there are a growing number of innovations in the field of genetic medicine, many of which emphasize health equity and offer promising alternatives to the current paradigm of genetic testing.

Genetic susceptibility to hereditary non-medullary thyroid cancer.

Non-medullary thyroid cancer (NMTC) is the most common type of thyroid cancer. With the increasing incidence of NMTC in recent years, the familial form of the disease has also become more common than previously reported, accounting for 5-15% of NMTC cases. Familial NMTC is further classified as non-syndromic and the less common syndromic FNMTC. Although syndromic NMTC has well-known genetic risk factors, the gene(s) responsible for the vast majority of non-syndromic FNMTC cases are yet to be identified. To date, several candidate genes have been identified as susceptibility genes in hereditary NMTC. This review summarizes genetic predisposition to non-medullary thyroid cancer and expands on the role of genetic variants in thyroid cancer tumorigenesis and the level of penetrance of NMTC-susceptibility genes.

Platelet Count and Survival after Cancer.

Thrombocytosis is associated with cancer progression and death for many cancer types. It is unclear if platelet count is also associated with cancer survival. We conducted a cohort study of 112,231 adults in Ontario with a diagnosis of cancer between January 2007 and December 2016. We included patients who had a complete blood count (CBC) completed in the 30 days prior to their cancer diagnosis. Subjects were assigned to one of three categories according to platelet count: low (≤25th percentile), medium (>25 to <75th percentile), and high (≥75th percentile). Study subjects were followed from the date of their cancer diagnosis for cancer-specific death. Of the 112,231 eligible cancer patients in the cohort study, 40,329 (35.9%) died from their cancer in the follow-up period. Relative to those with a medium platelet count, the rate of cancer-specific death was higher among individuals with a high platelet count (HR 1.52; 95%CI 1.48-1.55) and was lower among individuals with a low platelet count (HR 0.91; 95%CI 0.88-0.93). A high platelet count was associated with poor survival for many cancer types. Platelet count could potentially be used as a risk stratification measure for cancer patients.

Analysis of Platelet Count and New Cancer Diagnosis Over a 10-Year Period.

Importance: Individuals with cancer often have an elevated platelet count at the time of diagnosis. The extent to which an elevated platelet count is an indicator of cancer is unclear. Objective: To evaluate the association of an elevated platelet count with a cancer diagnosis. Design, Setting, and Participants: This nested case-control study included Ontario residents enrolled in the provincial health insurance plan who had 1 or more routine complete blood count (CBC) tests performed between January 1, 2007, and December 31, 2017, with follow-up through December 31, 2018. Case patients were individuals with a new cancer diagnosis during the observation period. Eligible control individuals were cancer free before the date of diagnosis for a case patient to whom they were matched. One case patient was matched to 3 controls based on sex, age, and health care use patterns. Data were analyzed from September 24, 2020, to July 13, 2021. Exposures: Case patients and controls were assigned to 1 of 5 exposure groups based on age- and sex-specific platelet count distributions in the control population: very low (≤10th percentile), low (>10th to 25th percentile), medium (>25th to <75th percentile), high (75th to <90th percentile), and very high (≥90th percentile). Main Outcomes and Measures: Odds ratios (ORs) were estimated for specific cancer sites for each category of platelet count at intervals up to 10 years after a blood test. Results: Of the 8 917 187 eligible Ontario residents with a routine CBC record available, 4 971 578 (55.8%) were women; the median age at the first CBC was 46.4 years (IQR, 32.5-59.5 years). Among individuals with a routine CBC record available, 495 341 (5.6%) received a diagnosis of first primary cancer during the 10-year observation period. The OR for a solid tumor diagnosis associated with a very high platelet count vs a medium platelet count in the 6-month period before the diagnosis was 2.32 (95% CI, 2.28-2.35). A very high platelet count was associated with colon (OR, 4.38; 95% CI, 4.22-4.54), lung (OR, 4.37; 95% CI, 4.22-4.53), ovarian (OR, 4.62; 95% CI, 4.19-5.09), and stomach (OR, 4.27; 95% CI, 3.91-4.66) cancers. Odds ratios attenuated with increasing time from CBC test to cancer diagnosis. Conclusions and Relevance: In this nested case-control study, an elevated platelet count was associated with increased risk of cancer at several sites. Our findings suggest that an elevated platelet count could potentially serve as a marker for the presence of some cancer types.

Surgeon and Patient Reports of Fertility Preservation Referral and Uptake in a Prospective, Pan-Canadian Study of Young Women with Breast Cancer.

BACKGROUND: Prompt referral by their surgeon enables fertility preservation (FP) by young women with breast cancer (YWBC) without treatment delay. Following a FP knowledge intervention, we evaluated surgeon and patient reports of fertility discussion, FP referral offer and uptake, and FP choices and reasons for declining FP among patients enrolled in the Reducing Breast Cancer in Young Women, prospective pan-Canadian study. METHODS: Between September 2015 and December 2020, 1271 patients were enrolled at 31 sites. For each patient, surgeons were sent a questionnaire inquiring whether: (1) fertility discussion was initiated by the surgical team; (2) FP referral was offered; (3) referral was accepted; a reason was requested for any "no" response. Patients were surveyed about prediagnosis fertility plans and postdiagnosis oncofertility management. RESULTS: Surgeon questionnaires were completed for 1068 (84%) cases. Fertility was discussed with 828 (84%) and FP consultation offered to 461 (47%) of the 990 YWBC with invasive disease. Among the 906 responding YWBC, referral was offered to 220 (82%) of the 283 (33%) with invasive disease who stated that they had definitely/probably not completed childbearing prediagnosis. Of these, 133 (47%) underwent FP. The two most common reasons for not choosing FP were cost and unwillingness to delay treatment. CONCLUSIONS: Although the rates of surgeon fertility discussion and FP referral was higher than most reports, likely due to our previous intervention, further improvement is desirable. FP should be offered to all YWBC at diagnosis, regardless of perceived childbearing intent. Cost remains an important barrier to FP uptake.

Do BARD1 Mutations Confer an Elevated Risk of Prostate Cancer?

The current cancer testing gene panels tend to be comprehensive rather than site-specific. BARD1 is one of the genes commonly included in the multi-cancer testing panels. Mutations in BARD1 confer an increase in the risk for breast cancer, but it is not studied whether or not they predispose to prostate cancer. To establish if BARD1 mutations also predispose to prostate cancer, we screened BARD1 in 390 Polish patients with hereditary prostate cancer. No truncating mutations were identified by sequencing. We also genotyped 5715 men with unselected prostate cancer, and 10,252 controls for three recurrent BARD1 variants, including p.Q564X, p.R658C and p.R659=. Neither variant conferred elevated risk of prostate cancer (ORs between 0.84 and 1.15, p-values between 0.57 and 0.93) nor did they influence prostate cancer characteristics or survival. We conclude that men with a BARD1 mutation are not at elevated prostate cancer risk. It is not justified to inform men about increased prostate cancer risk in case of identification of a BARD1 mutation. However, a female relative of a man with a BARD1 mutation may benefit from this information and be tested for the mutation, because BARD1 is a breast cancer susceptibility gene.

PALB2 mutations and prostate cancer risk and survival.

BACKGROUND: The objective of this study was to establish the contribution of PALB2 mutations to prostate cancer risk and to estimate survival among PALB2 carriers. METHODS: We genotyped 5472 unselected men with prostate cancer and 8016 controls for two Polish founder variants of PALB2 (c.509_510delGA and c.172_175delTTGT). In patients with prostate cancer, the survival of carriers of a PALB2 mutation was compared to that of non-carriers. RESULTS: A PALB2 mutation was found in 0.29% of cases and 0.21% of controls (odds ratio (OR) = 1.38; 95% confidence interval (CI) 0.70-2.73; p = 0.45). PALB2 mutation carriers were more commonly diagnosed with aggressive cancers of high (8-10) Gleason score than non-carriers (64.3 vs 18.1%, p < 0.0001). The OR for high-grade prostate cancer was 8.05 (95% CI 3.57-18.15, p < 0.0001). After a median follow-up of 102 months, the age-adjusted hazard ratio for all-cause mortality associated with a PALB2 mutation was 2.52 (95% CI 1.40-4.54; p = 0.0023). The actuarial 5-year survival was 42% for PALB2 carriers and was 72% for non-carriers (p = 0.006). CONCLUSION: In Poland, PALB2 mutations predispose to an aggressive and lethal form of prostate cancer.

The Screen Project: Guided Direct-To-Consumer Genetic Testing for Breast Cancer Susceptibility in Canada.

There is limited information of the outcomes of direct-to-consumer testing for BRCA1 and BRCA2 mutations. The Screen Project was initiated in 2017 to offer BRCA1 and BRCA2 genetic screening to all Canadians over the age of 18 who wish to know their mutation status. Patients enrolled in the study from 2017 to 2019 and were followed for one year after the receipt of a genetic test result. Study subjects registered online and were sent a saliva sample kit, which was shipped to the reference laboratory. Pre-test genetic counselling and counselling for mutation-negative subjects was optional and at the individual's discretion. There were 1269 tested individuals between March 2017 and January 2019. A total of 1157 (93%) were women and 87 (7%) were men. Sixty-six percent had a first- or second-degree relative with breast or ovarian cancer. Of the 1269 tested individuals, 30 (2.4%) had a pathogenic mutation in BRCA1 or BRCA2 (20 women and 10 men). Seventy-five percent of the female mutation carriers underwent a bilateral mastectomy and/or salpingo-oophorectomy within a year of receiving a positive result. Genetic counselling was available at no cost to all participants but was requested by only 5% of the non-carriers. The study subjects expressed a high degree of satisfaction with the process.