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Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n = 135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n = 137; 80×CRCs, 33×ECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.

Background Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer predisposition genes and be at higher risk for developing cancer. Methods This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken. Results Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing. Conclusions These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability.

The COVID-19 pandemic significantly shifted the context of artistic and creative work, forcing individuals to adapt to wide-reaching changes in the way they operated in both work and life. Relying on interviews with data from 66 U.S.-based arts graduates, this article speaks to needs in sustaining creative life and work after the first year of the pandemic. Interviewees related that their needs for a sustainable creative work and life were primarily that they needed the social and physical distancing restrictions of the pandemic to end, more time and capacity to be creative, and monetary support. Ultimately, we argue that the changing context of the pandemic required substantial entrepreneurial ability toward being adaptable, superseding capacity for creativity during the first year of the pandemic. Our findings reflect that when arts entrepreneurs’ self-structured careers required new or intensified effort toward non-arts aspects of their work, their feelings of, or capacity for, creativity may be diminished.

The COVID-19 pandemic significantly shifted the context of artistic and creative work, forcing individuals to adapt to wide-reaching changes in the way they operated in both work and life. Relying on interviews with data from 66 U.S.-based arts graduates, this article speaks to needs in sustaining creative life and work after the first year of the pandemic. Interviewees related that their needs for a sustainable creative work and life were primarily that they needed the social and physical distancing restrictions of the pandemic to end, more time and capacity to be creative, and monetary support. Ultimately, we argue that the changing context of the pandemic required substantial entrepreneurial ability toward being adaptable, superseding capacity for creativity during the first year of the pandemic. Our findings reflect that when arts entrepreneurs’ self-structured careers required new or intensified effort toward non-arts aspects of their work, their feelings of, or capacity for, creativity may be diminished.

Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA samples provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case–control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk. DNA methylation is associated with breast cancer risk. Here the authors measure DNA methylation in the blood of individuals from 25 Australian families with multiple cases of breast cancer but not known mutations associated with breast cancer risk to identify possible heritable methylation markers.

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r 2  > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer ( P  < 10 -7 ). Four of these contain plausible causative genes ( FGFR2 , TNRC9 , MAP3K1 and LSP1 ). At the second stage, 1,792 SNPs were significant at the P  < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach. Novel breast cancer genes Until the genome-wide association study on page 1087 was published online, known susceptibility genes — such as BRCA1 and BRCA2 — accounted for less than 25% of the familial risk of breast cancer. The new study, which involved 21,860 patients and 22,578 controls, has identified four genes positively associated with genetic susceptibility to breast cancer ( FGFR2 , TNRC9 , MAP3K1 and LSP1 ). Most previously identified breast cancer susceptibility genes are involved in DNA repair, but the newly discovered associations appear to relate more to the control of cell growth or to cell signalling. Only one of the genes — FGFR2 — had a clear prior relevance to breast cancer. The identification of these genes opens up new avenues of research into the causes of breast cancer. They may also become part of a new strategy to classify women's risk, paving the way for better disease prevention. Previous work has identified several genes where mutations lead to breast cancer, but other genetic and environmental factors must still be accounted for. A large study of genetic association with breast cancer points to four novel genes and many more genetic markers that should be pursued for their link to cancer susceptibility.

Women carrying germline mutations in BRCA1 or BRCA2 have significantly increased lifetime risks of breast and tubo-ovarian cancer. To manage the breast cancer risk women may elect to have breast screening by MRI/mammogram from age 30, to take risk-reducing medication, or to have a prophylactic bilateral mastectomy. To manage the tubo-ovarian cancer risk, the only effective strategy is to have a bilateral salpingo-oophorectomy, recommended by age 40 (BRCA1) or ‘around’ age 40 (BRCA2). Early studies suggested that uptake of these cancer risk-reducing strategies was low. More recent studies have revealed higher rates of uptake, however it is unclear whether uptake is genuinely improving or whether the higher uptake rates reflect changes in the populations studied. In this study we surveyed 193 BRCA1/2 mutation carriers in the state of Tasmania to determine the uptake of cancer risk-reducing strategies and what factors might influence women’s decisions in relation to both gynaecological and breast surgery. We observed that uptake of risk management strategies varied depending on the strength of the recommendation in the national guidelines. Uptake rates were > 90% for strategies which are strongly recommended, such as breast screening by MRI/mammogram and bilateral salpingo-oophorectomy, and were unaffected by demographic factors such as socio-economic disadvantage and educational achievement. Uptake rates were much lower for strategies which are presented in the guidelines as options for consideration and where patient choice and shared decision making are encouraged, such as prophylactic mastectomy (29%) and chemoprevention (1%) and in the case of prophylactic mastectomy, were influenced by both socio-economic advantage and educational achievement.

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein ( AIP ) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy.

Background Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HR adj  = 1.35; 95 % CI = 1.05–1.73), but the association weakened after 10 years (HR adj  = 1.13; 95 % CI = 0.91–1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HR adj  = 1.70; 95 % CI = 1.17–2.45). Conclusions ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.

Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.