Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma

Rare biallelic BLM gene mutations cause Bloom syndrome. Whether BLM heterozygous germline mutations (BLM^+/−) cause human cancer remains unclear. We sequenced the germline DNA of 155 mesothelioma patients (33 familial and 122 sporadic). We found 2 deleterious germline BLM^+/− mutations within 2 of 33 families with multiple cases of mesothelioma, one from Turkey (c.569_570del; p.R191Kfs*4) and one from the United States (c.968A>G; p.K323R). Some of the relatives who inherited these mutations developed mesothelioma, while none with nonmutated BLM were affected. Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline BLM^+/− mutations. Therefore, 7 of 155 apparently unrelated mesothelioma patients carried BLM^+/− mutations, significantly higher (P = 6.7E-10) than the expected frequency in a general, unrelated population from the gnomAD database, and 2 of 7 carried the same missense pathogenic mutation c.968A>G (P = 0.0017 given a 0.00039 allele frequency). Experiments in primary mesothelial cells from Blm^+/− mice and in primary human mesothelial cells in which we silenced BLM revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-α release. Blm^+/− mice injected intraperitoneally with asbestos had higher levels of proinflammatory M1 macrophages and of TNF-α, IL-1β, IL-3, IL-10, and IL-12 in the peritoneal lavage, findings linked to asbestos carcinogenesis. Blm^+/− mice exposed to asbestos had a significantly shorter survival and higher incidence of mesothelioma compared to controls. We propose that germline BLM^+/− mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma.

In the United States, the incidence rate of mesothelioma varies between fewer than one case per 100,000 persons in states with no asbestos industry to two to three cases per 100,000 persons in states with an asbestos industry (1, 2). Asbestos causes DNA damage and apoptosis (3) and promotes a chronic inflammatory reaction that supports the emergence of malignant cells (4). Fortunately, only a small fraction of exposed individuals develop mesothelioma; for example, 4.6% of deaths in miners who worked in asbestos mines for over 10 y were caused by mesothelioma (1). Therefore, multiple cases of mesothelioma in the same family are rare and suggest genetic predisposition (5). In 2001, we discovered that susceptibility to mesothelioma was transmitted in a Mendelian fashion across multiple generations in some Turkish families exposed to the carcinogenic fiber erionite, pointing to gene × environment interaction (G×E) as the cause (6). In 2011, we discovered that carriers of heterozygous germline BRCA1-associated protein–1 (BAP1) mutations (BAP1^+/−) developed mesothelioma and uveal melanoma (5), findings expanded and confirmed by us and by multiple research teams (reviewed in refs. 1, 7, 8). Moreover, heterozygous germline Bap1 mutations (Bap1^+/−) significantly increased susceptibility to asbestos-induced mesothelioma in mice (9, 10), evidence of G×E. Reduced BAP1 levels impair DNA repair (11) as well as different forms of cell death (3, 12) and induce metabolic alterations (13–15) that together favor cancer development and growth.Recent studies revealed that mesothelioma may also develop among carriers of germline mutations of additional tumor-suppressor genes that cause well-defined cancer syndromes, including MLH1 and MLH3 (Lynch syndrome), TP53 (Li–Fraumeni syndrome), and BRCA1-2 (Breast and Ovarian Cancer syndrome) (16, 17). When all germline mutations are combined, it has been estimated that about 12% of mesotheliomas occur in carriers of heterozygous germline mutations of BAP1, the most frequent mutation among patients with mesothelioma, or of other tumor suppressors. Some of these mutations may sensitize the host to asbestos carcinogenesis, according to a G×E scenario (17). Thus, presently, mesothelioma is considered an ideal model to study G×E in cancer (17). As part of the Healthy Nevada Project (HNP), we are studying G×E in northern Nevada, a region with an unusually high risk of exposure to carcinogenic minerals and arsenic, which may be related to the high cancer rates in this region (18). We are investigating genetic variants that may increase cancer risk upon exposure to carcinogens to implement preventive strategies.Biallelic mutations of the Bloom syndrome gene (BLM) cause Bloom syndrome, an autosomal-recessive tumor predisposition syndrome characterized by pre- and postnatal growth deficiency, photosensitivity, type 2 diabetes, and greatly increased risk of developing various types of cancers. BLM is a RecQ helicase enzyme that modulates DNA replication and repair of DNA damage by homologous recombination (19). In patients affected by Bloom syndrome, the absence of the BLM protein causes chromosomal instability, increased number of sister chromatid exchanges, and increased numbers of micronuclei (20–22). In addition, BLM is required for p53-mediated apoptosis (23), a process critical to eliminate cells that have accumulated DNA damage. Impaired DNA repair together with altered apoptosis resulted in increased cancer incidence (17, 24). Of course, inactivating germline BLM heterozygous (BLM^+/−) mutations are much more common than biallelic BLM (BLM^−/−) mutations, with an estimated frequency in the general population of 1 in 900 based on data from the Exome Aggregation Consortium (25). BLM^+/− mutation carriers do not show an obvious phenotype; however, some studies have suggested that carriers of these mutations may have an increased cancer risk (17, 24). Mice carrying Blm^+/− mutations are prone to develop a higher rate of malignancies in the presence of contributing factors, such as concurrent heterozygous mutations of the adenomatous polyposis coli (Apc) gene, or upon infection with murine leukemia virus (26). However, in studies in which Blm^+/− mice were crossed with tuberous sclerosis 1-deficient (Tsc1^+/−) mice that are predisposed to renal cystadenomas and carcinomas, Wilson et al. found that Tsc1^+/− Blm^+/− mice did not show significantly more renal cell carcinomas compared with Tsc1^+/− Blm^WT mice (27). In humans, a large study involving 1,244 patients with colon cancer and 1,839 controls of Ashkenazi Jewish ancestry, in which BLM^+/− frequency is as high as 1 in 100 individuals (28), suggested that carriers of germline BLM^+/− mutations might have a twofold increase in colorectal cancer (CRC) (29). A smaller study did not confirm these results, but reported a trend of increasing incidence of adenomas—premalignant lesions—among BLM^+/− mutation carriers (30). In addition, BLM^+/− mutations were found overrepresented among early-onset (<45 y old) CRC patients (25). Other studies associated BLM^+/− mutations to an increased risk of breast (31, 32) and prostate cancer (33), but the low power of these studies hampered definite conclusions. In summary, it appears possible that BLM^+/− mutations may increase cancer risk in the presence of contributing factors.     

Evaluation of burn severity in vivo in a mouse model using spectroscopic optical coherence tomography

Clinical management of burn injuries depends upon an accurate assessment of the depth of the wound. Current diagnostic methods rely primarily on subjective visual inspection, which can produce variable results. In this study, spectroscopic optical coherence tomography was used to objectively evaluate burn injuries in vivo in a mouse model. Significant spectral differences were observed and correlated with the depth of the injury as determined by histopathology. The relevance of these results to clinical burn management in human tissues is discussed.OCIS codes: (170.6510) Spectroscopy, tissue diagnostics; (110.4500) Optical coherence tomography     

Genotype–Phenotype Correlations by Ethnicity and Mutation Location in BRCA Mutation Carriers

The genotype–phenotype correlations of the specific BRCA1 and BRCA2 mutations in multi‐ethnic populations in USA have not yet been fully investigated. This study was designed to evaluate the effects of ethnicity at specific mutation locations and breast/ovarian cancer phenotypes. Our cohort included 445 women with different ethnic backgrounds who underwent BRCA genetic testing between 1997 and 2010. Known clinical and pathologic characteristics were compared with Chi‐Square Analysis or Fisher's Exact test as appropriate. The three most common mutation locations in BRCA1 (exons 2, 11, and 20) and BRCA2 (exons 10, 11, and 25) genes were chosen. Prevalence of BRCA1 exon 2 mutations were significantly higher in Ashkenazi Jewish (AJ) women compared to Caucasians (41% versus 15%; p = 0.001). Similarly, AJ women with breast cancer were more likely to have BRCA1 exon 2 mutation (47% positivity in AJ women versus 0–12.5% positivity in other ethnicities; p = 0.004). Women carrying the exon 20 BRCA1 mutation had the highest probability of having combined breast and ovarian cancers compared to women carrying other exon mutations (p = 0.05). The median age at initial cancer diagnosis, phenotypic features of breast cancer tumors, and overall survival did not vary significantly by ethnicity or mutation location. Our data suggest that ethnicity does not affect age of onset, overall survival or confer different risks of breast and ovarian cancer development in BRCA carriers. These results also suggest that women carrying the exon 20 BRCA1 mutation may warrant mutation‐specific counseling and be more aggressively managed for risk reduction.     

Evidence summaries and recommendations from the international evidence‐based guideline for the assessment and management of polycystic ovary syndrome: Lifestyle management

Lifestyle is fundamental in chronic disease prevention and management, and it has been recommended as a first‐line treatment in the Australian polycystic ovary syndrome (PCOS) guideline 2011. The first international evidence‐based guideline on PCOS was developed in 2018, which expanded the scope and evidence in the Australian guideline. This paper summarizes the lifestyle recommendations and evidence summaries from the guideline. International multidisciplinary guideline development groups delivered the International Evidence‐based Guideline for the Assessment and Management of Polycystic Ovary Syndrome 2018. The process followed the Appraisal of Guidelines for Research and Evaluation II and The Grading of Recommendations, Assessment, Development and Evaluation framework. Extensive communication and meetings addressed six prioritized clinical questions through five reviews. Evidence‐based recommendations were formulated before consensus voting within the panel. Evidence shows the benefits of multicomponent lifestyle intervention, efficacy of exercise and weight gain prevention with no specific diet recommended. Lifestyle management is the first‐line management in the intervention hierarchy in PCOS. Multicomponent lifestyle intervention including diet, exercise and behavioural strategies is central to PCOS management with a focus on weight and healthy lifestyle behaviours. The translation programme optimizes reach and dissemination for health professionals and consumers.     

Conversion to Complete Resection and/or Ablation Using Hepatic Artery Infusional Chemotherapy in Patients with Unresectable Liver Metastases from Colorectal Cancer: A Decade of Experience at a Single Institution

Background

When feasible, surgical treatment of colorectal liver metastases (CRLM) is the treatment of choice. Regional hepatic artery infusional (HAI) chemotherapy effectively treats CRLM. The combination of HAI and systemic chemotherapy may downsize tumors and allow for complete resection and/or ablation (R/A). This study analyzes the combination of HAI and systemic chemotherapy for treating unresectable CRLM, focusing on conversion to complete R/A.

Methods

All patients with unresectable CRLM treated with HAI and systemic chemotherapy from 2000 to 2009 were included. Patients who responded sufficiently to undergo complete R/A were compared to those who did not convert. Survival was compared using a landmark analysis to account for bias.

Results

A total of 373 patients were included; 93 patients (25 %) subsequently underwent complete R/A. The percentage of patients submitted to complete R/A increased from 16 % during 2000–2003 to 30 % during 2004–2009. Factors associated with conversion on multivariate analysis were more recent treatment (2004–2009), no prior chemotherapy, clinical risk score <3, treatment on clinical protocol, and younger age. Median and predicted 5-year survival from the time of HAI pump placement was 59 months and 47 %, respectively, in the patients who converted to complete R/A, compared with 16 months and 6 %, respectively in those who did not (p < 0.001).

Conclusions

Despite extensive disease, 25 % of patients with unresectable CRLM responded sufficiently to undergo complete R/A following HAI plus systemic chemotherapy. Combination HAI and systemic chemotherapy is an effective strategy to convert patients to complete resection with an associated excellent long-term survival.     

Predicting Dysplasia and Invasive Carcinoma in Intraductal Papillary Mucinous Neoplasms of the Pancreas: Development of a Preoperative Nomogram

Background

Clinical decision making for patients with intraductal papillary mucinous neoplasms (IPMN) of the pancreas is challenging. Even with strict criteria for resection, most resected lesions lack high-grade dysplasia (HGD) or invasive carcinoma.

Methods

We evaluated patients who underwent resection of histologically confirmed IPMN and had preoperative imaging available for review. A hepatobiliary radiologist blinded to histopathologic subtype reviewed preoperative imaging and recorded cyst characteristics. Patients with mixed-type IPMN were grouped with main-duct lesions for this analysis. Based on an ordinal logistic regression model, we devised two independent nomograms to predict the findings of adenoma, high-grade dysplasia (HGD–CIS), and invasive carcinoma, separately in both main and branch-duct IPMN. Bootstrap validation was used to evaluate the performance of these models, and a concordance index was derived from this internal validation.

Results

There were 219 patients who met criteria for this study. Branch-duct IPMN (bdIPMN) comprised 56 % of the resected lesions. The proportion of HGD–CIS was 15 % for bdIPMN and 33 % for main-duct lesions (mdIPMN); P = 0.003. Invasive carcinoma was identified in 15 % of bdIPMN and 41 % of main-duct lesions (P < 0.001). On multivariate regression, patient gender, history of prior malignancy, presence of solid component, and weight loss were found to be significantly associated with the ordinal outcome for patients with mdIPMN and built into the nomogram (concordance index 0.74). For patients with bdIPMN weight loss, solid component, and lesion diameter were associated with the outcome; (concordance index 0.74).

Conclusion

Based on the analysis of patients selected for resection, two nomograms were created that predict a patient’s individual likelihood of harboring HGD or invasive malignancy in radiologically diagnosed IPMN. External validation is ongoing.