The implementation of cancer molecular characterization in clinical practice has improved prognostic re-definition, extending the eligibility to a continuously increasing number of targeted treatments. Broad molecular profiling technologies better than organ-based approaches are believed to serve such dynamic purposes. We here present the workflow our institution adopted to run a comprehensive cancer genome profiling in clinical practice. This article describes the workflow designed to make a comprehensive cancer genome profiling program feasible and sustainable in a large-volume referral hospital.
Abstract Background Ovarian Cancer (OC) prevention and early-stage detection represents a challenge due to the lack of effective surveillance. The identification of high-risk women is crucial as it provides access to prophylactic oophorectomy and reduces disease burden. Next-Generation Sequencing approaches enable the investigation of several genes associated with monogenic hereditary cancer predisposition, including ovarian cancer. For family members of patients affected by ovarian cancer without identification of a germline pathogenic variant, despite the increased empirical risk (3 times) of ovarian cancer incidence, prophylactic surgery is not indicated but may be suggested as the only efficient strategy. Methods and Results We hereby present 2 cases of OC in which a germline heterozygous pathogenic variant in the ATM gene was identified: the first in the contest of Hereditary Breast and Ovarian Cancer (HBOC) family history and, in the other one, a late onset of neoplasms, to underline the importance of defining guidelines and management of moderate penetrance genes variants also for ovarian cancer prevention. Conclusions Carriers of heterozygous pathogenic variants in the ATM gene have an increased risk of neoplasms incidence, mostly breast but also of OC with an absolute estimated risk of 2–3 times greater than the general population. For these patients there is not well-established evidence of benefit in risk reducing bilateral Salpingo-oophorectomy.
Mutations in BRCA-genes have been identified as predisposing to hereditary breast and ovarian cancers. Little is known about how ovarian cancer risks differs across different BRCA mutation type. The purpose of our study is to identify the correlation between specific type of BRCA mutations and (1) age of onset of high-grade serous ovarian cancer (HGSOC) and (2) patients' survival.
Methodology
Retrospective multicentric series of newly diagnosed HGSOC-patients with FIGO Stage III-IV, assessed for germline (g)BRCA status. BRCA gene mutations were classified into 5 groups: deletion, insertion, no-sense, missense and splicing.
Result(s)*
A total of 214 patients were included in the analysis. 143 (67.1%) had a gBRCA1-pathogenic variant (PV) and 71 (33.1%) had a gBRCA2-PV. Overall, the mean age of onset was 54.75 years (10.9 SD) with a difference of around 4 years between patients having BRCA 1 and BRCA2 mutations (53yrs, SD 10.9 vs. 57.2yrs, SD 10.5; p=0.018). The most frequent mutation found was deletion (42.9%). Patients with no-sense mutation (18.2%) had the youngest age of onset, both in BRCA1 and BRCA2 subgroups, with an earlier occurrence of around 6 and 4 years respectively (BRCA1 group: 48.8yrs, SD 9.7 vs.54.7yrs, SD10.9; p=0.008) (BRCA2 group 53.0yrs SD 5.5 vs. 57.9yrs SD 10.9; p=0.04). Women with insertion (18.7%) had the oldest age of onset, both in BRCA 1 (57.7yrs, SD 11.7 vs. 52.2yrs, SD10.6; p=0.028) and BRCA2 (59.6yrs SD 10.1 vs. 56.6yrs SD 10.6) subgroups (p=ns) (table 1). No statistically significant difference in overall survival was found among the 5 groups examined (figure 1).
Conclusion*
Our study highlights for the first time that different types of BRCA mutations could indicate a different age for OC onset. If confirmed in larger series, it might have a relevant clinical impact, leading to a more tailored approach for risk-reducing surgery strategies for OC prevention. Moreover, as we initially include only advanced stages in our analysis, further investigation on the time of onset of early BRCA mutated OC is currently ongoing.
Glucose-6-phosphate dehydrogenase (G6PD), an X-linked hereditary deficiency, is the most common of all clinically significant enzyme defects. While many drugs are responsible for haemolytic anaemia in G6PD-deficient patients, acetaminophen's imputability is still under debate, although an overdose of this drug can provoke acute haemolytic events. We report a case of a Philipino child carrying the G6PD-Vanua Lava mutation with acute haemolytic crisis related to infection in progress and acetaminophen's administration. Fever and concomitant infection, through an increment of erythrocyte glutathione depletion, sensitized the infant to the haemolytic event. In this condition, acetaminophen (or paracetamol [PCM]) was capable of inducing a haemolytic crisis in our G6PD-deficient patient although administered under standard conditions. PCM seems to have induced the haemolytic event, probably by the alteration of its catabolism due to dehydration and fever. The enzymatic G6PD instability associated to the presence of the G6PD-Vanua Lava mutation could have led to an increment of red blood cells' sensitivity to lysis; hence, it is possible that PCM toxicity may also be due to the presence of this particular mutation. Finally, we propose a new biochemical classification of this G6PD variant.
