Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues.

Current sequencing methods are error-prone, which precludes the identification of low frequency mutations for early cancer detection. Duplex sequencing is a sequencing technology that decreases errors by scoring mutations present only in both strands of DNA. Our aim was to determine whether duplex sequencing could detect extremely rare cancer cells present in peritoneal fluid from women with high-grade serous ovarian carcinomas (HGSOCs). These aggressive cancers are typically diagnosed at a late stage and are characterized by TP53 mutations and peritoneal dissemination. We used duplex sequencing to analyze TP53 mutations in 17 peritoneal fluid samples from women with HGSOC and 20 from women without cancer. The tumor TP53 mutation was detected in 94% (16/17) of peritoneal fluid samples from women with HGSOC (frequency as low as 1 mutant per 24,736 normal genomes). Additionally, we detected extremely low frequency TP53 mutations (median mutant fraction 1/13,139) in peritoneal fluid from nearly all patients with and without cancer (35/37). These mutations were mostly deleterious, clustered in hotspots, increased with age, and were more abundant in women with cancer than in controls. The total burden of TP53 mutations in peritoneal fluid distinguished cancers from controls with 82% sensitivity (14/17) and 90% specificity (18/20). Age-associated, low frequency TP53 mutations were also found in 100% of peripheral blood samples from 15 women with and without ovarian cancer (none with hematologic disorder). Our results demonstrate the ability of duplex sequencing to detect rare cancer cells and provide evidence of widespread, low frequency, age-associated somatic TP53 mutation in noncancerous tissue.

Type B Lactic Acidosis in a Patient with Gastric Adenocarcinoma and Extensive Hepatic Metastases.

OBJECTIVE: We report the second case of gastric adenocarcinoma associated with type B lactic acidosis. CLINICAL PRESENTATION AND INTERVENTION: An 81-year-old man presenting with upper gastrointestinal bleeding was found to have an advanced gastric adenocarcinoma. He had persistently elevated serum lactate attributed to malignancy-associated type B lactic acidosis as a diagnosis of exclusion. As he remained clinically stable with a near-normal pH, his elevated lactate was not specifically treated. CONCLUSION: This patient had an unusual type B lactic acidosis associated with gastric cancer. In the absence of signs and symptoms of other etiologies of lactic acidosis, physicians should consider malignancy-associated type B lactic acidosis.