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Impact of the Identification of Nonhuman Genetic Signatures in the Diagnosis and Management of Carcinoma of Unknown Primary

Arantzazu Barquín García, Sara Palacios-Zambrano, Felipe Lozano Alarcón, Beatriz Paumard-Hernández, Miguel Quiralte Pulido, Paloma Navarro, Laura Rodríguez, Isabel Salas Villar, and Jesús García-Donas

This report presents the case of a 62-year-old woman who was diagnosed in 1999 with stage I cervical carcinoma treated by surgical resection. In 2021, she presented to the emergency department with a complaint of predominantly right-sided lower back pain. A CT scan of the lumbosacral region revealed a bone lesion in the L5 vertebra and retroperitoneal lymphadenopathies suggestive of malignancy. Histology of the L5 vertebra biopsy showed a poorly differentiated carcinoma with an inconclusive immunophenotypic profile. Treatment for carcinoma of unknown primary was started with a combination of carboplatin and paclitaxel every 21 days. A genomic study of the biopsy specimen performed on the FoundationOne CDx platform identified a nonhuman genetic signature compatible with HPV. The presence of HPV 18 DNA in the specimen was confirmed by PCR-reverse dot blot, and the immunophenotypic profile was expanded, revealing strong and diffuse p16 expression, thus corroborating the molecular findings. In view of these findings, the case was reclassified as a recurrence of the cervical adenocarcinoma that had been diagnosed and treated 23 years earlier. Based on the new results, and according to first-line cervical carcinoma protocols, bevacizumab at 15 mg/kg every 21 days was added to her chemotherapy regimen. The identification of HPV DNA sequences by next-generation sequencing facilitated the correct diagnosis and led to a modification of the first-line therapeutic approach.

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Exceptional Response to Temsirolimus in a Metastatic Clear Cell Renal Cell Carcinoma With an Early Novel MTOR-Activating Mutation

Juan Francisco Rodríguez-Moreno, María Apellaniz-Ruiz, Juan María Roldan-Romero, Ignacio Durán, Luis Beltrán, Cristina Montero-Conde, Alberto Cascón, Mercedes Robledo, Jesus García-Donas, and Cristina Rodríguez-Antona

mTOR pathway inhibitors are important drugs for the treatment of advanced renal cell carcinoma (RCC). However, no valid predictive markers have been identified to guide treatment selection and identify patients who are sensitive to these drugs. Mutations activating the mTOR pathway have been suggested to predict response; however, their predictive value is still unclear. Here, we present the genomic and functional characterization of a patient with metastatic clear cell RCC (ccRCC) who experienced a partial response to temsirolimus after a poor response to 2 previous lines of treatment. At the time of publication, the patient was disease-free 8 years after temsirolimus treatment. Multiregion whole-exome sequencing (WES) on 3 regions of the primary tumor, 1 metastasis, and blood revealed tumor mutations in driver genes in ccRCC: a missense mutation in VHL (p.W88L), a loss-of-function mutation in BAP1 (p.E454Rfs*15), and a novel missense mutation in MTOR (p.Y1974H). The MTOR mutation was present in all tumor regions, with similar allele frequency as the VHL mutation, and in vitro functional assessment of the MTOR variant demonstrated that it increased mTORC1 activity. Consistently, immunohistochemistry in the tumor samples demonstrated increased levels of phospho-S6. In conclusion, multiregion WES identified a novel MTOR mutation acquired early during tumor development as the event leading to a high sensitivity to temsirolimus treatment. This study supports tumor multiregion sequencing to detect truncal mutations in the mTOR pathway to identify patients sensitive to mTOR inhibitors.