bims-ovdlit 2022-12-18 papers

Issue of 2022‒12‒18
four papers selected by
Lara Paracchini
Humanitas Research

Int J Mol Sci. 2022 Nov 26. pii: 14814. [Epub ahead of print]23(23):

Using Genomic Variation to Distinguish Ovarian High-Grade Serous Carcinoma from Benign Fallopian Tubes.

Jesus Gonzalez-Bosquet, Nicholas D Cardillo, Henry D Reyes, Brian J Smith, Kimberly K Leslie, David P Bender, Michael J Goodheart, Eric J Devor.

The preoperative diagnosis of pelvic masses has been elusive to date. Methods for characterization such as CA-125 have had limited specificity. We hypothesize that genomic variation can be used to create prediction models which accurately distinguish high grade serous ovarian cancer (HGSC) from benign tissue.METHODS: In this retrospective, pilot study, we extracted DNA and RNA from HGSC specimens and from benign fallopian tubes. Then, we performed whole exome sequencing and RNA sequencing, and identified single nucleotide variants (SNV), copy number variants (CNV) and structural variants (SV). We used these variants to create prediction models to distinguish cancer from benign tissue. The models were then validated in independent datasets and with a machine learning platform.
RESULTS: The prediction model with SNV had an AUC of 1.00 (95% CI 1.00-1.00). The models with CNV and SV had AUC of 0.87 and 0.73, respectively. Validated models also had excellent performances.
CONCLUSIONS: Genomic variation of HGSC can be used to create prediction models which accurately discriminate cancer from benign tissue. Further refining of these models (early-stage samples, other tumor types) has the potential to lead to detection of ovarian cancer in blood with cell free DNA, even in early stage.

Keywords: RNA sequencing; genetic variation; ovarian cancer; prediction model; whole exome sequencing

DOI: https://doi.org/10.3390/ijms232314814

Nature. 2022 Dec 14.

Ovarian cancer mutational processes drive site-specific immune evasion.

Ignacio Vázquez-García, Florian Uhlitz, Nicholas Ceglia, Jamie L P Lim, Michelle Wu, Neeman Mohibullah, Juliana Niyazov, Arvin Eric B Ruiz, Kevin M Boehm, Viktoria Bojilova, Christopher J Fong, Tyler Funnell, Diljot Grewal, Eliyahu Havasov, Samantha Leung, Arfath Pasha, Druv M Patel, Maryam Pourmaleki, Nicole Rusk, Hongyu Shi, Rami Vanguri, Marc J Williams, Allen W Zhang, Vance Broach, Dennis S Chi, Arnaud Da Cruz Paula, Ginger J Gardner, Sarah H Kim, Matthew Lennon, Kara Long Roche, Yukio Sonoda, Oliver Zivanovic, Ritika Kundra, Agnes Viale, Fatemeh N Derakhshan, Luke Geneslaw, Shirin Issa Bhaloo, Ana Maroldi, Rahelly Nunez, Fresia Pareja, Anthe Stylianou, Mahsa Vahdatinia, Yonina Bykov, Rachel N Grisham, Ying L Liu, Yulia Lakhman, Ines Nikolovski, Daniel Kelly, Jianjiong Gao, Andrea Schietinger, Travis J Hollmann, Samuel F Bakhoum, Robert A Soslow, Lora H Ellenson, Nadeem R Abu-Rustum, Carol Aghajanian, Claire F Friedman, Andrew McPherson, Britta Weigelt, Dmitriy Zamarin, Sohrab P Shah.

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1-4 patterned by distinct mutational processes5,6, tumour heterogeneity7-9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11-13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFβ signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research.

DOI: https://doi.org/10.1038/s41586-022-05496-1

Nat Commun. 2022 Dec 13. 13(1): 7694

Tumor fractions deciphered from circulating cell-free DNA methylation for cancer early diagnosis.

Xiao Zhou, Zhen Cheng, Mingyu Dong, Qi Liu, Weiyang Yang, Min Liu, Junzhang Tian, Weibin Cheng.

Tumor-derived circulating cell-free DNA (cfDNA) provides critical clues for cancer early diagnosis, yet it often suffers from low sensitivity. Here, we present a cancer early diagnosis approach using tumor fractions deciphered from circulating cfDNA methylation signatures. We show that the estimated fractions of tumor-derived cfDNA from cancer patients increase significantly as cancer progresses in two independent datasets. Employing the predicted tumor fractions, we establish a Bayesian diagnostic model in which training samples are only derived from late-stage patients and healthy individuals. When validated on early-stage patients and healthy individuals, this model exhibits a sensitivity of 86.1% for cancer early detection and an average accuracy of 76.9% for tumor localization at a specificity of 94.7%. By highlighting the potential of tumor fractions on cancer early diagnosis, our approach can be further applied to cancer screening and tumor progression monitoring.

DOI: https://doi.org/10.1038/s41467-022-35320-3

Commun Biol. 2022 Dec 12. 5(1): 1362

L1CAM is required for early dissemination of fallopian tube carcinoma precursors to the ovary.

Kai Doberstein, Rebecca Spivak, Hunter D Reavis, Jagmohan Hooda, Yi Feng, Paul T Kroeger, Sarah Stuckelberger, Gordon B Mills, Kyle M Devins, Lauren E Schwartz, Marcin P Iwanicki, Mina Fogel, Peter Altevogt, Ronny Drapkin.

Most ovarian high-grade serous carcinomas (HGSC) arise from Serous Tubal Intraepithelial Carcinoma (STIC) lesions in the distal end of the fallopian tube (FT). Formation of STIC lesions from FT secretory cells leads to seeding of the ovarian surface, with rapid tumor dissemination to other abdominal structures thereafter. It remains unclear how nascent malignant cells leave the FT to colonize the ovary. This report provides evidence that the L1 cell adhesion molecule (L1CAM) contributes to the ability of transformed FT secretory cells (FTSEC) to detach from the tube, survive under anchorage-independent conditions, and seed the ovarian surface. L1CAM was highly expressed on the apical cells of STIC lesions and contributed to ovarian colonization by upregulating integrins and fibronectin in malignant cells and activating the AKT and ERK pathways. These changes increased cell survival under ultra-low attachment conditions that mimic transit from the FT to the ovary. To study dissemination to the ovary, we developed a tumor-ovary co-culture model. We showed that L1CAM expression was important for FT cells to invade the ovary as a cohesive group. Our results indicate that in the early stages of HGSC development, transformed FTSECs disseminate from the FT to the ovary in a L1CAM-dependent manner.

DOI: https://doi.org/10.1038/s42003-022-04314-8