Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers

Serebriiskii, Ilya G.; Pavlov, Valery; Tricarico, Rossella; Andrianov, Grigorii; Nicolas, Émmanuelle; Parker, Mitchell I.; Newberg, Justin Y.; Frampton, Garrett M.; Meyer, Joshua E.; Golemis, Erica A.

doi:10.1038/s41467-022-29227-2

Cited by 28 publications

(14 citation statements)

References 98 publications

(131 reference statements)

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“…Functional activities associated with immune response included regulation of granulocyte-macrophage colony-stimulating factor production, neutrophil migration, and regulation of leukocyte-mediated cytotoxicity. These findings are consistent with recent studies that showed that PTEN mutation was associated with microsatellite stability/instability and tumor mutational burden in colon cancer 48 . Both in vitro studies 49 and recent analyses of colon tumors 50 suggest that PTEN loss in colorectal carcinoma may activation of PI3K and upregulate PD-L1 expression.…”

Section: Discussionsupporting

confidence: 93%

Pan-cancer genomic analysis shows hemizygousPTENloss tumors are associated with immune evasion and poor outcome

Vidotto

Melo

Lautert-Dutra

et al. 2022

Preprint

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Somatic mutations of the PTEN tumor suppressor gene in tumors are associated with advanced disease, chemotherapy resistance, and poor survival. PTEN point mutations or deletions that inactivate one (hemizygous loss) or both genes (homozygous loss) are frequent somatic events in all cancers. Mouse models have shown that the tumor-promoting abilities of Pten loss can exhibit haploinsufficiency, with hemizygous loss being more tumorigenic than homozygous loss. Most PTEN biomarker studies of human tumors have not considered potential differences between hemi- and homozygous loss. To determine the oncogenic role of hemizygous PTEN loss in a range of solid tumors, we performed an analysis of 393 (4.03%) to be homozygous and 2292 (23.51%) hemizygous PTEN losses derived from 9,748 cases of the Cancer Genome Atlas (TCGA) cohort analyzing 31 tumor types. Both hemi- and homozygous PTEN loss were strongly associated with a less favorable outcome and the acquisition of genomic features of tumor progression. Combined survival analysis of the TCGA cohort showed that patients with hemizygous PTEN loss had worse outcomes than homozygous loss and PTEN intact (P<0.0001). Hemizygous loss in tumors of colon, head and neck and cervix had less favorable outcomes compared to homozygous loss and intact tumors. Tumors with hemizygous PTEN loss had significantly higher levels of nonsilent mutations, intratumor heterogeneity, aneuploidy, and percent genome altered compared to homozygous loss. These data suggest that the more extensive genomic diversity associated with hemizygous loss could be providing the selective advantage and worse outcome in these tumor types. Transcriptome analysis showed that most investigated tumors had immune-related pathways up- or downregulated when PTEN was lost. CIBERSORT analysis found that the imputed immune cell abundances were significantly altered for both types of PTEN loss, with changes in head and neck, cervix, stomach, prostate, brain, and colon being more evident in hemizygous loss tumors. Collectively, these data draw attention to the need for more comprehensive PTEN biomarker studies of the prognostic role of hemizygous loss. Future studies should also investigate the role of reduced levels of PTEN protein on differential treatment responses to chemo- or immunotherapy in specific tumor types.

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Section: Discussionsupporting

confidence: 93%

Pan-cancer genomic analysis shows hemizygousPTENloss tumors are associated with immune evasion and poor outcome

Vidotto

Melo

Lautert-Dutra

et al. 2022

Preprint

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“…Pt#2 with a POLE candidate PGV also harbored candidate PGVs in BRCA2, PDGFRA. In other studies, hypermutant ccRCCs also carried mutations in TP53, PTEN, VHL, and UNC5C (45,46). It is also possible that defects in polymerase genes affect cancer risk by affecting biological processes beyond DNA replication and repair.…”

Section: Discussionmentioning

confidence: 96%

Signatures of defective DNA repair and replication in early-onset renal cancer patients referred for germline genetic testing

Demidova

Serebriiskii

Vlasenkova

et al. 2022

Preprint

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Early-onset renal cell carcinoma (eoRCC) is typically associated with pathogenic germline variants (PGVs) in RCC familial syndrome genes. However, most eoRCC patients lack PGVs in familial RCC genes and their genetic risk remains undefined. Here, we analyzed biospecimens from 22 eoRCC patients that were seen at our institution for genetic counseling and tested negative for PGVs in RCC familial syndrome genes. We performed whole-exome sequencing (WES) and found enrichment of candidate pathogenic germline variants in DNA repair and replication genes, including multiple DNA polymerases. Induction of DNA damage in peripheral blood monocytes (PBMCs) significantly elevated numbers of γH2AX foci, a marker of double-stranded breaks, in PBMCs from eoRCC patients versus PBMCs from matched cancer-free controls. Knockdown of candidate PGVs in Caki RCC cells increased γH2AX foci. Immortalized patient-derived B cells bearing candidate PGVs in DNA polymerase genes (POLD1, POLH, POLE, POLK) had DNA replication defects compared to control cells. Renal tumors carrying these DNA polymerase variants were microsatellite stable but had a high mutational burden. Direct biochemical analysis of the variant Pol δ and Pol η polymerases revealed defective enzymatic activities. Together, these results suggest that constitutional defects in DNA repair such as DNA replication repair underlie a subset of eoRCC cases. These findings may provide opportunities for use of the DNA repair targeting agents for eoRCC treatment. Screening patient lymphocytes to identify these defects may provide insight into mechanisms of carcinogenesis in a subset of genetically undefined eoRCCs.Significance StatementScreening for DNA repair variation may provide a more comprehensive risk assessment for eoRCC patients. Evaluation of DNA repair defects may also provide insight into the cancer initiation mechanisms for subsets of eoRCCs and lay the foundation for targeting DNA repair vulnerabilities in eoRCC.

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“…In humans, different types of mutations and dosages of PTEN result in different diseases: heterozygous loss-of-function of PTEN has been associated with ASD (Busch et al, Transl Psychiatry, 2019; Butler et al, J Med Genet, 2005; Frazier et al, Mol Psychiatry, 2015, Serebriiskii et al, 2022), while both heterozygous and homozygous PTEN loss-of-function has been associated with tumor syndromes (Krohn et al, Am J Pathol, 2012; Wang et al, Clin Cancer Res, 1998). We therefore investigated whether different dosages of PTEN may result in different phenotypes also in brain organoids.…”

Section: Main Textmentioning

confidence: 99%

Cell-type specific developmental defects inPTEN-mutant cortical organoids converge on abnormal circuit activity

Pigoni

Uzquiano

Paulsen

et al. 2022

Preprint

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De novo heterozygous loss-of-function mutations in PTEN are strongly associated with Autism spectrum disorders (ASD); however, it is unclear how heterozygous mutations in this gene affects different cell types during human brain development, and how these effects vary across individuals. Here, we used human cortical organoids from different donors to identify cell-type-specific developmental events that are affected by heterozygous mutations in PTEN. We profiled individual organoids by single-cell RNA-seq, proteomics and spatial transcriptomics, and revealed abnormalities in developmental timing in human outer radial glia progenitors and deep layer cortical projection neurons, which varied with the donor genetic background. Calcium imaging in intact organoids showed that both accelerated and delayed neuronal development phenotypes resulted in similar abnormal activity of local circuits, irrespective of genetic background. The work reveals donor-dependent, cell-type specific developmental phenotypes of PTEN heterozygosity that later converge on disrupted neuronal activity.

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Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers

Cited by 28 publications

References 98 publications

Pan-cancer genomic analysis shows hemizygousPTENloss tumors are associated with immune evasion and poor outcome

Pan-cancer genomic analysis shows hemizygousPTENloss tumors are associated with immune evasion and poor outcome

Signatures of defective DNA repair and replication in early-onset renal cancer patients referred for germline genetic testing

Cell-type specific developmental defects inPTEN-mutant cortical organoids converge on abnormal circuit activity

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