502P Impact of different selection approaches for identifying Lynch syndrome-related colorectal cancer patients

Fanale, Daniele; Dimino, Alessandra; Filorizzo, Clarissa; Brando, Chiara; Incorvaia, Lorena; Magrin, Luigi; Sciacchitano, Roberta; Corsini, Lidia Rita; Fiorino, Alessia; Barraco, Nadia; Bono, Marco; Calò, Valentina; Cancelliere, D.; Cucinella, A.; Madonia, G; Pedone, Erika; Pivetti, Alessia; Scalia, R.; Russo, Antonio; Bazan, Viviana

doi:10.1016/j.annonc.2021.08.1021

Cited by 2 publications

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“…It is also the fifth leading cause of cancer mortality accounting for 6.9% of cancer deaths (Sung et al, 2021). While 75%-80% of breast cancer cases are usually sporadic, the rest of the cases are either familial (15%-20%) or hereditary (5%-10%) that are caused by germline variations in breast cancer associated genes (Fanale et al, 2020). Among these genes, Breast Cancer 1 (BRCA1) and Breast Cancer 2 (BRCA2) have been reported to have variations that increase the risk of developing breast and ovarian cancers by more than 60% basically suggesting these variations as one of the leading causes of breast and ovarian cancers (Gradishar et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Among these genes, Breast Cancer 1 (BRCA1) and Breast Cancer 2 (BRCA2) have been reported to have variations that increase the risk of developing breast and ovarian cancers by more than 60% basically suggesting these variations as one of the leading causes of breast and ovarian cancers (Gradishar et al, 2022). Nonetheless, the rate of non-BRCA pathogenic variations was higher than those of BRCA1 or BRCA2 pathogenic variations especially in bilateral breast cancer patients (Fanale et al, 2020). Thus, in addition to BRCA1 and BRCA2, many other genes have been identified as susceptibility genes for breast cancer (Angeli et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…More importantly, the selection of genes in the panel may not necessarily depend on their risk estimates, a situation which may result in an increase of VUS labels (Rainville and Rana, 2014). Given their earlier discovery, extensive data has been collected for the BRCA1/2 variations while this is not the case for many genes in the panel (Fanale et al, 2020). The bias towards BRCA1/BRCA2 is in fact aligned with the higher cancer risk associated with the variants occurring in these genes (Chen et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of AlphaFold structure-based protein stability prediction on missense variations in cancer

et al. 2023

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Identifying pathogenic missense variants in hereditary cancer is critical to the efforts of patient surveillance and risk-reduction strategies. For this purpose, many different gene panels consisting of different number and/or set of genes are available and we are particularly interested in a panel of 26 genes with a varying degree of hereditary cancer risk consisting of ABRAXAS1, ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MEN1, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and XRCC2. In this study, we have compiled a collection of the missense variations reported in any of these 26 genes. More than a thousand missense variants were collected from ClinVar and the targeted screen of a breast cancer cohort of 355 patients which contributed to this set with 160 novel missense variations. We analyzed the impact of the missense variations on protein stability by five different predictors including both sequence- (SAAF2EC and MUpro) and structure-based (Maestro, mCSM, CUPSAT) predictors. For the structure-based tools, we have utilized the AlphaFold (AF2) protein structures which comprise the first structural analysis of this hereditary cancer proteins. Our results agreed with the recent benchmarks that computed the power of stability predictors in discriminating the pathogenic variants. Overall, we reported a low-to-medium-level performance for the stability predictors in discriminating pathogenic variants, except MUpro which had an AUROC of 0.534 (95% CI [0.499–0.570]). The AUROC values ranged between 0.614–0.719 for the total set and 0.596–0.682 for the set with high AF2 confidence regions. Furthermore, our findings revealed that the confidence score for a given variant in the AF2 structure could alone predict pathogenicity more robustly than any of the tested stability predictors with an AUROC of 0.852. Altogether, this study represents the first structural analysis of the 26 hereditary cancer genes underscoring 1) the thermodynamic stability predicted from AF2 structures as a moderate and 2) the confidence score of AF2 as a strong descriptor for variant pathogenicity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of AlphaFold structure-based protein stability prediction on missense variations in cancer

et al. 2023

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“…Because of the advantage from costbenefit reduction, this approach provides a powerful enforcement for patients with LPVs and PVs in other genes, beyond BRCA1/2. Several germline PVs in susceptibility genes as CDH1, PALB2, PTEN, STK11, TP53, ATM, CHEK2, BARD1, BRLP1, RAD51C, and RAD51D (Shah et al, 2016;Fanale et al, 2020) can be associated with hereditary tumors. Most of these genes are involved in cell cycle checkpoint and DNA damage repair mechanism, and function together in these physiological pathways (Nielsen et al, 2016;Piombino et al, 2020;Neiger et al, 2021); therefore, a fundamental comprehension of the disease drivers in the cascades would facilitate the accurate evaluation of the genetic risk of cancer development (Yoshimura et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Clinical usefulness of NGS multi-gene panel testing in hereditary cancer analysis

et al. 2023

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Introduction: A considerable number of families with pedigrees suggestive of a Mendelian form of Breast Cancer (BC), Ovarian Cancer (OC), or Pancreatic Cancer (PC) do not show detectable BRCA1/2 mutations after genetic testing. The use of multi-gene hereditary cancer panels increases the possibility to identify individuals with cancer predisposing gene variants. Our study was aimed to evaluate the increase in the detection rate of pathogenic mutations in BC, OC, and PC patients when using a multi-gene panel.Methods: 546 patients affected by BC (423), PC (64), or OC (59) entered the study from January 2020 to December 2021. For BC patients, inclusion criteria were i) positive cancer family background, ii) early onset, and iii) triple negative BC. PC patients were enrolled when affected by metastatic cancer, while OC patients were all submitted to genetic testing without selection. The patients were tested using a Next-Generation Sequencing (NGS) panel containing 25 genes in addition to BRCA1/2.Results: Forty-four out of 546 patients (8%) carried germline pathogenic/likely pathogenic variants (PV/LPV) on BRCA1/2 genes, and 46 (8%) presented PV or LPV in other susceptibility genes.Discussion: Our findings demonstrate the utility of expanded panel testing in patients with suspected hereditary cancer syndromes, since this approach increased the mutation detection rate of 15% in PC, 8% in BC and 5% in OC cases. In absence of multi-gene panel analysis, a considerable percentage of mutations would have been lost.

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502P Impact of different selection approaches for identifying Lynch syndrome-related colorectal cancer patients

Cited by 2 publications

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Evaluation of AlphaFold structure-based protein stability prediction on missense variations in cancer

Evaluation of AlphaFold structure-based protein stability prediction on missense variations in cancer

Clinical usefulness of NGS multi-gene panel testing in hereditary cancer analysis

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