32fe8a0facdeace02506429576525a9c pmc_32796636.pdf 3e7347ed5c5f6104c4ac686245893ec8a621f210 pmc_32796636.pdf ce5143b5ea31c3189938869c1efb72e4a2e1cb244cf23bf21d2fe529bac0b97c pmc_32796636.pdf Title: Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients Subject: Background: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response. Patients and Methods: Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results. Results: Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R, T1156M in IRS2) and three in genes belonging to the LRIG family (T152T in LRIG1, S697L in LRIG2 and V812M in LRIG3). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response. Conclusions: This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors. Keywords: genetic variants; predictive biomarkers; anti-EGFR monoclonal antibodies; colorectal cancer; case-control study Author: Pau Riera, Benjamín Rodríguez-Santiago, Adriana Lasa, Lidia Gonzalez-Quereda, Berta Martín, Juliana Salazar, Ana Sebio, Anna C. Virgili, Jordi Minguillón, Cristina Camps, Jordi Surrallés and David Páez Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Tue Aug 11 12:53:53 2020 CEST ModDate: Tue Aug 11 12:53:53 2020 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 707814 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- GGSFVP+URWPalladioL-Ital Type 1 Custom yes yes no 97 0 BUIJVN+URWPalladioL-Bold Type 1 Custom yes yes no 98 0 JYPLJJ+VnURWPalladioL-Bold Type 1 Custom yes yes no 99 0 VGLXAR+URWPalladioL-Roma Type 1 Custom yes yes no 100 0 YHLBEF+VnURWPalladioL Type 1 Custom yes yes no 101 0 OFLXAT+Rpxr Type 1 Builtin yes yes no 102 0 YWGLGW+Rpxi Type 1 Builtin yes yes no 103 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 109 0 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GLIHIE+Calibri CID TrueType Identity-H yes yes yes 251 0 CKBPVA+EURM10 Type 1 Builtin yes yes no 460 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 03:41:12 CEST RepresentationInformation: pmc_32796636.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 11:47:14 CEST Size: 707814 Format: PDF Version: 1.5 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 0 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: ぉのぴひはつふっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸲ Item: Title: ぐちぴどづのぴびぜ〴ぜ〰ちのつぜ〴ぜ〰きづぴとはつびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぐちぴどづのぴぜ〴ぜ〰ぐはばふぬちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰ぇづのづぜ〴ぜ〰こづぬづっぴどはのぜ〴ぜ〰ちのつぜ〴ぜ〰ぐひどねづひぜ〴ぜ〰いづびどでのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰ぉびはぬちぴどはのぜ〴ぜ〰ちのつぜ〴ぜ〰けふちのぴどてどっちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰いぎぁぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰がどぢひちひべぜ〴ぜ〰ぐひづばちひちぴどはの〬ぜ〴ぜ〰こづぱふづのっどのでぜ〴ぜ〰げふのび〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぎぇこぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Children: Item: Title: ぐちぴどづのぴぜ〴ぜ〰ぐはばふぬちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰ぇづのづぜ〴ぜ〰こづぬづっぴどはのぜ〴ぜ〰ちのつぜ〴ぜ〰ぐひどねづひぜ〴ぜ〰いづびどでのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰ぉびはぬちぴどはのぜ〴ぜ〰ちのつぜ〴ぜ〰けふちのぴどてどっちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰いぎぁぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰がどぢひちひべぜ〴ぜ〰ぐひづばちひちぴどはの〬ぜ〴ぜ〰こづぱふづのっどのでぜ〴ぜ〰げふのび〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぎぇこぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: ぇづのづぜ〴ぜ〰こづぬづっぴどはのぜ〴ぜ〰ちのつぜ〴ぜ〰ぐひどねづひぜ〴ぜ〰いづびどでのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰ぉびはぬちぴどはのぜ〴ぜ〰ちのつぜ〴ぜ〰けふちのぴどてどっちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰いぎぁぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰がどぢひちひべぜ〴ぜ〰ぐひづばちひちぴどはの〬ぜ〴ぜ〰こづぱふづのっどのでぜ〴ぜ〰げふのび〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぎぇこぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: ぉびはぬちぴどはのぜ〴ぜ〰ちのつぜ〴ぜ〰けふちのぴどてどっちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰いぎぁぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰がどぢひちひべぜ〴ぜ〰ぐひづばちひちぴどはの〬ぜ〴ぜ〰こづぱふづのっどのでぜ〴ぜ〰げふのび〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぎぇこぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: がどぢひちひべぜ〴ぜ〰ぐひづばちひちぴどはの〬ぜ〴ぜ〰こづぱふづのっどのでぜ〴ぜ〰げふのび〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぎぇこぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: げづびふぬぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぐちぴどづのぴぜ〴ぜ〰ぐはばふぬちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ぇづのづぴどっぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰かげぁこ〬ぜ〴ぜ〰ぎげぁこ〬ぜ〴ぜ〰あげぁう〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぐぉか〳ぃぁぜ〴ぜ〰ぁびびづびびねづのぴぜ〴ぜ〰ちのつぜ〴ぜ〰ぐちぴどづのぴぜ〴ぜ〰こづぬづっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰ぉつづのぴどてどっちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぎはぶづぬぜ〴ぜ〰ぇづのづぴどっぜ〴ぜ〰ざちひどちのぴびぜ〴ぜ〰げづぬちぴづつぜ〴ぜ〰ぴはぜ〴ぜ〰ぁのぴど〭ぅぇうげぜ〴ぜ〰げづびばはのびづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Children: Item: Title: ぐちぴどづのぴぜ〴ぜ〰ぐはばふぬちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ぇづのづぴどっぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰かげぁこ〬ぜ〴ぜ〰ぎげぁこ〬ぜ〴ぜ〰あげぁう〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぐぉか〳ぃぁぜ〴ぜ〰ぁびびづびびねづのぴぜ〴ぜ〰ちのつぜ〴ぜ〰ぐちぴどづのぴぜ〴ぜ〰こづぬづっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰ぉつづのぴどてどっちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぎはぶづぬぜ〴ぜ〰ぇづのづぴどっぜ〴ぜ〰ざちひどちのぴびぜ〴ぜ〰げづぬちぴづつぜ〴ぜ〰ぴはぜ〴ぜ〰ぁのぴど〭ぅぇうげぜ〴ぜ〰げづびばはのびづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ぇづのづぴどっぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰かげぁこ〬ぜ〴ぜ〰ぎげぁこ〬ぜ〴ぜ〰あげぁう〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぐぉか〳ぃぁぜ〴ぜ〰ぁびびづびびねづのぴぜ〴ぜ〰ちのつぜ〴ぜ〰ぐちぴどづのぴぜ〴ぜ〰こづぬづっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰ぉつづのぴどてどっちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぎはぶづぬぜ〴ぜ〰ぇづのづぴどっぜ〴ぜ〰ざちひどちのぴびぜ〴ぜ〰げづぬちぴづつぜ〴ぜ〰ぴはぜ〴ぜ〰ぁのぴど〭ぅぇうげぜ〴ぜ〰げづびばはのびづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: かげぁこ〬ぜ〴ぜ〰ぎげぁこ〬ぜ〴ぜ〰あげぁう〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぐぉか〳ぃぁぜ〴ぜ〰ぁびびづびびねづのぴぜ〴ぜ〰ちのつぜ〴ぜ〰ぐちぴどづのぴぜ〴ぜ〰こづぬづっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰ぉつづのぴどてどっちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぎはぶづぬぜ〴ぜ〰ぇづのづぴどっぜ〴ぜ〰ざちひどちのぴびぜ〴ぜ〰げづぬちぴづつぜ〴ぜ〰ぴはぜ〴ぜ〰ぁのぴど〭ぅぇうげぜ〴ぜ〰げづびばはのびづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ぉつづのぴどてどっちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぎはぶづぬぜ〴ぜ〰ぇづのづぴどっぜ〴ぜ〰ざちひどちのぴびぜ〴ぜ〰げづぬちぴづつぜ〴ぜ〰ぴはぜ〴ぜ〰ぁのぴど〭ぅぇうげぜ〴ぜ〰げづびばはのびづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: いどびっふびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: ぃはのっぬふびどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: GGSFVP+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 121 FontDescriptor: FontName: GGSFVP+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: BUIJVN+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: BUIJVN+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: 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