PO.CL09.01 · 临床研究

不同的KRAS突变密码子在结直肠癌中与微卫星不稳定性存在差异关联

Distinct KRAS mutation codons differentially associate with microsatellite instability in colorectal carcinoma

编号 5336 展板 4 时间 4/21 09:00–12:00 区域 Section 46 主讲 J. Bryan, MD;MPH

分会场 Precision Oncology and Real World Data

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作者与单位 Authors & Affiliations

Mark Evans¹, Vishal Chandan², Kenna Shaw³, Scott Kopetz⁴, Anirban Maitra⁵, Julian Bryan⁶

¹Caris Life Sciences, Irving, TX,²UC Irvine School of Medicine, Irvine, CA,³Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, UT MD Anderson Cancer Ctr., Houston, TX,⁴UT MD Anderson Cancer Center, Houston, TX,⁵NYU Langone Health, New York, NY,⁶MD Anderson Cancer Center, Houston, TX

摘要 Abstract

中文摘要

背景：MSI/MMR和KRAS是结直肠癌（CRC）中用于PD1抑制剂、EGFR单抗和KRAS G12C抑制剂的关键生物标志物。据报道，MSI高在KRAS突变型CRC中较少见。然而，由于KRAS突变位置影响蛋白功能和CRC病理生理，我们假设MSI也因KRAS突变位点而异。方法：在2个数据库（MSK-CHORD和Caris CODEai）中使用逻辑回归按KRAS突变位置评估MSI高的患病率。排除BRAF V600E型CRC。结果：在MSK-CHORD的4,805例CRC（非BRAF V600E、NRAS野生型、无既往EGFR单抗）中，8.7%为MSI-H。然而，MSI-H患病率因KRAS突变位点差异显著：KRAS野生型为8.8%，密码子13/61/146型CRC为13.5-15.9%；但仅5.1%的密码子12突变型CRC为MSI-H（所有p≤0.001）。值得注意的是，MSI-H在KRAS密码子内部也有差异：仅2.0%的G12C和2.8%的G12V（均为C>A）为MSI-H，而G12D为7.8%、G12A为4.8%、G12S为3.8%。为验证机构发现，我们分析了一家大型参考实验室的数据。在Caris CODEai的83,532例非BRAF V600E型CRC中，5.4%为MSI-H。同样，MSI-H患病率因KRAS突变位点而异：KRAS野生型为6.4%，密码子13/61/117/146为5.6-6.9%，密码子14/59突变型CRC为19.2-26.9%；相比之下密码子12突变型CRC仅为1.9%（所有p<0.001）。我们随后在Caris CODEai的其他癌症类型中检验了这一发现。在胰腺癌中观察到相似的结果：在40,497例中仅0.7%为MSI-H，从KRAS野生型的0.7%到密码子12/61的0.4-0.5%，但密码子13为7.8%（p<0.001）。结论：MSI-H患病率因CRC中KRAS突变位置而异，密码子12突变（尤其是C>A）与低MSI-H率相关，而密码子13/59/61/146突变在MSI-H型CRC中富集。我们的数据提示，MSI/MMR突变过程与不同的密码子分辨率下的KRAS生物学相关，并可能产生特定的KRAS突变，这值得进一步研究，并可能完善预测性生物标志物的解读。$$table_{639CE3DC-D7C9-4D54-BCC3-73A53B9D4E63}$$ MSK-CHORD CRC中按KRAS状态的MSI-High患病率 KRAS_状态总数_n MSI-H_n MSI-H_% 野生型 2510 222 8.8 密码子_12 1517 78 5.1 密码子_13 436 49 13.5 密码子_59 10 5 50.0 密码子_61 94 13 13.8 密码子_117 26 8 30.8 密码子_146 164 26 15.9 密码子_12内 G12A_(C>G) 104 5 4.8 G12C_(C>A) 153 3 2.0 G12D_(C>T) 658 51 7.8 G12R_(C>G) 24 2 8.3 G12S_(C>T) 105 4 3.8 G12V_(C>A) 469 13 2.8 密码子_13内 G13C_(C>A) 19 2 10.5 G13D_(C>T) 412 55 13.4 密码子_61内 Q61H_(T>G,T>A) 50 5 10.0 Q61K_(GA>TT, G>T, GA>TG) 21 8 38.1 Q61L_(T>A) 7 0 0 Q61R_(T>C, TT>GC) 15 0 0 密码子_146内 A146P_(C>G) 9 2 22.2 A146T_(C>T) 128 23 18.0 A146V_(G>A) 26 1 3.9 密码子_59内 A59T_(C>T) 10 5 50.0 密码子_117内 K117N_(T>A,T>G) 24 8 33.3

查看英文原文 English abstract

Background: MSI/MMR and KRAS are key biomarkers in colorectal carcinomas (CRC) for PD1 inhibitors, EGFR mAbs, and KRAS G12C inhibitors. MSI High is reported to be less common in KRAS mutant CRC. However, because KRAS mutation location influences protein function and CRC pathophysiology, we hypothesized that MSI also differs by KRAS mutation site. Methods: MSI High prevalence was assessed by KRAS mutation location in CRCs using logistic regression in 2 databases: MSK-CHORD, and Caris CODEai. BRAF V600E CRCs were excluded. Results: In MSK-CHORD's 4,805 CRCs (non BRAF V600E, NRAS wt, and no prior EGFRmab), 8.7% were MSI-H. However, MSI-H prevalence differed markedly by KRAS mutation site: 8.8% of KRAS wt and 13.5-15.9% of codon 13/61/146 CRCs; but only 5.1% of codon 12 mutant CRCs were MSI-H (all p≤0.001). Notably, MSI-H also varied within KRAS codons: only 2.0% of G12C and 2.8% of G12V (both C>A) were MSI-H, vs 7.8% of G12D, 4.8% of G12A, and 3.8% of G12S. For confirmation of institutional findings, we analyzed data from a large reference laboratory. In Caris CODEai's 83,532 non BRAF V600E CRCs, 5.4% were MSI-H. Again, MSI-H prevalence varied by KRAS mutation site: 6.4% of KRAS wt, 5.6-6.9% of codon 13/61/117/146, and 19.2-26.9% of codon 14/59 mutant CRCs were MSI-H; compared to only 1.9% of codon 12 mut CRCs (all p<0.001). We then tested this finding in other cancer types in Caris CODEai. A similar result was observed in pancreatic cancer: among 40,497 only 0.7% were MSI-H, from 0.7% of KRAS wt to 0.4-0.5% of codon 12/61, but 7.8% of codon 13 (p<0.001). Conclusions: MSI-H prevalence varied by KRAS mutation location in CRC, with codon 12 muts-especially C>A-associated with low MSI-H rates, whereas codon 13/59/61/146 muts were enriched among MSI-H CRCs. Our data suggest that MSI/MMR mutational processes are associated with distinct codon-resolved KRAS biology and may give rise to specific KRAS muts, which warrants further investigation and could refine predictive biomarker interpretation.$$table_{639CE3DC-D7C9-4D54-BCC3-73A53B9D4E63}$$ MSI-High prevalence by KRAS status in MSK-CHORD CRC KRAS_ status Total_ n MSI-H_ n MSI-H_ % wt 2510 222 8.8 codon_12 1517 78 5.1 codon_13 436 49 13.5 codon_59 10 5 50.0 codon_61 94 13 13.8 codon_117 26 8 30.8 codon_146 164 26 15.9 in_codon_12 G12A_(C>G) 104 5 4.8 G12C_(C>A) 153 3 2.0 G12D_(C>T) 658 51 7.8 G12R_(C>G) 24 2 8.3 G12S_(C>T) 105 4 3.8 G12V_(C>A) 469 13 2.8 in_codon_13 G13C_(C>A) 19 2 10.5 G13D_(C>T) 412 55 13.4 in_codon_61 Q61H_(T>G,T>A) 50 5 10.0 Q61K_ (GA>TT, G>T, GA>TG) 21 8 38.1 Q61L_(T>A) 7 0 0 Q61R_(T>C, TT>GC) 15 0 0 in_codon_146 A146P_(C>G) 9 2 22.2 A146T_(C>T) 128 23 18.0 A146V_(G>A) 26 1 3.9 in_codon_59 A59T_(C>T) 10 5 50.0 in_codon_117 K117N_(T>A,T>G) 24 8 33.3

利益披露 Disclosure

M. Evans, Caris Life Sciences Employment, Stock. V. Chandan, None.. A. Maitra, None. J. Bryan, AstraZeneca Other, Consulting (ended).

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