The landscape of MAP3K1/MAP2K4 alterations in gastrointestinal (GI) malignancies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4113-4113
Author(s):  
Matthew K Stein ◽  
Andrew Elliott ◽  
Jimmy J. Hwang ◽  
Emil Lou ◽  
Moh'd M. Khushman ◽  
...  
Keyword(s):  
Similar Rate ◽  
Braf V600e ◽  
High Status ◽  
Cancer Models ◽  
Programmed Death ◽  
Tumor Mutational Burden ◽  
And Gender ◽  
Next Generation Sequencing Ngs ◽  
Deficient Mismatch Repair ◽  
Generation Sequencing

4113 Background: Inactivating alterations in MAP3K1/MAP2K4 occur in various solid tumors, sensitize cancer models to MEK inhibitors, and have co-mutation partners which may enable therapeutic targeting. Methods: We retrospectively reviewed 20290 GI malignancy patients (pts), comprised of 9986 colorectal carcinoma (CRC) and 10304 non-CRC, whose tumors were profiled with Caris Life Sciences from 2015-2019. Profiling included immunohistochemistry (IHC) with programmed death ligand-1 (PD-L1), next-generation sequencing (NGS), tumor mutational burden (TMB) and deficient mismatch repair or microsatellite instability-high status (dMMR/MSI-H). Results: MAP3K1/MAP2K4-alteration ( MAP3K1/MAP2K4-MT) was more frequent in CRC than non-CRC pts (2.0% v. 1.2%, p<0.0001), with truncating mutations representing the majority of lesions along both genes. While MAP3K1/MAP2K4-MT CRC pts were similar in age and gender to wild-type (WT), mutated non-CRC pts were older (median age 69 v. 65 years) and more likely female (51% v. 42%) compared to WT (both p<0.05). MAP3K1/MAP2K4-MT CRC (25% v. 7%) and non-CRC (30% v. 3%) were more frequently dMMR/MSI-H than WT pts (both p<0.0001). MAP3K1/MAP2K4-MT CRC cases were affiliated with higher TMB and similar rate of PD-L1 expression compared to WT. A higher rate of MAP3K1/MAP2K4-MT CRC pts were right-sided (36% v. 22%, p<0.0001) and transverse (8% v. 4%, p<0.05) compared to WT, whereas a higher frequency of WT cases were left-sided (20% v. 28%, p<0.05) and rectal (15% v 23%, p<0.05). Of microsatellite stable (MSS) CRC pts, those with MAP3K1/MAP2K4-MT were more likely PIK3CA (26% v. 17%) and APC (85% v. 78%) and less-likely TP53 (64% v. 77%) co-mutated versus WT MSS pts (all p<0.05); no difference was seen in BRAF V600E, ERBB2/ ERBB3 or KRAS co-mutation rate in MSS pts. In both all-comers and MSS CRC, MAP3K1/MAP2K4-MT pts were more frequently co-mutated than WT with ARID1A, POLE, ATM, BRCA2 and PIK3R1 (all ≥7% of MAP3K1/MAP2K4-MT pts, p<0.0001). A higher frequency of all-comer non-CRC GI malignancy pts with MAP3K1/MAP2K4-MT were co-mutated with PIK3CA (13% v. 6%), ERBB2/ERBB3 (8% v. 3%) or APC (13% v. 5%) compared to WT (all p<0.01). For MSS non-CRC GI cases, ARID1A (50% v. 30%) and SMAD4 (21% v. 12%) were more frequently co-mutated in MAP3K1/MAP2K4-MT versus WT pts (all p<0.05). Conclusions: Truncating MAP3K1/MAP2K4 alterations occur in nearly 2% of GI malignancy pts and are more commonly associated with dMMR/MSI-H than WT. Potentially targetable co-mutation partners implicated in MAPK and PI3K pathways as well as POLE, BRCA2 and ATM warrant further evaluation.

Molecular comparison between peritoneal metastases (PM) and primary gastric (GC) and gastroesophageal junction (GEJ) cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4053-4053
Author(s):  
Matthew K Stein ◽  
Joanne Xiu ◽  
Michael Gary Martin ◽  
Axel Grothey ◽  
Philippe Prouet ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Programmed Death ◽  
Signet Ring ◽  
Tumor Mutational Burden ◽  
Molecular Comparison ◽  
Positive Score ◽  
The Mean ◽  
Combined Positive Score ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

4053 Background: PM from GC or GEJ portend a poor prognosis and molecular differences are ill defined. Methods: We compared genomic profiles of primary (P) GC and GEJ with PM patients (pts) and other metastases (OM) sent to Caris Life Sciences. Testing comprised immunohistochemistry (IHC) including programmed death ligand 1 (PD-L1) combined positive score (CPS), copy number alterations (CNA), 592-gene next-generation sequencing (NGS), microsatellite instability (MSI) and tumor mutational burden (TMB). Results: 1366 cases were identified: 1041 GC (707 P, 98 PM, 236 OM) and 325 GEJ (248 P, 5 PM, 72 OM). PM were increased in GC versus GEJ (9% v. 2%, p < 0.0001). 91% GC and 93% GEJ were adenocarcinoma (AD); GC were more likely signet ring (SR) histology versus GEJ (11% v. 3%, p < 0.0001) and GC PM were more likely SR versus other OM or P (13% v. 12% v. 7%, p = 0.067). The mean age of PM pts (57 years) was younger than primary GC (63, p = 0.002) and OM (61; p = 0.044). More PM GC pts were female than P or OM (48% v. 35% v. 34%, p = 0.03). No molecular profiling differences were seen between GEJ and GC pts and they were combined for analysis; findings from 1246 AD pts are shown below (see Table). OM (9%, p = 0.041) had more CNA in CCNE1 than PM (2%, p = 0.041) or P (5%, p = 0.002). Conclusions: Compared to P and OM GC, PM pts were younger, more likely female and had a higher incidence of SR histology. PD-L1, HER2 IHC and ERBB2 CNA were reduced in PM versus P, suggesting novel therapeutic targets are needed. [Table: see text]

Concordance of blood and tissue TMB from NGS testing in real-world settings and their ability to predict response to immunotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2540-2540
Author(s):  
Emma Sturgill ◽  
Amanda Misch ◽  
Carissa Jones ◽  
Daniel Luckett ◽  
Xiaotong Fu ◽  
...  
Keyword(s):  
Real World ◽  
Standard Of Care ◽  
Circulating Tumor Dna ◽  
High Status ◽  
Specimen Collection ◽  
Community Oncology ◽  
Positive Linear Correlation ◽  
Tumor Mutational Burden ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

2540 Background: Tumor mutational burden (TMB) detected by tissue-based Next Generation Sequencing (NGS) is a biomarker for immunotherapy (IO) response. Plasma-based NGS vendors have developed methods for quantifying TMB from circulating tumor DNA; however, the concordance of blood-TMB (bTMB) and tissue-TMB (tTMB) in real-world settings has not been examined. In this study, we analyzed paired bTMB-tTMB values from cancer patients in community oncology clinics who underwent both plasma- and tissue-based NGS testing to determine whether bTMB predicts response to IO equal to tTMB. Methods: We analyzed 112 patient-matched bTMB-tTMB pairs from 102 unique patients in community oncology settings who received both plasma- and tissue-based NGS profiling at any point in care. NGS results were reported by Foundation Medicine (n = 28 plasma, n = 66 tissue), Guardant Health (n = 78 plasma), and Caris Life Sciences (n = 42 tissue). NGS results were linked with electronic medical records in Genospace, Sarah Cannon’s precision medicine platform. Pearson’s correlation (r) and Lin’s concordance (ρ) coefficients were used for statistical analysis. Results: bTMB exceeded the patient-matched tTMB by an average 2.4-fold; therefore, while the two values showed a positive linear correlation (r2= 0.62, p = 0.01e-27) their concordance was only moderate (ρ = 0.58, n = 112). Gastrointestinal cancers exhibited the lowest correlation (r2= 0.01, p = 0.5) and concordance (ρ = 0.03, n = 35). The discordance between bTMB and tTMB was not an outcome of the specimens being collected on different dates, as the bTMB/tTMB ratio did not correlate with the time between plasma and tissue specimen collection (r2= 0.003, p = 0.84, n = 112). While a majority of bTMB-tTMB pairs had agreement in high vs. low status (High ≥ 10 mut/Mb; Low < 10 mut/Mb), a considerable portion were bTMB-High/tTMB-Low (see table). Strikingly, the bTMB-High/tTMB-Low patients who received IO had an average time to treatment failure (TTF) that surpassed that of the bTMB-High/tTMB-High cohort (see table). Considering bTMB alone, patients with a high status outperformed those with a low status on IO (bTMB-High: TTF = 200 days, n = 21; bTMB-Low: TTF = 125 days, n = 12). Conclusions: In real-world settings where tissue- and plasma-based NGS panels are ordered as standard of care, bTMB values are consistently higher than tTMB values. This discrepancy leads to plasma-based tests resulting a TMB-High designation more frequently than tissue-based NGS tests. Patients who are TMB-High by plasma perform relatively well on IO, indicating that bTMB may be a particularly effective biomarker of IO sensitivity.[Table: see text]

scholarly journals Next-Generation Sequencing Reveals Potentially Actionable Alterations in the Majority of Patients With Lymphoid Malignancies

2017 ◽  
pp. 1-13 ◽  
Author(s):  
Aaron M. Goodman ◽  
Michael Choi ◽  
Matthew Wieduwilt ◽  
Carolyn Mulroney ◽  
Caitlin Costello ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Median Number ◽  
Targeted Drugs ◽  
Next Generation ◽  
Lymphoid Malignancies ◽  
Tumor Mutational Burden ◽  
Approved Drugs ◽  
Next Generation Sequencing Ngs ◽  
Fda Approved Drugs ◽  
Generation Sequencing

Purpose Next-generation sequencing (NGS) identifies potentially targetable alterations by US Food and Drug Administration (FDA)–approved drugs and/or by available experimental agents that may not have otherwise been contemplated. Many targeted drugs have been developed for diverse solid cancers; a smaller number of genomically targeted drugs have been approved for lymphoid malignancies. Materials and Methods We analyzed NGS results from 60 patients with various lymphoid malignancies and found 224 alterations (median per patient, three alterations). Results Forty-nine patients (82%) had potentially actionable alterations with the use of FDA-approved drugs and/or experimental therapies; only 11 patients (18%) had no theoretically actionable alterations. Only three patients (5%) had an alteration for which an approved drug in the disease is available (on label); 45 patients (75%) had an alteration for which an approved drug is available for another disease (off label). The median number of alterations per patient potentially actionable by an FDA-approved drug was one. Of note, 19 (32%) of 60 patients had intermediate to high tumor mutational burden, which may predict response to certain immunotherapy agents. Conclusion NGS identifies alterations that may be pharmacologically tractable in most patients with lymphoid malignancies, albeit with drugs that have usually been developed in the context of solid tumors. These observations merit expanded exploration in the clinical trials setting.

Impact of next-generation sequencing (NGS) on diagnostic and therapeutic options in soft-tissue and bone sarcoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11001-11001 ◽  
Author(s):  
Mrinal M. Gounder ◽  
Siraj Mahamed Ali ◽  
Victoria Robinson ◽  
Mark Bailey ◽  
Richard Ferraro ◽  
...  
Keyword(s):  
Clear Cell ◽  
Study Drug ◽  
Bone Sarcoma ◽  
Resistance Mutations ◽  
Glomus Tumors ◽  
Therapeutic Implications ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

11001 Background: The utility of NGS in management of sarcoma pts remains undefined. Methods: We retrospectively analyzed the NGS profile of patients who were sequenced using a panel of 405 cancer-related genes in DNA and 265 genes rearranged in RNA. Diagnostic and therapeutic implications of mutations (mut) were evaluated through published literature (OncoKb.org, Pubmed). An algorithm was applied to determine germline mut. Following IRB approval, we evaluated the clinical outcomes of pts who underwent NGS at MSKCC. Results: From 2012–2016, 5635 pts worldwide with 56 histologies were tested. Median age of 52 yrs ( < 1-88), 52% females and sarcoma NOS (n = 858) was most frequent. Tumors were sequenced to a mean coverage of 634X; 1165 fusions and > 60,000 mut were found. Mut suspicious for germline defects were seen in 542 pts (9.6%) in known and novel genes ( BRCA, ARID1, FANC). Tumor mutational burden was 2.5/Mb (0–329) and glomus tumors and EHE had the highest and lowest mut, respectively. 16% and 7% of pts had treatment-linked alterations (TLA) known to respond to an FDA approved or study drug, respectively. 42% of pts had TLA eligible for NCI-MATCH, ASCO-TAPUR or other studies. Novel TLA include AKT, ESR1, BRCA, NTRK, PTCH1, SMARCB1 and others. Of the 107 MSKCC pts with clinical data, 60/107 (57%) had at least one TLA, of which 31 (30%) enrolled on a matched trial and 26 pts were ineligible or lacked access to trials. Partial/complete responses were seen with inhibitors to NTRK, IDH1, BRAF, PI3K/mTOR, MDM2, SMARCB1 and others. NGS changed the initial pathology diagnosis and treatments in 5% pts (e.g. LMS to liposarcoma, clear cell to melanoma). Resistance mutations averted futile therapies in 5% pts (e.g. Rb loss and palbociclib in liposarcoma). Conclusions: Our data suggests that NGS has a significant impact in aiding diagnosis and selecting matched therapies in sarcoma. Suspected germline aberrations, while intriguing, needs further validation.

Highly accurate NGS-based multi-gene testing in the diagnosis of thyroid nodules with indeterminate cytology.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13579-e13579
Author(s):  
Yuntao Song ◽  
Bin Zhang ◽  
Tonghui Ma
Keyword(s):  
Next Generation Sequencing ◽  
Mutation Analysis ◽  
Predictive Value ◽  
Thyroid Nodules ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Gene Testing ◽  
Indeterminate Cytology ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

e13579 Background: Thyroid nodules are highly prevalent, Fine-needle aspiration (FNA) is the standard pre-operative tool for diagnosis. However, some of the samples are classified as indeterminate, which leads to unnecessary surgery. BRAF V600E mutation is often used as a diagnostic marker for thyroid cancer, and it is highly specific for papillary thyroid carcinoma (PTC). But BRAF mutation is rarely occurred in thyroid nodules with indeterminate cytology. To diagnose the indeterminate thyroid nodules precisely, some NGS-based multi-gene testing panel has been developed and clinically used in America and Europe, but rare research was reported in China. In this study, we evaluated the value of a next-generation sequencing (NGS) panel to cancer diagnosis in indeterminate thyroid nodules. Methods: From February 2018 to September 2018, 360 patients with thyroid nodules who underwent FNA at Peking University Cancer Hospital were enrolled. And the FNA samples with indeterminate cytology were evaluated using a next-generation sequencing (NGS) assay, including 16 genes analyzed for point mutations and 26 types of gene fusions. Diagnostic performance of this multi-gene testing panel was compared with BRAF V600E single gene mutation analysis. Results: 141 nodules were cytologically indeterminate among 360 patients on FNA biopsy, 72 of which were resected and analyzed by NGS successfully. Histologic analysis after surgery revealed 41 (56.9%) cancers in these 72 patients. The multi-gene testing assay could classify 30/41 cancers correctly, showing a sensitivity of 73.2%, specificity of 96.8%, positive predictive value of 96.8%, and negative predictive value of 73.2%. The diagnostic accuracy of the multi-gene testing was significantly higher than the BRAF V600E mutation analysis (83.3% vs 73.6%, x2= 31.588, p < 0.01). Conclusions: Our study demonstrated that the multi-gene testing provided both high sensitivity and high specificity for cancer detection in thyroid nodules with indeterminate cytology, and its accuracy was much higher than BRAF V600E mutation test.

Population-based screening for BRAF V600E in metastatic colorectal cancer (mCRC) to reveal true prognosis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3579-3579
Author(s):  
Jenny E. Chu ◽  
Benny Johnson ◽  
Van K. Morris ◽  
Kanwal Pratap Singh Raghav ◽  
Lucas Swanson ◽  
...  
Keyword(s):  
Stage Iv ◽  
Population Based ◽  
Braf V600e ◽  
Baseline Characteristic ◽  
Wild Type ◽  
Md Anderson ◽  
Next Generation Sequencing Ngs ◽  
Referral Bias ◽  
Generation Sequencing ◽  
Worse Prognosis

3579 Background: BRAFV600E ( BRAF) mutations (mts) portend poor prognosis in mCRC and patients (pts) may die before ascertainment. Since 2014, Vancouver Coastal Health (VCH) has performed reflex hereditary screening of CRCs with BRAF and mismatch repair (MMR) immunohistochemistry (IHC). We evaluated this BRAF mt population-based cohort ( BRAFPOP) to establish the true prognosis of BRAF mts in mCRC. Methods: We reviewed all mCRCs from VCH between 4/2014 and 5/2018 for BRAF by IHC (VE1 antibody). Overall survival (OS) from stage IV diagnosis was compared to mCRCs with next generation sequencing (NGS) determined BRAF mts ( BRAFNGS) from BC Cancer & MD Anderson. BRAFNGS OS did not differ by center (p = 0.77). Results: See table for BRAF cohort baseline characteristic comparison. BRAFPOP pts had worse OS than BRAFNGS pts (HR 2.5, 95% CI 1.6 – 3.9, P < 0.0001). Median OS for all BRAF mt pts was 17.9 mos. Both groups had worse OS than wild type pts (P < 0.0001). 52 (81%) of BRAFPOP pts were referred to oncology, 40 (63%) received chemotherapy, and 12 (19%) had NGS BRAF testing. BRAFPOP pts who had NGS testing with BRAF mts had OS comparable to other BRAFNGS pts (P = 0.89) and better OS than BRAFPOP pts that never had NGS testing (HR 0.37, 95% CI 0.18-0.76, P = 0.030). Pts with BRAF mts and MMR deficiency (dMMR) (n = 40) had worse OS than MMR proficiency (pMMR, n = 202) (1.6, 95% CI 1.0-2.5, P = 0.011). This was driven by BRAFPOP dMMR pts (HR 1.9, 95% CI 0.9-4.0, P = 0.036) as no difference was seen by MMR in BRAFNGS pts (HR 1.3, 95% CI 0.8-2.2, P = 0.30). Conclusions: Current estimates of prognosis for mCRC with BRAF mts likely underestimate its impact due to referral bias for NGS testing. BRAF mts with dMMR are associated with worse prognosis than pMMR. This appears driven by BRAFPOP pts. [Table: see text]

scholarly journals Rectosigmoid-Junction Squamous Cell Carcinoma With pMMR/MSS Achieved a Partial Response Following PD-1 Blockade Combined With Chemotherapy: A Case Report

2021 ◽  
Vol 11 ◽  
Author(s):  
Yanxin He ◽  
Lunqing Wang ◽  
Xiao Li ◽  
Tongsong Zhang ◽  
Tingting Song ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Partial Response ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Clinical Activity ◽  
Rectosigmoid Junction ◽  
Programmed Death ◽  
Tumor Mutational Burden ◽  
Microsatellite Stability ◽  
Generation Sequencing

Colorectal squamous cell carcinoma (SCC) is extremely rare and associated with a poor prognosis. And the pMMR/MSS colorectal cancer is related to a limited response to programmed death ligand-1 (PD-1) blockade monotherapy. However, the clinical activity of PD-1 blockade monotherapy or combination therapy in colorectal SCC is unknown. One patient with rectosigmoid-junction SCC was treated with PD-1 blockade combined with chemotherapy. After 3 months of PD-1 blockade and chemotherapy, the computed tomography imaging showed that this patient achieved a partial response. The next generation sequencing and immunohistochemistry analysis showed that the patient had tumors with proficient mismatch repair (pMMR) and microsatellite stability (MSS), strong PD-L1 expression, and tumor mutational burden-high (TMB-High), respectively. This case suggests that PD-1 blockade combined with chemotherapy might be an effective therapy for colorectal SCC with pMMR/MSS status. Moreover, the PD-L1 expression and TMB might be the potential predictors of PD-1 blockade response for colorectal SCC patients.

Comparative genomic profiling (CGP) of refractory/metastatic penile (mPSCC) and non-penile cutaneous squamous cell carcinoma (mCSCC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 552-552 ◽  
Author(s):  
Joseph M Jacob ◽  
Oleg Shapiro ◽  
Elizabeth Kate Ferry ◽  
Laurie M. Gay ◽  
Julia Andrea Elvin ◽  
...  
Keyword(s):  
Uv Light ◽  
Treatment Options ◽  
Comparative Genomic ◽  
High Status ◽  
Genomic Profiling ◽  
Exposed Skin ◽  
Ffpe Samples ◽  
Tumor Mutational Burden ◽  
Tumor Types ◽  
Generation Sequencing

552 Background: mPSCC is an aggressive malignancy with limited treatment options. Using CGP, we compared the therapy impacting genomic alterations (GA) between mPSCC and cutaneous mCSCC. Methods: DNA was extracted from 40 microns of FFPE samples from 78 cases of mPSCC and 338mCSCC.Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assayto a mean coverage depth of > 500X. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: mPSCC patients were younger than mCSCC (Table). Both tumors types feature high CDKN2A, TERT and FAT1 GA frequencies. NOTCH1 and PTCH1 GA are also more common in mCSCC than mPSCC. CD274 ( PD-L1) amplification was rare in both tumor types. Targeted therapy opportunities in mPSCC included alterations in kinase pathways ( EGFR GA in 6%; FGFR3 and ERBB2 GA in 4%); MTOR pathway ( NF1 GA in 7% and PTENGA in4%) and DNA repair pathway ( BRCA2and ATMGA in 7%). TMB was significantly higher in the UV light exposed mSCC than mPSCC with both tumor types having potential for responsiveness to immunotherapies. MSI-High status was extremely rare for both mPSCC and mCSCC. HPV viral DNA was identified in 29% on mPSCC but only in 5% of mCSCC. TP53 GA were significantly more frequent in HPV- than HPV+ mPSCC and mCSCC respectively (P < 0.0001 for both). Clinical outcomes of selected patients will be presented. Conclusions: mPSCC is a unique subtype of SCC with distinctive genomic features that contrast with those identified in mCSCC of non-penile UV light exposed skin. Given the potential opportunities for targeted therapies and immunotherapies that can be uncovered, continued study of CGP for the guidance of treatment for patients with mPSCC appears warranted.[Table: see text]

Molecular comparison of primary colorectal cancer (pCRC) with peritoneal metastases (PM).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 498-498 ◽  
Author(s):  
Matthew K Stein ◽  
Forrest W Williard ◽  
Miriam Tsao ◽  
Benjamin Deschner ◽  
Paxton Vandiver Dickson ◽  
...  
Keyword(s):  
Copy Number Variants ◽  
Peritoneal Metastases ◽  
Primary Colorectal Cancer ◽  
Not Otherwise Specified ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Molecular Comparison ◽  
Poor Outcomes ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

498 Background: PM from CRC are associated with poor outcomes; however, molecular differences are not defined. Methods: We compared tumor profiles of pCRC and PM patients (pts) from Caris Life Sciences. Testing included next-generation sequencing (NGS) of 592 genes, immunohistochemistry (IHC), copy number variants (CNV), microsatellite instability (MSI) and tumor mutational burden (TMB). Mutations were termed pathogenic (PATH) or variants of undetermined significance (VUS). TMB in mutations/Mb (MMB) was compared. Results: 617 pCRC and 348 PM pts had similar gender (55% male) and age (median 59). 232 pCRC were left-sided (LS), 189 right-sided (RS), 147 rectum (R) and 49 not otherwise specified (NOS); PM were 45 RS, 29 LS, 22 R and 252 NOS. For pts with IHC testing, expression was increased in PM in TOPO1 (62% v. 52%, p < 0.01), ERCC1 (27% v. 18%, p < 0.01) and MLH1 (96% v. 92%, p < 0.05) and decreased in PD-1 (36% v. 65%, p < 0.01), TOP2A (76% v. 100%, p < 0.01) and PTEN (64% v. 72%, p < 0.05). By sidedness, LS PM were more frequently TOP01 and PD-L1 and less commonly MGMT positive compared to pCRC. PTEN IHC was higher in R pCRC than PM. 7 CNVs were increased in PM ( ADGR2A2, CCND1, ELL, FGF3, FGF4, JAK3 and PDGFRB) and FLT3 CNVs were decreased. MYC CNVs were more common in RS PM compared to pCRC. No difference was seen in PM and pCRC PATHs in KRAS, BRAF, SMAD2, SMAD4, PTEN. PM had more PATHs in GNAS (8% v. 1%, p < 0.01) while pCRC PATHs were increased in APC (76% v. 48%, p < 0.01), TP53 (72% v. 53%, p < 0.01), ARID1A (29% v. 12%, p < 0.05), PIK3CA (22% v. 15%, p < 0.05) and FBXW7 (13% v. 7%, p < 0.01). LS PM had increased FLCN PATHs (12% v. 2%, p < 0.01); R PM had more PATHs in KMT2D (20% v. 1%, p < 0.01) and RNF43 (13% vs. 3%, p < 0.05). VUS were increased in 39/592 (7%) genes for PM compared to pCRC. No MSI or fusion difference was seen. 53% pCRC (median = 8) pts had TMB ≥8 MMB compared to 43% PMs (median = 7; p = 0.03); no TMB difference was seen for LS, RS or R subgroups. Conclusions: Compared to pCRC, PM had more PATHs in GNAS and less in classic CRC markers APC and TP53. While TMB was generally lower in PM, differences in IHC expression, CNV and VUSs may serve as biomarkers for PM requiring further study.

Sign in / Sign up

Export Citation Format

Share Document