ACTIN-292: Add Chromosomal Rearrangements

orange-datamodel/src/main/java/com/hartwig/hmftools/datamodel/purple/ChromosomalRearrangements.java

@@ -0,0 +1,16 @@
+package com.hartwig.hmftools.datamodel.purple;
+
+import org.immutables.gson.Gson;
+import org.immutables.value.Value;
+import org.jetbrains.annotations.NotNull;
+import org.jetbrains.annotations.Nullable;
+
+@Gson.TypeAdapters
+@Value.Immutable
+@Value.Style(passAnnotations = { NotNull.class, Nullable.class })
+public interface ChromosomalRearrangements
+{
+    boolean hasTrisomy1q();
+
+    boolean hasCodeletion1p19q();
+}

orange-datamodel/src/main/java/com/hartwig/hmftools/datamodel/purple/PurpleRecord.java

@@ -21,6 +21,9 @@ public interface PurpleRecord
     @NotNull
     PurpleCharacteristics characteristics();
 
+    @NotNull
+    ChromosomalRearrangements chromosomalRearrangements();
+
     @NotNull
     List<PurpleDriver> somaticDrivers();
 

orange-datamodel/src/test/resources/minimally.empty.orange.json

@@ -86,7 +86,11 @@
     "allSomaticGeneCopyNumbers": [],
     "allSomaticGainsLosses": [],
     "reportableSomaticGainsLosses": [],
-    "suspectGeneCopyNumbersWithLOH": []
+    "suspectGeneCopyNumbersWithLOH": [],
+    "chromosomalRearrangements": {
+      "hasTrisomy1q": false,
+      "hasCodeletion1p19q": false
+    }
   },
   "linx": {
     "allSomaticStructuralVariants": [],

orange-datamodel/src/test/resources/minimally.populated.orange.json

@@ -324,7 +324,11 @@
         "maxCopyNumber": 1.2,
         "minMinorAlleleCopyNumber": 0.4
       }
-    ]
+    ],
+    "chromosomalRearrangements": {
+      "hasTrisomy1q": false,
+      "hasCodeletion1p19q": false
+    }
   },
   "linx": {
     "allSomaticStructuralVariants": [

orange-datamodel/src/test/resources/real.orange.json

@@ -2,8 +2,8 @@
   "sampleId": "Test",
   "samplingDate": {
     "year": 2024,
-    "month": 8,
-    "day": 1
+    "month": 9,
+    "day": 12
   },
   "experimentType": "WHOLE_GENOME",
   "configuredPrimaryTumor": [
@@ -736,7 +736,11 @@
     ],
     "reportableGermlineFullLosses": [],
     "allGermlineLossOfHeterozygosities": [],
-    "reportableGermlineLossOfHeterozygosities": []
+    "reportableGermlineLossOfHeterozygosities": [],
+    "chromosomalRearrangements": {
+      "hasTrisomy1q": false,
+      "hasCodeletion1p19q": false
+    }
   },
   "linx": {
     "somaticDrivers": [

orange/README.md

@@ -145,6 +145,9 @@ interesting and added to the report:
        A maximum of 10 additional gains (sorted by minimum copy number) and 10 additional losses are reported as potentially interesting:
         - For a band with more than one gene amplified, the gene with the highest minimum copy number is picked.
         - For a band with a loss that has no losses reported in this band already, an arbitrary gene is picked.
+- Potentially interesting chromosomal rearrangements:
+    1. 1q trisomy: In case 98% of 1q has copy number > 2.8 AND 90% of 1q has copy number < 3.5
+    2. 1p19q co-deletion: In case 98% of 1p and 98% of 19q have MACN < 0.2
 - Other potentially relevant fusions. A maximum of 10 additional fusions (picked arbitrarily) are reported as potentially interesting:
     1. Any fusion that is not reported and has a reported type other than NONE.
     2. Any fusion in a gene that is configured as an oncogene in the driver gene panel.
@@ -264,6 +267,7 @@ investigate potential causes for QC failure.
 - Upcoming:
     - Add presence of tumor stats to quality control page and to orange-datamodel
     - Ensure only exonic variants that are phased with reported variants are shown in 'potentially interesting' section
+    - Add potentially interesting chromosomal rearrangements (1q trisomy and 1p19q co-deletion) to report
 - [3.7.0](https://github.com/hartwigmedical/hmftools/releases/tag/orange-v3.7.0):
     - Add unreported reason to fusions in ORANGE
     - Add etiology information to signatures and sort by allocation

orange/src/main/java/com/hartwig/hmftools/orange/algo/OrangeAlgo.java

@@ -23,15 +23,15 @@
 import com.hartwig.hmftools.common.drivercatalog.panel.DriverGene;
 import com.hartwig.hmftools.common.drivercatalog.panel.DriverGeneFile;
 import com.hartwig.hmftools.common.ensemblcache.EnsemblDataCache;
-import com.hartwig.hmftools.common.metrics.BamFlagStats;
-import com.hartwig.hmftools.common.metrics.BamMetricsSummary;
 import com.hartwig.hmftools.common.fusion.KnownFusionCache;
 import com.hartwig.hmftools.common.genome.refgenome.RefGenomeVersion;
 import com.hartwig.hmftools.common.hla.LilacSummaryData;
 import com.hartwig.hmftools.common.isofox.IsofoxData;
 import com.hartwig.hmftools.common.isofox.IsofoxDataLoader;
 import com.hartwig.hmftools.common.linx.LinxData;
 import com.hartwig.hmftools.common.linx.LinxDataLoader;
+import com.hartwig.hmftools.common.metrics.BamFlagStats;
+import com.hartwig.hmftools.common.metrics.BamMetricsSummary;
 import com.hartwig.hmftools.common.peach.PeachGenotype;
 import com.hartwig.hmftools.common.peach.PeachGenotypeFile;
 import com.hartwig.hmftools.common.pipeline.PipelineVersionFile;
@@ -68,6 +68,7 @@
 import com.hartwig.hmftools.orange.algo.plot.DummyPlotManager;
 import com.hartwig.hmftools.orange.algo.plot.FileBasedPlotManager;
 import com.hartwig.hmftools.orange.algo.plot.PlotManager;
+import com.hartwig.hmftools.orange.algo.purple.ChromosomalRearrangementsDeterminer;
 import com.hartwig.hmftools.orange.algo.purple.GermlineGainLossFactory;
 import com.hartwig.hmftools.orange.algo.purple.GermlineLossOfHeterozygosityFactory;
 import com.hartwig.hmftools.orange.algo.purple.PurpleData;
@@ -207,8 +208,10 @@ public OrangeRecord run(@NotNull OrangeConfig config) throws Exception
         PurpleVariantFactory purpleVariantFactory = new PurpleVariantFactory(pave);
         GermlineGainLossFactory germlineGainLossFactory = new GermlineGainLossFactory(ensemblDataCache);
         GermlineLossOfHeterozygosityFactory germlineLOHFactory = new GermlineLossOfHeterozygosityFactory(ensemblDataCache);
+        ChromosomalRearrangementsDeterminer chromosomalRearrangementsDeterminer =
+                ChromosomalRearrangementsDeterminer.createForRefGenomeVersion(config.refGenomeVersion());
         PurpleInterpreter purpleInterpreter = new PurpleInterpreter(purpleVariantFactory, germlineGainLossFactory,
-                germlineLOHFactory, driverGenes, linx, chord, config.convertGermlineToSomatic());
+                germlineLOHFactory, driverGenes, linx, chromosomalRearrangementsDeterminer, chord, config.convertGermlineToSomatic());
         PurpleRecord purple = purpleInterpreter.interpret(purpleData);
 
         ImmuneEscapeRecord immuneEscape = ImmuneEscapeInterpreter.interpret(purple, linx);

orange/src/main/java/com/hartwig/hmftools/orange/algo/purple/ChromosomalRearrangementsDeterminer.java

@@ -0,0 +1,107 @@
+package com.hartwig.hmftools.orange.algo.purple;
+
+import java.util.List;
+
+import com.google.common.annotations.VisibleForTesting;
+import com.hartwig.hmftools.common.genome.refgenome.RefGenomeCoordinates;
+import com.hartwig.hmftools.common.genome.refgenome.RefGenomeFunctions;
+import com.hartwig.hmftools.common.purple.PurpleCopyNumber;
+import com.hartwig.hmftools.datamodel.orange.OrangeRefGenomeVersion;
+
+import org.jetbrains.annotations.NotNull;
+
+public final class ChromosomalRearrangementsDeterminer
+{
+    @NotNull
+    private final RefGenomeCoordinates refGenomeCoordinates;
+
+    @NotNull
+    public static ChromosomalRearrangementsDeterminer createForRefGenomeVersion(@NotNull final OrangeRefGenomeVersion refGenomeVersion)
+    {
+        return new ChromosomalRearrangementsDeterminer(resolveRefGenomeCoordinates(refGenomeVersion));
+    }
+
+    @VisibleForTesting
+    ChromosomalRearrangementsDeterminer(@NotNull final RefGenomeCoordinates refGenomeCoordinates)
+    {
+        this.refGenomeCoordinates = refGenomeCoordinates;
+    }
+
+    private static final double LOWER_THRESHOLD_TRISOMY = 2.8;
+    private static final double UPPER_THRESHOLD_TRISOMY = 3.5;
+    private static final double THRESHOLD_DELETION = 0.2;
+    private static final double LOWER_LIMIT_PERCENTAGE_TRISOMY = 0.98;
+    private static final double UPPER_LIMIT_PERCENTAGE_TRISOMY = 0.90;
+    private static final double UPPER_LIMIT_PERCENTAGE_DELETION = 0.98;
+
+    private static final String CHR_1 = "1";
+    private static final String CHR_19 = "19";
+
+    public boolean determine1qTrisomy(@NotNull List<PurpleCopyNumber> allSomaticCopyNumbers)
+    {
+        int centromere1 = refGenomeCoordinates.centromere(CHR_1);
+        int length1QArm = refGenomeCoordinates.length(CHR_1) - centromere1;
+        int lengthAboveLowerThreshold = 0;
+        int lengthBelowUpperThreshold = 0;
+
+        for(PurpleCopyNumber copyNumber : allSomaticCopyNumbers)
+        {
+            String chromosome = RefGenomeFunctions.stripChrPrefix(copyNumber.chromosome());
+            if(chromosome.equals(CHR_1) && overlapsWithQArm(copyNumber, centromere1))
+            {
+                int length = copyNumber.start() > centromere1 ? copyNumber.length() : copyNumber.end() - centromere1 + 1;
+
+                if(copyNumber.averageTumorCopyNumber() > LOWER_THRESHOLD_TRISOMY)
+                {
+                    lengthAboveLowerThreshold += length;
+                }
+                if(copyNumber.averageTumorCopyNumber() < UPPER_THRESHOLD_TRISOMY)
+                {
+                    lengthBelowUpperThreshold += length;
+                }
+            }
+        }
+
+        return (double) lengthAboveLowerThreshold / length1QArm > LOWER_LIMIT_PERCENTAGE_TRISOMY
+                && (double) lengthBelowUpperThreshold / length1QArm > UPPER_LIMIT_PERCENTAGE_TRISOMY;
+    }
+
+    public boolean determine1p19qCodeletion(@NotNull List<PurpleCopyNumber> allSomaticCopyNumbers)
+    {
+        int centromere1 = refGenomeCoordinates.centromere(CHR_1);
+        int centromere19 = refGenomeCoordinates.centromere(CHR_19);
+        int length19QArm = refGenomeCoordinates.length(CHR_19) - centromere19;
+        int lengthDeletion1p = 0;
+        int lengthDeletionChr19 = 0;
+
+        for(PurpleCopyNumber copyNumber : allSomaticCopyNumbers)
+        {
+            String chromosome = RefGenomeFunctions.stripChrPrefix(copyNumber.chromosome());
+            if(chromosome.equals(CHR_1) && copyNumber.start() < centromere1 && copyNumber.minorAlleleCopyNumber() < THRESHOLD_DELETION)
+            {
+                int length = copyNumber.end() < centromere1 ? copyNumber.length() : centromere1 - copyNumber.start() + 1;
+                lengthDeletion1p += length;
+            }
+            if(chromosome.equals(CHR_19) && overlapsWithQArm(copyNumber, centromere19)
+                    && copyNumber.minorAlleleCopyNumber() < THRESHOLD_DELETION)
+            {
+                int length = copyNumber.start() > centromere19 ? copyNumber.length() : copyNumber.end() - centromere19 + 1;
+                lengthDeletionChr19 += length;
+            }
+        }
+
+        return (double) lengthDeletion1p / centromere1 > UPPER_LIMIT_PERCENTAGE_DELETION
+                && (double) lengthDeletionChr19 / length19QArm > UPPER_LIMIT_PERCENTAGE_DELETION;
+    }
+
+    @NotNull
+    private static RefGenomeCoordinates resolveRefGenomeCoordinates(@NotNull OrangeRefGenomeVersion refGenomeVersion)
+    {
+        return refGenomeVersion == OrangeRefGenomeVersion.V38 ? RefGenomeCoordinates.COORDS_38 : RefGenomeCoordinates.COORDS_37;
+    }
+
+    private static boolean overlapsWithQArm(@NotNull PurpleCopyNumber copyNumber, int centromere)
+    {
+        return copyNumber.start() > centromere || (copyNumber.start() < centromere && centromere < copyNumber.end());
+    }
+}

orange/src/main/java/com/hartwig/hmftools/orange/algo/purple/PurpleInterpreter.java

@@ -33,6 +33,8 @@
 import com.hartwig.hmftools.datamodel.linx.LinxBreakendType;
 import com.hartwig.hmftools.datamodel.linx.LinxRecord;
 import com.hartwig.hmftools.datamodel.linx.LinxSvAnnotation;
+import com.hartwig.hmftools.datamodel.purple.ChromosomalRearrangements;
+import com.hartwig.hmftools.datamodel.purple.ImmutableChromosomalRearrangements;
 import com.hartwig.hmftools.datamodel.purple.ImmutablePurpleCharacteristics;
 import com.hartwig.hmftools.datamodel.purple.ImmutablePurpleFit;
 import com.hartwig.hmftools.datamodel.purple.ImmutablePurpleGainLoss;
@@ -68,21 +70,26 @@ public class PurpleInterpreter
     private final List<DriverGene> driverGenes;
     @NotNull
     private final LinxRecord linx;
+    @NotNull
+    private final ChromosomalRearrangementsDeterminer chromosomalRearrangementsDeterminer;
     @Nullable
     private final ChordData chord;
     boolean convertGermlineToSomatic;
 
     public PurpleInterpreter(@NotNull final PurpleVariantFactory purpleVariantFactory,
             @NotNull final GermlineGainLossFactory germlineGainLossFactory,
             @NotNull final GermlineLossOfHeterozygosityFactory germlineLossOfHeterozygosityFactory,
-            @NotNull final List<DriverGene> driverGenes, @NotNull final LinxRecord linx, @Nullable final ChordData chord,
+            @NotNull final List<DriverGene> driverGenes, @NotNull final LinxRecord linx,
+            @NotNull ChromosomalRearrangementsDeterminer chromosomalRearrangementsDeterminer,
+            @Nullable final ChordData chord,
             boolean convertGermlineToSomatic)
     {
         this.purpleVariantFactory = purpleVariantFactory;
         this.germlineGainLossFactory = germlineGainLossFactory;
         this.germlineLossOfHeterozygosityFactory = germlineLossOfHeterozygosityFactory;
         this.driverGenes = driverGenes;
         this.linx = linx;
+        this.chromosomalRearrangementsDeterminer = chromosomalRearrangementsDeterminer;
         this.chord = chord;
         this.convertGermlineToSomatic = convertGermlineToSomatic;
     }
@@ -186,6 +193,7 @@ public PurpleRecord interpret(@NotNull PurpleData purple)
                 .reportableGermlineFullLosses(reportableGermlineFullLosses)
                 .allGermlineLossOfHeterozygosities(allGermlineLossOfHeterozygosities)
                 .reportableGermlineLossOfHeterozygosities(reportableGermlineLossOfHeterozygosities)
+                .chromosomalRearrangements(createChromosomalRearrangements(purple, chromosomalRearrangementsDeterminer))
                 .build();
     }
 
@@ -444,4 +452,14 @@ private static PurpleCharacteristics createCharacteristics(@NotNull PurpleData p
                 .svTumorMutationalBurden(purple.purityContext().svTumorMutationalBurden())
                 .build();
     }
+
+    @NotNull
+    private static ChromosomalRearrangements createChromosomalRearrangements(@NotNull PurpleData purple,
+            @NotNull ChromosomalRearrangementsDeterminer chromosomalRearrangementsDeterminer)
+    {
+        return ImmutableChromosomalRearrangements.builder()
+                .hasTrisomy1q(chromosomalRearrangementsDeterminer.determine1qTrisomy(purple.allSomaticCopyNumbers()))
+                .hasCodeletion1p19q(chromosomalRearrangementsDeterminer.determine1p19qCodeletion(purple.allSomaticCopyNumbers()))
+                .build();
+    }
 }

orange/src/main/java/com/hartwig/hmftools/orange/report/chapters/SomaticFindingsChapter.java

@@ -6,6 +6,7 @@
 import com.hartwig.hmftools.datamodel.linx.FusionLikelihoodType;
 import com.hartwig.hmftools.datamodel.linx.LinxFusion;
 import com.hartwig.hmftools.datamodel.orange.OrangeRecord;
+import com.hartwig.hmftools.datamodel.purple.ChromosomalRearrangements;
 import com.hartwig.hmftools.datamodel.purple.CopyNumberInterpretation;
 import com.hartwig.hmftools.datamodel.purple.PurpleDriver;
 import com.hartwig.hmftools.datamodel.purple.PurpleGainLoss;
@@ -23,6 +24,7 @@
 import com.hartwig.hmftools.orange.report.interpretation.PurpleQCInterpretation;
 import com.hartwig.hmftools.orange.report.interpretation.VariantDedup;
 import com.hartwig.hmftools.orange.report.tables.BreakendTable;
+import com.hartwig.hmftools.orange.report.tables.ChromosomalRearrangementsTable;
 import com.hartwig.hmftools.orange.report.tables.DnaFusionTable;
 import com.hartwig.hmftools.orange.report.tables.GainLossTable;
 import com.hartwig.hmftools.orange.report.tables.HomozygousDisruptionTable;
@@ -158,6 +160,7 @@ private void addSomaticAmpDels(@NotNull Document document)
         String nearDriverGainsTitle = "Potentially interesting near-driver amps";
         String suspectGainsTitle = "Other regions with amps";
         String suspectLossesTitle = "Regions with deletions in genes in other autosomal regions";
+        String chromosomalRearrangementsTitle = "Potentially interesting chromosomal rearrangements";
 
         if(PurpleQCInterpretation.isContaminated(report.purple().fit().qc()))
         {
@@ -166,6 +169,7 @@ private void addSomaticAmpDels(@NotNull Document document)
             document.add(tables.createNotAvailable(nearDriverGainsTitle, contentWidth()));
             document.add(tables.createNotAvailable(suspectGainsTitle, contentWidth()));
             document.add(tables.createNotAvailable(suspectLossesTitle, contentWidth()));
+            document.add(tables.createNotAvailable(chromosomalRearrangementsTitle, contentWidth()));
         }
         else
         {
@@ -190,6 +194,9 @@ private void addSomaticAmpDels(@NotNull Document document)
             List<PurpleGainLoss> suspectLosses = selectLosses(report.purple().additionalSuspectSomaticGainsLosses());
             String titleSuspectLosses = suspectLossesTitle + " (" + suspectLosses.size() + ")";
             document.add(GainLossTable.build(titleSuspectLosses, contentWidth(), max10(suspectLosses), report.isofox(), reportResources));
+
+            ChromosomalRearrangements chromosomalRearrangements = report.purple().chromosomalRearrangements();
+            document.add(ChromosomalRearrangementsTable.build(chromosomalRearrangementsTitle, contentWidth(), chromosomalRearrangements, reportResources));
         }
     }
 

orange/src/main/java/com/hartwig/hmftools/orange/report/tables/ChromosomalRearrangementsTable.java

@@ -0,0 +1,35 @@
+package com.hartwig.hmftools.orange.report.tables;
+
+import com.hartwig.hmftools.datamodel.purple.ChromosomalRearrangements;
+import com.hartwig.hmftools.orange.report.ReportResources;
+import com.hartwig.hmftools.orange.report.util.Cells;
+import com.hartwig.hmftools.orange.report.util.Tables;
+import com.itextpdf.layout.element.Cell;
+import com.itextpdf.layout.element.Table;
+
+import org.apache.logging.log4j.util.Strings;
+import org.jetbrains.annotations.NotNull;
+
+public final class ChromosomalRearrangementsTable
+{
+    @NotNull
+    public static Table build(@NotNull String title, float width, @NotNull ChromosomalRearrangements chromosomalRearrangements,
+            @NotNull ReportResources reportResources)
+    {
+        Cells cells = new Cells(reportResources);
+        Table table = Tables.createContent(width,
+                new float[] { 2, 1, 3 },
+                new Cell[] { cells.createHeader("Chromosomal rearrangement"), cells.createHeader("Detected?"),
+                        cells.createHeader(Strings.EMPTY) });
+
+        table.addCell(cells.createContent("1q trisomy"));
+        table.addCell(cells.createContent(chromosomalRearrangements.hasTrisomy1q() ? "Yes" : "No"));
+        table.addCell(cells.createContent(Strings.EMPTY));
+
+        table.addCell(cells.createContent("1p19q co-deletion"));
+        table.addCell(cells.createContent(chromosomalRearrangements.hasCodeletion1p19q() ? "Yes" : "No"));
+        table.addCell(cells.createContent(Strings.EMPTY));
+
+        return new Tables(reportResources).createWrapping(table, title);
+    }
+}