#!/usr/bin/perl
use strict;
use warnings;

die "useage:perl $0 input output project" unless @ARGV == 3;

my ($input, $output, $project) = @ARGV;

my $cancer_type = ($project =~ /^lung/i) ? "B2" : ($project =~ /^crc/i) ? "B10" : "B1";

##将点突变信息记录到%mut
open MUT, "/dataseq/jmdna/codes/reportbase/snv_indel_mutation.csv";
<MUT>;
my %mut;
while (<MUT>) {
    my @line = split(/,/);
    $mut{$line[0]}{$line[1]} = $line[2];
}

##将用药信息记录到%therapy
#open THERAPY,"/home/jm001/project/pancancer_controlsample/650/Tissue/DEMO2/Pros/targetTherapy.txt";
open THERAPY, "/dataseq/jmdna/codes/reportbase/targetTherapy.txt";
my $h1 = <THERAPY>;
chomp $h1;
my %therapy;
while (<THERAPY>) {
    chomp;
    my @line = split("\t");
    push @{$therapy{$line[0]}{$line[1]}}, $_ if ($line[9] ne 'D' and $line[5] ne 'CSCO' and $line[2] !~ /Leukemia|Lymphoma|Myeloid/i);
}

##药物翻译信息
open DRUG, "/dataseq/jmdna/codes/reportbase/target_drug.txt";
my %drug;
<DRUG>;
while (<DRUG>) {
    chomp;
    my @line = split(/\t/);
    next unless $line[1];
    foreach my $drug (split(/\|/, $line[0])) {
        $drug{lc $drug} = $line[1];
    }
}

##疾病翻译信息
open DIS, "/dataseq/jmdna/codes/reportbase/cancer_type.txt";
my (%dis, %dis2);
<DIS>;
while (<DIS>) {
    chomp;
    my @line = split(/\t/);
    $dis{lc $line[0]} = $line[1];
    push @{$dis2{$line[3]}}, $line[0];
    push @{$dis2{$line[4]}}, $line[0];
}

open IN, "$input";
open POS, ">$output.pos.txt";
open NEG, ">$output.neg.txt";
open VUS, ">$output.vus.txt";
my $h2 = <IN>;
chomp $h2;
my (@pos, @neg, @vus);
while (<IN>) {
    chomp;
    my @line = split("\t");
    my ($protein, $mut_type);
    my $gene = $line[7];
    if ($line[11] =~ /(\w+):(\w+):exon(\d+):c\.(\S+):p\.(\S+)$/) {
        my $exon = $3;
        my $codon = $4;
        if ($5 =~ /\d+X$|\d+\*$/ or $line[10] eq 'stopgain' or $line[10] eq 'frameshift deletion' or $line[10] eq 'frameshift insertion') {
            $protein = 'Truncating Mutations';
        }
        else {
            $protein = $5;
        }
        $mut_type = ($codon =~ /del/) ? ("Exon $exon deletion") : ($codon =~ /ins/) ? ("Exon $exon insertion") : ("Exon $exon mutation");
    }
    elsif ($line[6] =~ /splicing/) {
        $protein = 'Truncating Mutations';
        $mut_type = '';
    }
    elsif ($line[10] =~ /skipping/) {
        $protein = 'Exon 14 skipping Mutations';
        $mut_type = '';
    }
    else {
        print $_;
    }

    ##若突变不存在于%mut,写入@vus,若突变存在于%mut且neutral，写入@neg;若基因不存在于%therapy，写入@vus;
    if (not exists $mut{$gene}{$protein}) {
        if ($line[18] =~ /benign/i and $line[18] !~ /sensitivity|pathogenic|uncertain|\./i and $line[13] ne '.') {
            push @neg, "$_\t.";
        }
        else {
            push @vus, "$_\t.";
        }
    }
    else {
        if ($mut{$gene}{$protein} =~ /neutral/i) {
            push @neg, "$_\t$mut{$gene}{$protein}";
        }
        elsif ($mut{$gene}{$protein} =~ /Inconclusive/i) {
            push @vus, "$_\t$mut{$gene}{$protein}";
        }
        else {
            if (not exists $therapy{$gene}) {
                if ($line[15] =~ /benign/i and $line[18] !~ /sensitivity|pathogenic|uncertain|\./i and $line[13] ne '.') {
                    push @neg, "$_\t$mut{$gene}{$protein}";
                }
                else {
                    push @vus, "$_\t$mut{$gene}{$protein}";
                }
            }
            else {
                my $bool = 0;
                ##
                if (exists $therapy{$gene}{$protein}) {
                    foreach my $entry (@{$therapy{$gene}{$protein}}) {
                        my @line = split("\t", $entry);
                        if (($line[5] eq "FDA" or $line[5] eq "NCCN" or $line[5] eq "NMPA") and (lc $line[2] eq "solid tumor" or grep {lc $line[2] eq lc $_} @{$dis2{$cancer_type}})) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t适应症" . "\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                        elsif (($line[5] eq "FDA" or $line[5] eq "NCCN" or $line[5] eq "NMPA") and (lc $line[2] ne "solid tumor" and grep {lc $line[2] ne lc $_} @{$dis2{$cancer_type}})) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t非适应症" . "\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                        elsif (lc $line[2] eq "solid tumor" or grep {lc $line[2] eq lc $_} @{$dis2{$cancer_type}}) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t\.\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                    }
                }
                ##
                if (exists $therapy{$gene}{'Mutation'}) {
                    foreach my $entry (@{$therapy{$gene}{'Mutation'}}) {
                        my @line = split("\t", $entry);
                        if (($line[5] eq "FDA" or $line[5] eq "NCCN" or $line[5] eq "NMPA") and (lc $line[2] eq "solid tumor" or grep {lc $line[2] eq lc $_} @{$dis2{$cancer_type}})) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t适应症" . "\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                        elsif (($line[5] eq "FDA" or $line[5] eq "NCCN" or $line[5] eq "NMPA") and (lc $line[2] ne "solid tumor" and grep {lc $line[2] ne lc $_} @{$dis2{$cancer_type}})) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t非适应症" . "\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                        elsif (lc $line[2] eq "solid tumor" or grep {lc $line[2] eq lc $_} @{$dis2{$cancer_type}}) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t\.\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                    }
                }
                ##
                if ($protein =~ /^(\w\d+)\w$/ and exists $therapy{$gene}{$1}) {
                    foreach my $entry (@{$therapy{$gene}{$1}}) {
                        my @line = split("\t", $entry);
                        if (($line[5] eq "FDA" or $line[5] eq "NCCN" or $line[5] eq "NMPA") and (lc $line[2] eq "solid tumor" or grep {lc $line[2] eq lc $_} @{$dis2{$cancer_type}})) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t适应症" . "\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                        elsif (($line[5] eq "FDA" or $line[5] eq "NCCN" or $line[5] eq "NMPA") and (lc $line[2] ne "solid tumor" and grep {lc $line[2] ne lc $_} @{$dis2{$cancer_type}})) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t非适应症" . "\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                        elsif (lc $line[2] eq "solid tumor" or grep {lc $line[2] eq lc $_} @{$dis2{$cancer_type}}) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t\.\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                    }
                }
                #
                if ($protein =~ /^(\w\d+)\w$/ and exists $therapy{$gene}{$1 . "X"}) {
                    foreach my $entry (@{$therapy{$gene}{$1 . "X"}}) {
                        my @line = split("\t", $entry);
                        if (($line[5] eq "FDA" or $line[5] eq "NCCN" or $line[5] eq "NMPA") and (lc $line[2] eq "solid tumor" or grep {lc $line[2] eq lc $_} @{$dis2{$cancer_type}})) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t适应症" . "\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                        elsif (($line[5] eq "FDA" or $line[5] eq "NCCN" or $line[5] eq "NMPA") and (lc $line[2] ne "solid tumor" and grep {lc $line[2] ne lc $_} @{$dis2{$cancer_type}})) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t非适应症" . "\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                        elsif (lc $line[2] eq "solid tumor" or grep {lc $line[2] eq lc $_} @{$dis2{$cancer_type}}) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t\.\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                    }
                }
                #
                if (exists $therapy{$gene}{$mut_type}) {
                    foreach my $entry (@{$therapy{$gene}{$mut_type}}) {
                        my @line = split("\t", $entry);
                        if (($line[5] eq "FDA" or $line[5] eq "NCCN" or $line[5] eq "NMPA") and (lc $line[2] eq "solid tumor" or grep {lc $line[2] eq lc $_} @{$dis2{$cancer_type}})) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t适应症" . "\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                        elsif (($line[5] eq "FDA" or $line[5] eq "NCCN" or $line[5] eq "NMPA") and (lc $line[2] ne "solid tumor" and grep {lc $line[2] ne lc $_} @{$dis2{$cancer_type}})) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t非适应症" . "\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                        elsif (lc $line[2] eq "solid tumor" or grep {lc $line[2] eq lc $_} @{$dis2{$cancer_type}}) {
                            push @pos, "$_\t$mut{$gene}{$protein}\t" . join("\t", @line[0 .. 9, 14]) . "\t\.\t" . &drug($line[3]) . "\t" . $dis{lc $line[2]};
                            $bool = 1;
                        }
                    }
                }

                if ($bool == 0) {
                    if ($line[15] =~ /benign/i and $line[15] !~ /sensitivity|pathogenic|uncertain|\./i and $line[14] ne '.') {
                        push @neg, "$_\t$mut{$gene}{$protein}";
                    }
                    else {
                        push @vus, "$_\t$mut{$gene}{$protein}";
                    }
                }
            }
        }
    }
}

sub drug {
    my $drugs = shift @_;
    my @translation;
    foreach my $drug (split(/,/, $drugs)) {
        if ($drug =~ /\+/) {
            my $plus;
            foreach my $drug_c (split(/\s+\+\s+/, $drug)) {
                my $new = (exists $drug{lc $drug_c}) ? $drug{lc $drug_c} : ($drug_c);
                $plus .= " + $new";
            }
            $plus =~ s/^ \+ //;
            push @translation, $plus;
        }
        else {
            my $new = (exists $drug{lc $drug}) ? $drug{lc $drug} : ($drug);
            push @translation, $new;
        }
    }
    return (join(",", @translation));
}

my $h = $h2 . "\tfun_change\t" . join("\t", (split("\t", $h1))[0 .. 9, 14]) . "\tLabel\tDrugCn\tIndication";
if (@pos) {
    print POS "$h\n";
    print POS join("\n", @pos) . "\n";
}

if (@neg) {
    print NEG $h2 . "\tfun_change\n";
    print NEG join("\n", @neg) . "\n";
}

if (@vus) {
    print VUS $h2 . "\tfun_change\n";
    print VUS join("\n", @vus) . "\n";
}