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Oncology
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Hereditary Diffuse Gastric Cancer (HDGC)

Hereditary diffuse gastric cancer (HDGC) is a highly penetrant, yet rare, autosomal dominant condition that predisposes to diffuse gastric cancer and lobular breast cancer.  It accounts for <1% of all gastric cancers and is caused by mutations in the CDH1 gene.

Hereditary diffuse gastric cancer (HDGC) is a highly penetrant, yet rare, autosomal dominant condition that predisposes to diffuse gastric cancer and lobular breast cancer.  It accounts for <1% of all gastric cancers and is caused by mutations in the CDH1 gene.

CDH1 coding exons 1-16 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-16. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by incorporating the gDNA onto a microfluidics chip, along with primer pairs followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing, or with insufficient read depth coverage for reliable heterozygous variant detection. Potentially homozygous variants, variants in regions complicated by pseudogene interference, and variant calls not satisfying depth of coverage and variant allele frequency quality thresholds are verified by Sanger sequencing. Gross deletion/duplication analysis of CDH1 using multiplex ligation-dependent probe amplification (MLPA) is also performed.

1. Fitzgerald RC, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010; 47:436-444.

Genes analyzed
Code
Test Name
Turnaround
Genes
4726
CDH1 seq and del/dup
5-14 days
1 Gene
CDH1 seq and del/dup
1 Gene
CDH1
Test Requisition Form
Cancer (Abbreviated)
(EN)

Option to modify frequency and initial age of mammogram/breast MRI, colonoscopy, or other screening as appropriate Consideration of prophylactic surgery, such as gastrectomy, or other risk-reducing measures, as appropriate  Identify at-risk family members

Test Description

CDH1 coding exons 1-16 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-16. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by incorporating the gDNA onto a microfluidics chip, along with primer pairs followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing, or with insufficient read depth coverage for reliable heterozygous variant detection. Potentially homozygous variants, variants in regions complicated by pseudogene interference, and variant calls not satisfying depth of coverage and variant allele frequency quality thresholds are verified by Sanger sequencing. Gross deletion/duplication analysis of CDH1 using multiplex ligation-dependent probe amplification (MLPA) is also performed.

1. Fitzgerald RC, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010; 47:436-444.