Colorectal cancer (CRC) and endometrial cancer (EC) have a highly heritable component.
Approximately 25% of CRC or EC patients have another first or second-degree relative who
is also affected by CRC or EC, and there are at least 32 known high penetrance CRC/EC
germline predisposition genes. The overarching goal of this protocol is to (a) discover
novel mechanisms in intestinal carcinogenesis and genes inducing genetic predisposition,
(b) identify new genes and proteins that are amenable to targeted therapy and precision
prevention drug intervention and biomarker development in Hereditary Cancer Syndromes.
To accomplish these goals, the investigators plan to pursue the following aims:
Study the genomic and epigenetic profile of polyps and carcinomas arising in the
upper gastrointestinal tract, lower gastrointestinal tract, normal mucosa from both
locations, other GI organs, endometrium, and germline DNA of patients diagnosed with
Hereditary Cancer Syndromes and a sporadic CRC/EC cohort as a comparator and
control.
To determine the differences in gene expression and protein profiles between polyps
and carcinomas arising in the upper gastrointestinal tract, lower gastrointestinal
tract, normal mucosa from both locations, other GI organs, endometrium, and
peripheral blood monocytes (PBMs) in patients with Hereditary Cancer Syndromes and a
sporadic CRC/EC cohort as a comparator and control.
To identify molecular pathways that are preferentially deregulated in polyps and
carcinomas of patients diagnosed with Hereditary Cancer Syndromes and a sporadic
CRC/EC cohort as a comparator and control that are amenable to therapeutic
intervention.
To assess different blood serum markers (e.g., peripheral blood lymphocytes (PBMs),
circulating tumor DNA (ctDNA) and others and correlate these findings with tissue
markers of patients diagnosed with Hereditary Cancer Syndromes and a sporadic CRC/EC
cohort as a comparator and control.
To determine differences in microRNA (miRNA) and long non-coding RNA (lncRNA)
profiles between polyps and carcinomas arising in the upper gastrointestinal tract
and lower gastrointestinal tract, normal mucosa from both locations, other GI
organs, endometrium, and PBMs in patients with Hereditary Cancer Syndromes and a
sporadic cohort CRC/EC as a comparator and control.
To study the molecular alterations, epigenetic changes, copy number changes, gene
expression and miRNA profiles and to establish pathologic correlates of the stem
cells and other cellular populations of the intestinal crypts in carcinomas,
adenomatous and normal intestinal epithelium biopsies, endometrial polyps and normal
endometrium biopsies, through different molecular techniques.
To validate the functional activity of the pathways identified in the human samples
using animal model systems and basic molecular biology experiments.
To develop organoids from adenocarcinomas, polyps, and normal intestinal mucosa
samples in patients with Hereditary Cancer Syndromes and a sporadic cohort as a
comparator and control. These organoids will be derived from tissue biopsies of
different parts of the intestinal tract, other GI organs, and endometrium in order
to perform assessment of drug sensitivity and molecular biology experiments to
understand the biology and carcinogenesis of the intestine.
To test the activity of drug agents using patient-derived xenografts in
immune-deficient mice. The tissues used for the xenografts will come from patients
diagnosed with CRCs, ECs, other GI organs, or polyps.
To accomplish these goals, the investigators will obtain normal mucosa, polyp tissue and
carcinoma (tumor tissue) arising in the upper gastrointestinal tract (mainly the
duodenum, but also other potential locations such as the esophagus, GE junction, stomach,
and small bowel), lower gastrointestinal tract (mainly the colorectum), paired normal
mucosa samples, endometrial tissue, and blood and/or saliva as a source of genomic DNA,
RNA, and protein.
The biospecimen samples will be collected in the context of standard of care (SOC)
endoscopic procedure(s) and/or from pathologic specimens obtained during gastrointestinal
(GI) endoscopy procedures and surgery performed at Weill Cornell or New York Presbyterian
Hospital, including diagnostic testing, clinic and/or treatment visit and/or from
residual blood or tissues already collected by other protocols or archived by the Center
for Advanced Digestive Care (CADC) biobank (IRB Protocol: 0908010582). These tissue
samples and blood samples were collected in the context of routine care and procedures
performed at Weill-Cornell and NYPH. Biospecimen samples will also be collected in the
context of SOC transvaginal ultrasound, hysteroscopy and endometrium biopsy performed at
Weill Cornell or New York Presbyterian Hospital, including diagnostic testing, clinic
and/or treatment visit.
Blood samples will be collected at the time blood is taken for clinical care. The
investigators will register, collect, process and store frozen blood, frozen normal and
diseased tissue and FFPE (formalin fixed paraffin embedded) specimens.
This will be an invaluable annotated hereditary CRC/EC registry and tissue repository
that will be available to the Weill Cornell Community upon appropriate approval. Subjects
that provide informed consent will agree to collection and storage of clinical data. For
the purposes of this project, clinical data includes all data collected for standard
clinical purposes (e.g., demographics, medical issues, prognostic data, treatment data,
outcomes).