ABOUT

INT²GRATE stands for INTegrated INTerpretation of GeRmline And Tumor gEnomes. The INT²GRATE platforms have been developed based on a basic and yet important principle that cancer patients have two sets of genomes: constitutional and somatic genomes. The integrated assessment of germline and somatic-derived data reveals a new wealth of genetic knowledge from the interplay of the two genomes. This integrated measure is an objective indication of the status of cancer progression at the molecular and cellular levels. It is arguably free of confounding genetic host factors such as penetrance and variable expressivity of alleles and factors influencing population genetic structure.

INT²GRATE utilizes key signature profiles of tumors along with clinical genetic data to assess the possible role and clinical utility of germline variants in selected cancer syndromes. INT²GRATE web portal facilitates the collation of necessary data, as provided by the user, in specific genes to assess the INT²GRATE category. It further provides a downloadable copy of the INT²GRATE variant assessment for data sharing.

INT²GRATE enables the sharing of variant information from both tumor and germline clinical data. Using a custom-made INT²GRATE submission schema, germline variants and the associated tumor-derived and clinical data are systematically shared in publicly accessible databases. This novel method of processing and sharing comprehensive integrated germline and somatic evidence is a crucial step in advancing precision oncology in genomics. INT²GRATE Oncology Consortium is a registered submitter organization in ClinVar.

The original concept behind INT²GRATE can be accessed  here. In selected inherited cancer syndromes, INT²GRATE requires a) germline variants in relevant cancer susceptibility genes, b) personal and familial genetics information, and c) somatic genomic information and relevant tumor signature profiles. Detailed requirements for each cancer syndrome can be found on the respective INT²GRATE page for each disease.

Rana HQ, Koeller DR, Walker M, Unal B, Levine AS, Chittenden A, Isidro RA, Hayes CP, Manam MD, Buehler RM, Manning DK, Barletta JA, Hornick JL, Garber JE, Ghazani AA, Int2grate Oncology Consortium. Advancing Precision Oncology in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Integrated Interpretation and Data Sharing of the Germline and Tumor Genomes. Cancers (Basel). 2024 Feb 26;16(5):947. doi: 10.3390/cancers16050947. PMID: 38473309; PMCID: PMC10931192.

Isidro RA, Chittenden A, Walker M, Schwartz A, Koeller DR, Hayes CP, Unal B, Manam MD, Buehler RM, Manning DK, Sholl LM, Redston MS, Yurgelun MB, Rana HQ, Garber JE, Ghazani AA. Development and evaluation of INT2GRATE: a platform for comprehensive assessment of the role of germline variants informed by tumor signature profile in Lynch syndrome. Front Oncol. 2024 Jan 24;13:1284690. doi: 10.3389/fonc.2023.1284690. PMID: 38344144; PMCID: PMC10854004.

Schwartz A, Manning DK, Koeller DR, Chittenden A, Isidro RA, Hayes CP, Abraamyan F, Manam MD, Dwan M, Barletta JA, Sholl LM, Yurgelun MB, Rana HQ, Garber JE, Ghazani AA.  An integrated somatic and germline approach to aid interpretation of germline variants of uncertain significance in cancer susceptibility genes. Front Oncol. 2022 Aug 25;12:942741. doi: 10.3389/fonc.2022.942741. PMID: 36091175; PMCID: PMC9453486.

Koeller DR, Manning DK, Schwartz A, Chittenden A, Hayes CP, Abraamyan F, Rana HQ, Lindeman NI, Garber JE, Ghazani AA. An optimized protocol for evaluating pathogenicity of VHL germline variants in patients suspected with von Hippel-Lindau syndrome: Using somatic genome to inform the role of germline variants. MethodsX. 2022 Jun 18;9:101761. doi: 10.1016/j.mex.2022.101761. PMID: 35774415; PMCID: PMC9237939.

Manning DK, Shivdasani P, Koeller DR, Schwartz A, Rana HQ, Garber JE, Lindeman NI, Ghazani AA. Assessment of genomic alterations in non-syndromic von Hippel-Lindau: Insight from integrating somatic and germline next generation sequencing genomic data. Data Brief. 2021 Dec 1;39:107653. doi: 10.1016/j.dib.2021.107653. PMID: 34934780; PMCID: PMC8661471.

Rana HQ, Koeller DR, Schwartz A, Manning DK, Schneider KA, Krajewski KM, Choueiri TK, Lindeman NI, Garber JE, Ghazani AA. Pathogenicity of VHL variants in families with non-syndromic von Hippel-Lindau phenotypes: An integrated evaluation of germline and somatic genomic results. Eur J Med Genet. 2021 Dec;64(12):104359. doi: 10.1016/j.ejmg.2021.104359. Epub 2021 Oct 8. PMID: 34628056.

NCCN Clinical Practice Guidelines Genetic/Familial High-Risk Assessment: Colorectal. Available at:  https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf

PREMM5 Lynch-Syndrome Prediction Model 

Lynch-Syndrome Screening Network – Amsterdam II Criteria