Research in the laboratory focuses on two areas:

• Characterization of novel cancer predisposing genes in humans;

• Genetic epidemiologic studies to describe penetrance, modifying effect, and phenotype/clinical outcome associated with germline genetic alterations in cancer patients and their families.

Our laboratory collaborated on the original description of mutation distribution in BRCA1¹ and BRCA2.²  We confirmed the prevalence of the BRCA1*185delAG in a genetic isolate of Ashkenazim, and were the first to describe a founder mutation BRCA2*6174delT in this same group.^3,4 We noted this to be the most common BRCA mutation reported worldwide.

Subsequently, the laboratory has had a special interest in Ashkenazi founder mutations for other cancer susceptibility genes; we collaborated with the Vogelstein laboratory to describe the colon cancer founder mutation APC*I1307K,⁵ which we discovered to be associated with breast cancer susceptibility.⁶ We also described the novel colon cancer founder mutation of MSH2*1906G>C,⁷and reported the association of the Ashkenazi BLMASH mutation with increased risk of colorectal cancer.⁸ Recently, we worked in collaboration with colleagues in the US and Israel to describe a novel Ashkenazi founder mutation in CHEK2.⁹

Taking advantage of the extended regions of linkage disequilibrium we have described surrounding these founder mutations in the Ashkenazim,^10,11 we are currently focused on exploiting these observations to identify novel cancer predisposition genes in this genetic isolate. We have recently completed a 'proof of principal' experiment utilizing linkage disequilibrium mapping to "re-discover" the BLM and MSH2 founder mutations,¹² and we have also utilized this technique to rediscover BRCA2 and map loci for novel breast cancer susceptibility loci.¹³

Ongoing studies are utilizing the Affymetrix SNP platform, which provides 500K high-density genomic scans. Experiments are underway to utilize LD mapping of low-penetrance alleles predisposing to both breast and colon cancer, as well as non-Hodgkin's lymphoma. The experimental approaches used in these studies is based on the "Peto enriched case" method and takes advantage of extensive ascertainments of multiplex families that are wild type for known cancer-predisposing alleles.

Theoretical development of mathematical genetic models in collaboration with colleagues in the Department of Biostatistics and Epidemiology,¹⁴ is also an active area of study within the group.

The laboratory has focused on candidate genes with a strong biological rational for which functional studies have been performed to suggest a basis for site-specific cancer susceptibility. In collaboration with Joan Massague, the group originally reported a hypomorphic allele in the type TGF beta type I receptor.^15,16,17,18

In collaboration with colleagues at Northwestern, we are continuing to study mutations in both TGF beta ligand and type I receptor, which together affect TGF beta signaling and are associated with cancer risk in large-case control studies. Other candidate genes investigated in genetic epidemiologic studies have included ATM,¹⁹ CHEK2,²⁰ and founder mutations of BRCA1 and BRCA2 associated with risk for colon cancer, prostate cancer, and lymphoma.^21,22,23

Recently, in collaboration with the laboratory of Dr. A. Levine, we have been examining candidate single nucleotide polymorphisms in p53 signaling pathways, and have noted strong associations with subtypes of non-Hodgkin's lymphoma and departure from Hardy-Weinberg equilibrium of this SNP in BRCA-associated breast cancer. Additional studies are underway. A systematic effort to analyze single nucleotide polymorphisms in DNA damage response and repair pathways in non-Hodgkin's lymphoma is underway utilizing an ascertainment of 100 kindreds affected by familial lymphoid cancers.^24,25,26

A separate area of focus in the laboratory is directed by Dr. Mark Robson. He has been conducting retrospective cohort studies within the Ashkenazi genetic isolate. These studies have addressed the clinical behavior and outcome of patients carrying germline BRCA mutations.^{27,28,29,30,31,32} Dr. Robson aims to exploit the biology of BRCA1 and BRCA2 to define tailored therapeutic approaches to these cohorts. A case-control study will analyze the possible phenotypic hallmarks of radiation sensitivity in this cohort.

A third area of focus within the laboratory is directed by Dr. Noah Kauff working in collaboration with Dr. Nikolai Pavletich at SKI and Dr. Chris Sander in Computational Biology. Dr Kauff is analyzing structure/ function relationships associated with missense mutations of BRCA2 observed in the clinical patient population. Dr. Kauff is modeling the possible functional significance of these mutations and then testing these hypotheses in a large association study to define the cancer risks associated with these alleles.

Finally, the Clinical Genetics Service also maintains a clinical laboratory. The Laboratory of Diagnostic Molecular Genetics is headed by Dr. Jeff Boyd and Dr. Cindy Yee. Although devoted extensively to clinical genotyping, the laboratory does serve as an important stimulus for clinical descriptive reports focused on genotype-phenotype correlations, penetrance, and clinical outcome. ^{33 34 35 36 27 38 39 40}