Carolyn A. Deters

Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: The familial atypical multiple mole melanoma-pancreatic carcinoma syndrome

Hereditary pancreatic carcinoma shows extant phenotypic and genotypic heterogeneity as evidenced by its integral association with a variety of hereditary cancer syndromes inclusive of the familial atypical multiple mole melanoma (FAMMM) syndrome in concert with CDKN2A (p16) germline mutations.

Characterization of a Recurrent Germ Line Mutation of the E-Cadherin Gene: Implications for Genetic Testing and Clinical Management

Purpose: To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals. Experimental Design: We ascertained 31 HDGC previously unreported families, including 10 isolated early-onset diffuse gastric cancer (DGC) cases. Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing. Results: We identified eight inactivating and one missense CDH1 germ line mutation. The missense mutation conferred in vitro loss of protein function. Two families had the previously described 1003C>T nonsense mutation. Haplotype analysis revealed this to be a recurrent and not a founder mutation. Thirty-six percent (5 of 14) of the families with a documented DGC diagnosed before the age of 50 and other cases of gastric cancer carried CDH1 germ line mutations. Two of 10 isolated cases of DGC in individuals ages <35 years harbored CDH1 germ line mutations. One mutation positive family was ascertained through a family history of lobular breast cancer (LBC) and another through an individual with both DGC and LBC. Occult DGC was identified in five of six prophylactic gastrectomies done on asymptomatic, endoscopically negative 1003C>T mutation carriers. Conclusions: In addition to families with a strong history of early-onset DGC, CDH1 mutation screening should be offered to isolated cases of DGC in individuals ages <35 years and for families with multiple cases of LBC, with any history of DGC or unspecified GI malignancies. Prophylactic gastrectomy is potentially a lifesaving procedure and clinical breast screening is recommended for asymptomatic mutation carriers.

Hereditary Pancreatic Cancer

Hereditary pancreatic cancer (PC) appears to be exceedingly heterogeneous, as evidenced by its association with a variety of integrally associated diverse cancers and/or differing mendelian inherited cancer syndromes, which include the Lynch syndrome II variant of hereditary nonpolyposis colorectal cancer, hereditary breast-ovarian cancer syndrome in families with the BRCA2 mutation, hereditary pancreatitis, Peutz-Jeghers polyposis and the familial atypical multiple-mole melanoma syndrome in families with the CDKN2A(p16) germline mutation. Because of this heterogeneity, we provide a conservative estimate that about 5% (1,460) of PC cases in the US annually are hereditary. Although this number is relatively small, members of hereditary PC families serve as excellent models for studying the etiology, natural history, biomarkers, pathogenesis, potential carcinogenic exposures and their perturbation of underlying genetic events, and treatment of PC. These individuals would benefit greatly from method(s) capable of detecting cancer at an early stage, and such knowledge would also be useful for improving the diagnosis of the much more common ‘sporadic’ form of PC.

Familial pancreatic carcinoma in Jews

Abstract Pancreatic cancer (PC) is the most fatal of all gastrointestinal cancers, wherein its mortality compares strikingly with its incidence. Unfortunately, 80--90% of PCs are diagnosed in the nonresectable stage. While the lifetime risk of PC in developed countries is approximately 1–3%, it is the fifth most common cause of cancer deaths among both males and females in Western countries. It occurs in excess in Jews. Approximately 5–10% of PC shows familial clustering. Examination of such familial clusters must take into consideration cancers of diverse anatomic sites, such as malignant melanoma in the familial atypical multiple melanoma (FAMMM) syndrome due to the CDKN2A (p16) germline mutation, and combinations of colorectal and endometrial carcinoma, ovarian carcinoma, and several other cancers in hereditary nonpolyposis colorectal cancer (HNPCC), which are due to mismatch repair germline mutations, the most common of which are MSH2 and MLH1. Other hereditary disorders predisposing to PC include Peutz–Jeghers syndrome, due to the STK11 mutation, familial pancreatitis due to the cationic trypsinogen gene, site-specific familial pancreatic cancer which may be due to the 4q32–34 mutation, hereditary breast–ovarian cancer (HBOC) syndrome that is due to BRCA2 and possibly some families with HBOC that is due to BRCA1, familial adenomatous polyposis due to the ATP gene, and ataxia telangiectasia due to the ATM germline mutation. This extant heterogeneity mandates that the physician be knowledgeable about these PC-prone syndromes which play such an important role when considering the differential diagnosis of hereditary PC. Unfortunately, there are no PC screening programs with acceptable sensitivity and specificity. However, the gold standard for screening at this time is endoscopic ultrasound. Clearly, there is a great need for the development of novel screening approaches with acceptable sensitivity and specificity. Further research is needed to elucidate those etiologic factors that contribute to the apparent excess of PC in Ashkenazi Jews. Attention should also be given to the search for mutations predisposing to PC in Jews so that opportunities to learn more about the diseases pathogenesis, as well as screening and control, may take place.

Familial sarcoma: challenging pedigrees

BACKGROUND. Partially due to the rare occurrence of soft tissue and osteogenic sarcomas in the general population, scant attention has been given to their hereditary etiology. Their overall poor prognosis might be ameliorated through an understanding of their environmental and hereditary causal factors, and/or their interactions, thereby contributing to earlier diagnosis and even the development of molecularly based targeted therapy. METHODS. The authors selected 10 sarcoma-prone families from their extensive hereditary cancer-prone family resource and focused on their challenging diagnostic, surveillance, and management features. The family study protocol included the compilation of a detailed family history of malignant disease of all anatomic sites and the collection of all available primary medical and pathology documents for verification. Genetic counseling was provided before DNA collection and at disclosure of results. RESULTS. These families displayed marked phenotypic and genotypic heterogeneity. In one of these families, 16 relatives had sarcomas, with 2 of the 16 each having 2 metachronous sarcomas; to our knowledge, this represents the greatest number of sarcomas reported in any family described to date. Two familial atypical multiple-mole melanoma syndrome kindreds with the CDKN2A mutation showed the association of sarcoma with malignant melanoma, whereas one family had several pancreatic carcinomas. Other families with sarcoma had hereditary nonpolyposis colorectal carcinoma with MSH2 mutation, hereditary breast carcinoma with BRCAI mutation, and p53 mutation in a Li-Fraumeni syndrome. CONCLUSIONS. Sarcoma-prone families reported in the current study were selected carefully to depict clinicopathology and compliance features, the understanding of which could elucidate the etiologic role of genetic factors in concert with the phenotypic and genotypic heterogeneity encountered in such families. The lack of a population-based data set for these families posed a limitation.BACKGROUND Partially due to the rare occurrence of soft tissue and osteogenic sarcomas in the general population, scant attention has been given to their hereditary etiology. Their overall poor prognosis might be ameliorated through an understanding of their environmental and hereditary causal factors, and/or their interactions, thereby contributing to earlier diagnosis and even the development of molecularly based targeted therapy. METHODS The authors selected 10 sarcoma-prone families from their extensive hereditary cancer-prone family resource and focused on their challenging diagnostic, surveillance, and management features. The family study protocol included the compilation of a detailed family history of malignant disease of all anatomic sites and the collection of all available primary medical and pathology documents for verification. Genetic counseling was provided before DNA collection and at disclosure of results. RESULTS These families displayed marked phenotypic and genotypic heterogeneity. In one of these families, 16 relatives had sarcomas, with 2 of the 16 each having 2 metachronous sarcomas; to our knowledge, this represents the greatest number of sarcomas reported in any family described to date. Two familial atypical multiple-mole melanoma syndrome kindreds with the CDKN2A mutation showed the association of sarcoma with malignant melanoma, whereas one family had several pancreatic carcinomas. Other families with sarcoma had hereditary nonpolyposis colorectal carcinoma with MSH2 mutation, hereditary breast carcinoma with BRCA1 mutation, and p53 mutation in a Li-Fraumeni syndrome. CONCLUSIONS Sarcoma-prone families reported in the current study were selected carefully to depict clinicopathology and compliance features, the understanding of which could elucidate the etiologic role of genetic factors in concert with the phenotypic and genotypic heterogeneity encountered in such families. The lack of a population-based data set for these families posed a limitation.

Mutational load distribution analysis yields metrics reflecting genetic instability during pancreatic carcinogenesis

Considering carcinogenesis as a microevolutionary process, best described in the context of metapopulation dynamics, provides the basis for theoretical and empirical studies that indicate it is possible to estimate the relative contribution of genetic instability and selection to the process of tumor formation. We show that mutational load distribution analysis (MLDA) of DNA found in pancreatic fluids yields biometrics that reflect the interplay of instability, selection, accident, and gene function that determines the eventual emergence of a tumor. An in silico simulation of carcinogenesis indicates that MLDA may be a suitable tool for early detection of pancreatic cancer. We also present evidence indicating that, when performed serially in individuals harboring a p16 germ-line mutation bestowing a high risk for pancreatic cancer, MLDA may be an effective tool for the longitudinal assessment of risk and early detection of pancreatic cancer.