By the Pricking of My Thumbs, Something Wicked This Way Comes: Sporadic Cancers Versus Eponymous Hereditary Cancer Predisposition Syndromes

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  • a Division of Hematology and Oncology, Department of Medicine
  • b Department of Pathology
  • c Department of Surgery, General Surgical Oncology Section, University of Alabama at Birmingham, Birmingham, Alabama.

Advances in cancer genomics have led to the recognition of a growing number of high-penetrance single-gene cancer predisposition syndromes. Frequently, the suspicion for a hereditary syndrome is raised by a strongly positive family history. However, other features, such as younger-than-usual age at diagnosis and rare histology should also prompt consideration of a genetic syndrome. Common malignancies frequently show a positive family history without an eponymous syndrome being recognized. This article reports on a case with an unusual constellation of malignancies with distinctive pathologies, which raised suspicion for an eponymous cancer pre-disposition syndrome. Absent a positive family history, a de novo mutation—an alteration in a gene that is present for the first time in a family member as a result of a mutation in a germ cell of one of the parents or in the fertilized ovum—was suspected. The authors discuss indications for genetic counseling and testing, limitations, and the evidence that supports the recommendations as formulated by working groups and the NCCN. Most frequently, these recommendations are reasonable statements based on the natural history of the disease, but without population-based studies for many rare syndromes, the actual penetrance, variable expressivity, and actual associated cancer risk are unknown.

As genetic testing becomes increasingly available in contemporary oncology and as more germline mutations associated with a high risk of cancer are discovered, the clinician's responsibility increases to recognize the small but growing minority of patients with hereditary cancer predisposition syndromes. Experts estimate that these patients constitute approximately 5% to 10% of all patients with cancer.1 Most frequently, suspicion of a hereditary syndrome is raised by a family history of multiple family members affected by the same or similar diagnoses across consecutive generations. This report presents the case of a patient without significant family history but with an unusual constellation of malignancies and pathologies, which prompted further investigation for an eponymous syndrome—a high-penetrance cancer predisposition syndrome associated with a well-defined genetic alteration. We discuss the diagnostic process, the indications for genetic consultation, and the limitations of evidence-based recommendations.

Case Report

A 51-year-old woman of Hispanic descent was in her usual state of health when she underwent a screening colonoscopy. The colonoscopy showed at least 4 sessile polyps in the descending colon and rectum. One polyp excised from the descending colon was tubular adenoma, and the other 3 were poorly differentiated adenocarcinomas with signet-ring cell features. Although imaging studies were not consistent with distant metastases, a sharply circumscribed lytic lesion in the left iliac wing was noted. In the context of investigating the incidental findings, the patient underwent upper endoscopy, which revealed multiple nodules, primarily involving the proximal third of the stomach. The distal stomach and antrum were spared. Biopsy results of these nodules were consistent with poorly differentiated adenocarcinoma with signet-ring cell features, similar to the pathology of the colonic lesions (Figure 1).

The patient underwent further staging using PET. No lymphatic or hepatic metastases were identified, but the osteolytic lesion in the left iliac wing was hypermetabolic, and new right axillary lymphadenopathy was seen. In the context of investigating for a breast primary malignancy, an area of architectural distortion and suspicious enhancement was found on MRI of the right breast. On pathology, this lesion was consistent with infiltrating mammary carcinoma with predominantly lobular features and lobular carcinoma in situ (Figure 2). The specimen was positive for estrogen and progesterone receptors on immunohistochemistry; Her2 was nonamplified. In addition to the different histologic appearances of the gastric and breast biopsies, the absence of staining for mammaglobin, and estrogen and progesterone receptors on the gastric specimen confirmed them to be distinct primary cancers.

Figure 1
Figure 1

Gastric biopsies. (A) Low-power magnification (hematoxylin-eosin, original magnification ×4) of the gastric biopsy specimen. The histologic findings are consistent with poorly differentiated adenocarcinoma with signet-ring cell features. (B) High-power magnification (hematoxylin-eosin, original magnification ×40) of the gastric biopsy specimen. (C) Immunohistochemistry for cytokeratin 7 (×4); the neoplastic cells were strongly positive for cytokeratin 7. (D) Immunohistochemistry for cytokeratin 7; higher magnification (×40) shows the sheets of discohesive cells with abundant vacuolated cytoplasm and eccentrically placed nuclei.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 1; 10.6004/jnccn.2012.0004

Clinically, aside from skeletal pain that developed later, a striking contradiction was noted between the extent of disease and the patient's minimal symptom burden. Physical examination was negative for abnormal findings. A thorough family history was unrevealing. She had one brother, who was diagnosed with colonic polyps on routine screening colonoscopy and was fine. Her grandparents on both sides lived to 98 to 100 years. After her father was diagnosed with a benign colonic tumor in his 60s, the patient underwent a screening colonoscopy in her 30s; the results were normal.

Considering that surgery for her primary breast tumor would not be curative in the context of skeletal metastases and the high morbidity and mortality of a combined gastrectomy and colectomy, the patient was placed on anastrozole and zoledronic acid while considering chemotherapy when her gastrointestinal malignancies become symptomatic or meta-static. Early-stage signet-ring cell gastric carcinoma usually has a favorable prognosis (5-year survival rate of 94.3%),2 but the inability to perform gastrectomy, advanced-stage disease, and coexistent malignancies in this case altered her prognosis significantly. Her disease remains stable on PET, with at least mild improvement of the primary breast lesion 9 months after the original diagnosis. The patient was offered genetic counseling and testing.

Discussion

Sporadic Cancer Versus Hereditary Syndromes

Several features in this case support the consideration of genetic counseling despite the negative family history: multiple and multifocal primary tumors in the same organ, concurrent primary tumors in different organs, rare histology,3 and phenotype that “fits” an eponymous genetic syndrome. Other features that should raise the suspicion of a hereditary syndrome include a younger-than-usual age at diagnosis, bilateral occurrence in paired organs, and the presence of rare diseases, congenital defects, traits, or precursor lesions known to be associated with hereditary syndromes.3

Despite the increasing recognition of hereditary syndromes, most cancers are sporadic. Frequently, a positive family history is seen, but no hereditary syndrome is recognized. In lieu of available genetic testing and in view of available risk-modifying interventions, cancer risk estimates may rely on prediction models, such as those developed for breast cancer,4 and risk stratification, such as that used in colorectal cancer risk assessment.5

Absent a single-gene high-penetrance syndrome (as is the case for most patients), the magnitude of effect of a positive family history on cancer risk is more accurately assessed by population-based registry studies.6-8 Studies based on the Utah Population Database and Swedish Family-Cancer Database have been useful in providing a global view of the familial relative risk of cancer8 and have shown that, for common cancers, a substantial proportion of risk is attributable to familial factors.9,10 Data analyzed by cancer site yielded familial relative risks greater than 1 for all sites,6-8 indicating that family history of cancer in first-degree relatives is uniformly a risk factor for cancer.

Figure 2
Figure 2

Breast biopsies. (A) Low-power magnification (hematoxylin-eosin, original magnification ×4) of the breast biopsy specimen consistent with infiltrating mammary carcinoma with predominately lobular features. (B) High-power magnification (hematoxylin-eosin, original magnification ×40) of the breast biopsy at the site of invasive growth. (C) Lobular carcinoma in situ (hematoxylin-eosin, original magnification ×40). (D) Immunohistochemistry for estrogen receptors (×40). Cancer cells stained strongly positive for estrogen (shown) and progesterone receptors. Her2 was not amplified.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 1; 10.6004/jnccn.2012.0004

Indications for Genetic Testing

Incorporating advances in cancer genomics, NCCN issued Clinical Practice Guidelines in Oncology (NCCN Guidelines) on diagnosis, treatment, and preventive interventions for eponymous cancer susceptibility syndromes.5,11,12 The NCCN Guidelines serve as an open resource for clinicians who are still responsible for recognizing these syndromes and referring patients appropriately for genetic counseling. Given the rarity of these syndromes and the inherent difficulty in conducting prospective clinical studies, the evidence supporting these guidelines is primarily reasonable consensus statements based on the natural history of the syndromes. Nonetheless, the need for high-level evidence cannot be underestimated.

Recommendations for preventive interventions in these syndromes build on cancer risk estimates that, without population-based data on penetrance and variable expressivity, often include ascertainment bias. This sampling bias emanates from initial clinical studies that are conducted in rare familial clusters with high expression of the disease, leading to overestimation of penetrance and underestimation of the variable expressivity of the syndrome. This is illustrated in the case of BRCA1 mutations. Although the lifetime cumulative risk of breast cancer was initially estimated at 87%,13 a probably more accurate assessment (65%) is provided by a pooled analysis of 22 studies involving patients unselected for family history.14 Single nucleotide polymorphisms15 and nongenetic factors such as parity16 can modify cancer risk and may account for this discrepancy in estimates. Nonetheless, familial breast-ovarian cancer constitutes one of the few cancer predisposition syndromes in which an invasive risk-reducing intervention is supported by prospective studies.17

Because the performance characteristics of genetic testing can be poor if the pretest probability for a specific mutation is low, the NCCN Guidelines incorporate diagnostic criteria from many syndrome-specific working groups that must be fulfilled before referring for genetic consultation. Previous investigation of likely diagnoses is necessary to guide consultation and eliminate unnecessary testing and cost.

Hereditary Syndromes Associated With Breast, Gastric, and Colorectal Malignancies

A list of hereditary syndromes associated with breast, gastric, and colorectal cancer is provided in Table 1. For many syndromes, clinical phenotypes have not been subjected to rigorous statistical analysis.3 The spectrum of malignancies can be broad in some instances, as in Bloom syndrome, in which every cell capable of division is susceptible to malignant transformation.3

Table 1Table 1Table 1

Many genetic syndromes outlined in Table 1 can be eliminated based on the absence of distinctive defects, traits, or lesions. In ataxia-telangiectasia, non-Hodgkin's lymphomas and leukemias are the most frequent malignancies; however, an excess risk for breast, gastric, and colorectal cancer in heterozygous mutation carriers in the absence of other features of the syndrome has also been reported.18 The patient had none of the nonmalignant manifestations of the syndrome, and the distinctive histologic features of her malignancies made this diagnosis less likely. Cowden syndrome is associated with breast cancer, but the association with gastrointestinal malignancies is unclear, and the patient did not have pathognomonic mucocutaneous lesions. The absence of mucocutaneous pigmentations and lesions such as neurofibromas and café-au-lait macules eliminated Peutz-Jeghers syndrome and neurofibromatosis type I, respectively.

Colorectal cancer arising from adenomatous and hamartomatous polyps constitutes the principal malignancy of familial adenomatous polyposis and juvenile familial polyposis, respectively. Colon cancer is also the hallmark of Lynch syndrome (hereditary non-polyposis colorectal cancer) and MYH-associated polyposis. In Lynch syndrome, colon cancer typically involves the right colon and is usually diagnosed in the patient's mid-40s. In MYH-associated polyposis, biallelic mutations in MYH (a base excision repair gene) lead to somatic mutations in APC and, thus, a usually attenuated familial adenomatous polyposis phenotype. Although these syndromes have been associated with gastric cancer, breast cancer is not a typical feature.

Increased risk for gastric and colon cancers has been reported in familial breast-ovarian cancer 1,19 but breast (typically triple-negative) and ovarian cancer are its defining features.3 Breast cancer is also seen in Li-Fraumeni syndrome; however, usually the onset is earlier, and malignancies such as sarcoma, adrenocortical carcinoma, and brain tumors are more typical. Other syndromes that may be considered include heterozygosity for NBS1 mutations20 and familial breast-ovarian cancer 2. However, this particular constellation of malignancies and their distinctive pathologic features are highly consistent with the phenotype of hereditary diffuse gastric cancer syndrome (HDGC).

HDGC

Significant advancement in understanding the genetic pathophysiology of gastric cancer has been made with the discovery of inactivating germline mutations of the E-cadherin gene CDH1 in families with multiple cases of early-onset diffuse gastric cancer.21 Mutations of CDH1 have been identified in patients of diverse ethnic backgrounds, and an association with breast (primarily lobular) and possibly colorectal (characteristically signetring cell) cancers has been recognized.22 CDH1 mutations are inherited in an autosomal-dominant pattern, with incomplete but high penetrance.22 The causative mutations are typically truncating, whereas the pathogenicity of missense mutations requires in vitro or in silico confirmation.23,24 Genetic testing of the proband requires sequencing of the entire gene, because the pathogenic mutations are distributed throughout the gene and few recurring mutations have been identified.23,25

Although the patient did not meet the clinical criteria for HDGC of the International Gastric Cancer Linkage Consortium,23 the description of de novo CDH1 mutations in sporadic early-onset gastric cancer24 and the significant implications for her children justified genetic consultation and testing for HDGC. If a deleterious CDH1 mutation is identified in the proband, testing of other family members for the identified mutation should be recommended. Given the syndrome's high penetrance, the aggressive phenotype of gastric cancer, and the absence of effective clinical screening, prophylactic gastrectomy in CDH1 mutation carriers should be offered. This recommendation is further justified by the high frequency of occult gastric cancer found in surgical specimens of asymptomatic patients,25 despite the high mortality and nearly 100% morbidity associated with gastrectomy.

Genetic testing also has limitations, and the detection rate of CDH1 mutations, even among carefully selected patients, does not exceed 50%.23 In this case, genetic testing of family members will not be informative; however, intensive endoscopic surveillance and breast cancer screening are recommended.

Conclusions

Advances in cancer genomics have led to the increasing recognition of hereditary cancer predisposition syndromes. Referral for genetic counseling and appropriate genetic testing should be considered in patients with a strong family history, even if an eponymous syndrome cannot be recognized, or in patients with unusual presentations. Recommended risk-reducing interventions in hereditary syndromes are most commonly based on the natural history of the disease, but population-based studies are needed to more accurately assess cancer risk.

*

Macbeth, William Shakespeare, Act IV, scene 1.

The authors have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors.

References

  • 1

    Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol 2005;23:276-292.

  • 2

    Jiang CG, Wang ZN, Sun Z. Clinicopathologic characteristics and prognosis of signet ring cell carcinoma of the stomach: results from a Chinese mono-institutional study. J Surg Oncol 2011;103:700-703.

    • Search Google Scholar
    • Export Citation
  • 3

    Lindor NM, McMaster ML, Lindor CJ, Greene MH. Concise handbook of familial cancer susceptibility syndromes - second edition. J Natl Cancer Inst 2008;38(Suppl):1-93.

    • Search Google Scholar
    • Export Citation
  • 4

    National Cancer Institute. Breast Cancer Risk Assessment Tool. 2011 Available at http://www.cancer.gov/bcrisktool/. Accessed December 7, 2011.

    • Search Google Scholar
    • Export Citation
  • 5

    Burt RW, Barthel JS, Cannon J. NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening. Version 2, 2011. Available at http://www.nccn.org/professionals/physician_ gls/pdf/colorectal_screening.pdf. Accessed December 7, 2011.

    • Search Google Scholar
    • Export Citation
  • 6

    Dong C, Hemminki K. Modification of cancer risks in offspring by sibling and parental cancers from 2,112,616 nuclear families. Int J Cancer 2001;92:144-150.

    • Search Google Scholar
    • Export Citation
  • 7

    Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH. Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst 1994;86:1600-1608.

    • Search Google Scholar
    • Export Citation
  • 8

    Risch N. The genetic epidemiology of cancer: interpreting family and twin studies and their implications for molecular genetic approaches. Cancer Epidemiol Biomarkers Prev 2001;10:733-741.

    • Search Google Scholar
    • Export Citation
  • 9

    Hemminki K, Czene K. Attributable risks of familial cancer from the Family-Cancer Database. Cancer Epidemiol Biomarkers Prev 2002;11:1638-1644.

    • Search Google Scholar
    • Export Citation
  • 10

    Kerber RA, O'Brien E. A cohort study of cancer risk in relation to family histories of cancer in the Utah population database. Cancer 2005;103:1906-1915.

    • Search Google Scholar
    • Export Citation
  • 11

    Daly MB, Allen J, Axilbund JE. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1, 2011. Available at http://www. nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed December 7, 2011.

    • Search Google Scholar
    • Export Citation
  • 12

    Bevers TB, Armstrong DK, Arun BK. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer Risk Reduction. Version 3, 2011. Available at http://www.nccn.org/professionals/physician_gls/pdf/breast_risk.pdf. Accessed December 7, 2011.

    • Search Google Scholar
    • Export Citation
  • 13

    Ford D, Easton DF, Bishop DT. Risks of cancer in BRCA1- mutation carriers: Breast Cancer Linkage Consortium. Lancet 1994;343:692-695.

  • 14

    Antoniou A, Pharoah PD, Narod S. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003;72:1117-1130.

    • Search Google Scholar
    • Export Citation
  • 15

    Antoniou AC, Wang X, Fredericksen ZS. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet 2010;42:885-892.

    • Search Google Scholar
    • Export Citation
  • 16

    Milne RL, Osorio A, Ramon y Cajal T. Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 2010;119:221-232.

    • Search Google Scholar
    • Export Citation
  • 17

    Domchek SM, Friebel TM, Singer CF. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010;304:967-975.

    • Search Google Scholar
    • Export Citation
  • 18

    Thompson D, Duedal S, Kirner J. Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 2005;97:813-822.

  • 19

    Brose MS, Rebbeck TR, Calzone KA. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 2002;94:1365-1372.

    • Search Google Scholar
    • Export Citation
  • 20

    di Masi A, Antoccia A. NBS1 heterozygosity and cancer risk. Curr Genomics 2008;9:275-281.

  • 21

    Guilford P, Hopkins J, Harraway J. E-cadherin germline mutations in familial gastric cancer. Nature 1998;392:402-405.

  • 22

    Cisco RM, Ford JM, Norton JA. Hereditary diffuse gastric cancer: implications of genetic testing for screening and prophylactic surgery. Cancer 2008;113(7 Suppl):1850-1856.

    • Search Google Scholar
    • Export Citation
  • 23

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

    • Search Google Scholar
    • Export Citation
  • 24

    Suriano G, Oliveira C, Ferreira P. Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands. Hum Mol Genet 2003;12:575-582.

    • Search Google Scholar
    • Export Citation
  • 25

    Kaurah P, MacMillan A, Boyd N. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 2007;297:2360-2372.

    • Search Google Scholar
    • Export Citation

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Correspondence: Tina E. Wood, MD, University of Alabama at Birmingham, North Pavillion, 1530 Third Avenue South, Birmingham, AL 35294. E-mail: tina.wood@ccc.uab.edu
  • View in gallery

    Gastric biopsies. (A) Low-power magnification (hematoxylin-eosin, original magnification ×4) of the gastric biopsy specimen. The histologic findings are consistent with poorly differentiated adenocarcinoma with signet-ring cell features. (B) High-power magnification (hematoxylin-eosin, original magnification ×40) of the gastric biopsy specimen. (C) Immunohistochemistry for cytokeratin 7 (×4); the neoplastic cells were strongly positive for cytokeratin 7. (D) Immunohistochemistry for cytokeratin 7; higher magnification (×40) shows the sheets of discohesive cells with abundant vacuolated cytoplasm and eccentrically placed nuclei.

  • View in gallery

    Breast biopsies. (A) Low-power magnification (hematoxylin-eosin, original magnification ×4) of the breast biopsy specimen consistent with infiltrating mammary carcinoma with predominately lobular features. (B) High-power magnification (hematoxylin-eosin, original magnification ×40) of the breast biopsy at the site of invasive growth. (C) Lobular carcinoma in situ (hematoxylin-eosin, original magnification ×40). (D) Immunohistochemistry for estrogen receptors (×40). Cancer cells stained strongly positive for estrogen (shown) and progesterone receptors. Her2 was not amplified.

  • 1

    Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol 2005;23:276-292.

  • 2

    Jiang CG, Wang ZN, Sun Z. Clinicopathologic characteristics and prognosis of signet ring cell carcinoma of the stomach: results from a Chinese mono-institutional study. J Surg Oncol 2011;103:700-703.

    • Search Google Scholar
    • Export Citation
  • 3

    Lindor NM, McMaster ML, Lindor CJ, Greene MH. Concise handbook of familial cancer susceptibility syndromes - second edition. J Natl Cancer Inst 2008;38(Suppl):1-93.

    • Search Google Scholar
    • Export Citation
  • 4

    National Cancer Institute. Breast Cancer Risk Assessment Tool. 2011 Available at http://www.cancer.gov/bcrisktool/. Accessed December 7, 2011.

    • Search Google Scholar
    • Export Citation
  • 5

    Burt RW, Barthel JS, Cannon J. NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening. Version 2, 2011. Available at http://www.nccn.org/professionals/physician_ gls/pdf/colorectal_screening.pdf. Accessed December 7, 2011.

    • Search Google Scholar
    • Export Citation
  • 6

    Dong C, Hemminki K. Modification of cancer risks in offspring by sibling and parental cancers from 2,112,616 nuclear families. Int J Cancer 2001;92:144-150.

    • Search Google Scholar
    • Export Citation
  • 7

    Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH. Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst 1994;86:1600-1608.

    • Search Google Scholar
    • Export Citation
  • 8

    Risch N. The genetic epidemiology of cancer: interpreting family and twin studies and their implications for molecular genetic approaches. Cancer Epidemiol Biomarkers Prev 2001;10:733-741.

    • Search Google Scholar
    • Export Citation
  • 9

    Hemminki K, Czene K. Attributable risks of familial cancer from the Family-Cancer Database. Cancer Epidemiol Biomarkers Prev 2002;11:1638-1644.

    • Search Google Scholar
    • Export Citation
  • 10

    Kerber RA, O'Brien E. A cohort study of cancer risk in relation to family histories of cancer in the Utah population database. Cancer 2005;103:1906-1915.

    • Search Google Scholar
    • Export Citation
  • 11

    Daly MB, Allen J, Axilbund JE. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1, 2011. Available at http://www. nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed December 7, 2011.

    • Search Google Scholar
    • Export Citation
  • 12

    Bevers TB, Armstrong DK, Arun BK. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer Risk Reduction. Version 3, 2011. Available at http://www.nccn.org/professionals/physician_gls/pdf/breast_risk.pdf. Accessed December 7, 2011.

    • Search Google Scholar
    • Export Citation
  • 13

    Ford D, Easton DF, Bishop DT. Risks of cancer in BRCA1- mutation carriers: Breast Cancer Linkage Consortium. Lancet 1994;343:692-695.

  • 14

    Antoniou A, Pharoah PD, Narod S. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003;72:1117-1130.

    • Search Google Scholar
    • Export Citation
  • 15

    Antoniou AC, Wang X, Fredericksen ZS. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet 2010;42:885-892.

    • Search Google Scholar
    • Export Citation
  • 16

    Milne RL, Osorio A, Ramon y Cajal T. Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 2010;119:221-232.

    • Search Google Scholar
    • Export Citation
  • 17

    Domchek SM, Friebel TM, Singer CF. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010;304:967-975.

    • Search Google Scholar
    • Export Citation
  • 18

    Thompson D, Duedal S, Kirner J. Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 2005;97:813-822.

  • 19

    Brose MS, Rebbeck TR, Calzone KA. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 2002;94:1365-1372.

    • Search Google Scholar
    • Export Citation
  • 20

    di Masi A, Antoccia A. NBS1 heterozygosity and cancer risk. Curr Genomics 2008;9:275-281.

  • 21

    Guilford P, Hopkins J, Harraway J. E-cadherin germline mutations in familial gastric cancer. Nature 1998;392:402-405.

  • 22

    Cisco RM, Ford JM, Norton JA. Hereditary diffuse gastric cancer: implications of genetic testing for screening and prophylactic surgery. Cancer 2008;113(7 Suppl):1850-1856.

    • Search Google Scholar
    • Export Citation
  • 23

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

    • Search Google Scholar
    • Export Citation
  • 24

    Suriano G, Oliveira C, Ferreira P. Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands. Hum Mol Genet 2003;12:575-582.

    • Search Google Scholar
    • Export Citation
  • 25

    Kaurah P, MacMillan A, Boyd N. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 2007;297:2360-2372.

    • Search Google Scholar
    • Export Citation
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