—  SYMPOSIUM #55  —

New Frontiers in Breast Pathology
Moderator: Dr. Sunil Lakhani

Section 6 - Familial Susceptibility to Breast and GI Cancers: New Links

David Huntsman


A. Lobular Breast Cancer and Diffuse Gastric Cancer: loss of E-cadherin
In 1998, three different Maori families from New Zealand with hereditary diffuse gastric cancer (HDGC) were found to have germline mutations in the E-cadherin gene (CDH1) [1]. This was subsequently confirmed in families from different geographic backgrounds [2]. Since then we have found germline mutations in CDH1 in greater than 40% of families with at least two cases of gastric cancer with at least one diagnosed as diffuse gastric cancer before the age of 50 [3]. The lifetime risk of developing gastric cancer for CDH1 mutation carriers is greater than 70% [4]. E-cadherin acts as a tumour suppressor in these families; loss of expression of the wildtype allele or loss of heterozygosity is typically attributed to promoter hypermethylation. In normal epithelial cells E-cadherin is able to mediate cell-cell adhesion and knits together epithelial cells, playing a significant role in epithelial cell architecture and prevention of cell invasion.

Lobular breast cancer accounts for 10% to 15% of all breast cancers and its incidence is increased among HDGC kindreds. It should not be surprising that a linkage has been identified between lobular carcinoma of the breast and HDGC, given the known heterogeneity of hereditary forms of carcinoma of the breast. Indeed, the first family with multiple generations of carcinoma of the breast segregating in a pattern consonant with an autosomal dominant mode of genetic transmission was described by Paul Broca, the famous French surgeon, in the French literature [5]. His study of his wife's family was initiated when his wife developed breast cancer. Broca had the wisdom in those pre-Mendelian times to call attention to the combination of breast and gastrointestinal tract cancer in this family, which was transmitted through four generations (Figure 1). We believe that lobular carcinoma of the breast in concert with HDGC should be a new entry into the growing plethora of breast cancer prone syndromes which clearly reflect its profound genotypic and phenotypic heterogeneity (Figure 2).

Lobular breast cancers are characterized by infiltrative cancer cells which are isolated and dispersed in rich stromal tissue [6] and its pathologic appearance is remarkably similar to diffuse gastric cancer. The incidence of lobular breast carcinomas is increased in HDGC kindreds with germline CDH1 mutations This is not unexpected as loss of E-cadherin expression is a key feature of both lobular breast and diffuse gastric cancers and CDH1 somatic mutations are found in lobular breast cancer but not infiltrating ductal carcinoma [7]. Loss of E-cadherin expression likely contributes to the histopatholgic appearance of both lobular breast cancers and diffuse gastric cancers and it has been shown that 50% of these cancers have mutations in the CDH1 gene that is not found in non-cancerous tissue from the same patients [7, 8]. There is an additional association between germline CDH1 mutations and lobular breast cancer [2, 3, 9]. Female CDH1 mutation carriers have a 40% risk of developing breast cancer [4]. When pathology was available, these cases were shown to be lobular breast cancers. Clustering of lobular breast cancers with HDGC families has led to the misclassification of families as breast cancer kindreds who test negative for BRCA1/2 mutations. We have also found germline CDH1 mutations in pure breast cancer families with confirmed lobular breast cancer cases. We conclude that lobular breast cancer should be considered part of the HDGC syndrome and patients diagnosed with lobular breast cancer, especially at younger ages, should trigger requests for gastric cancer family history.

B. Autosomal Dominant Hereditary Colon Cancer

I. Lynch Syndrome (Hereditary Nonpolyposis Colon Cancer (HNPCC))
Lynch syndrome or HNPCC is the most prevalent of the autosomal dominant cancer susceptibility syndromes. This disease confers increased risk for colon cancer with a lesser penetrance for other cancers such as endometrium, stomach, ovary, pancreas, small bowel biliary tract, and the ureteric tract [10]. Lynch syndrome is caused by mutations in one of five mismatch repair genes (hMSH2, hMLH1, hMSH6, hPMS1, hPMS2) though approximately 10% to 30% of patients who meet strict clinical criteria for Lynch syndrome have no detectable mutations in these genes. Penetrance is 85% to 90% for colorectal cancers [11]. Muir-Torre syndrome is an HNPCC variant typified by HNPCC associated cancers and sebaceous adenomas.

Breast cancer is not an integral tumour in Lynch syndrome as the evidence for germline mutations in any of the mismatch repairs in breast cancer patients is weak. However, mutations in hMLH1 gene were found to segregate with breast cancer within a large HNPCC kindred and these breast cancers exhibited microsatellite instability which is a characteristic of mutations in the mismatch repair genes [12]. Also, a case of an hMSH2 mutation carrier with breast cancer who demonstrated loss of the hMSH2 wildtype allele along with microsatellite instability in breast tumour tissue has been, suggesting that loss of the hMSH2 gene may be an event associated with breast tumorigenesis [13]. However, Scott et al. have shown that breast cancer is not significantly overrepresented in HNPCC families with hMSH2 mutations though there appeared to be a slight increased incidence of this disease in hMLH1 mutation carriers [14].

Although breast cancer is not a major part of Lynch syndrome, the mismatch repair genes are often inactivated in breast tumours and reports of somatic abnormalities in the mismatch repair genes in breast cancers. Comparison of transcript levels for these genes between breast epithelial and breast tumour derived cells demonstrated decreased mRNA levels for hPMS2, hMSH2, and hMSH6 in the tumour derived cell lines [15]. Analysis of primary invasive breast cancers has demonstrated that 25% of tumours were immunonegative for MSH2 staining and this correlated with increased expression of p53 and p185 (an epidermal growth factor receptor) [16]. While there is little agreement on whether mutations in the HNPCC associated mismatch repair genes confer an increased risk for breast cancer, it seems that when there are breast cancer cases in HNPCC families, they occur at a very early age suggesting that these mutations accelerate breast tumour formation [17]. This may occur due to accumulation of mutations in genes involved in breast cancer progression that occur due to mutations in the mismatch repair genes. There have been other suggestions from studies examining individuals with both colorectal and breast cancers that HNPCC associated mutations increase the risk specifically for colorectal cancer while additional mutations in the CHEK2 gene are responsible for the breast cancer predisposition [18, 19].

II. Familial Adenomatous Polyposis (FAP)
Familial adenomatous polyposis (FAP) although rare is perhaps the best known of the hereditary colon cancer syndromes [20]. FAP is caused by germline mutations in the adenomatous polyposis coli (APC)gene, typically in the first third of the gene and mutations in this gene are found in 60-80% of classical FAP patients and 10-30% of attenuated FAP patients. APC is an integral component of the Wnt signalling pathway and associates with alpha- and beta-catenin, directing the degradation of beta-catenin. Its involvement with the catenins suggests that APC may be involved in cell adhesion. Both alpha and beta-catenin bind to E-cadherin, the susceptibility gene associated with HDGC and increased lobular breast cancer risk.

As is the case with HNPCC, there does not appear to be an increased risk of breast cancer for patients with APC mutations. However, promoter hypermethylation in the APC gene was observed in 28% of breast tumours but only in 10% of benign breast tissue, though this difference was not statistically significant [21]. Other studies have reported that 47% to 49% of primary breast tumours had promoter hypermethylation at the APC locus [22, 23]. In a series of lobular breast carcinomas, APC promoter hypermethylation was found in 52% of cases and loss of heterozygosity was found in 23% of cases [24].

FAP and Lynch syndromes are part of a family of inherited gastrointestinal polyposis syndromes. These syndromes are characterized by either adenomatous or hamartomatous polyps and localized cell overgrowth. Inherited hamartomatous syndromes occur at 1/10 the frequency of adenomatous syndromes and account for less than 1% of colorectal cancers in North America [25, 26, 27]. Included amongst inherited hamartomatous syndromes, are Cowden's disease and Peutz-Jegher syndrome.

Hamartomatous Polyposis Syndromes

(i) Cowden's Disease
The incidence of Cowden's disease is 1 in 200,000 and the majority of patients with Cowden's disease (80%) have germline mutations in the tumour suppressor gene, PTEN (phosphatise and tensin homolog) [28]. The Bannayan-Ruvalcaba-Riley syndrome shares clinical symptoms with Cowden's disease and 60% of these patients have germline PTEN mutations [29]; this suggests that these two diseases may be allelic or possibly the same syndrome.

Cowden syndrome usually presents in the third decade and clinical manifestations of this disease include lesions of the skin, mucous membranes, breast, and thyroid and hamartomatous polyps of the colon and intestine. Breast cancer is the most serious complication of this disease and affects 36% of patients and thyroid cancer affects an additional 10% [30]. It is unclear whether patients with this disease have an increased risk for intestinal cancers [31, 32]. In general, the gastrointestinal polyps occurring as a result of this disease are benign, however there has been at least one documented case of gastric carcinoma in situ in a patient with Cowden's disease [33]

(ii) Peutz-Jeghers Syndrome
The incidence of Peutz-Jeghers syndrome is 1 in 200,000 and penetrance is variable even within single families [20]. This disease is characterized by germline mutations in the gene that encodes the serine/threonine kinase STK 11 located on chromosome 19 [34, 35]. Polyps are prevalent in the small intestine and occasionally stomach and large bowel. This disease is associated with an increased risk for both intestinal malignancies and non-intestinal malignancies including breast cancers. The overall incidence of malignancy is though to be 20-50% and the lifetime risk for cancer for patients with Peutz-Jeghers syndrome is 93% [36]. Gastrointestinal malignancies are the definitive malignancies in this syndrome, though this occurs at a lower rate than what is observed in either FAP or HNPCC. The relative risks compared to unaffected individuals for gastric and breast cancers were reported in one study to be 213 and 15 respectively [37]. However, a more recent study has reported the relative risks for breast and gynaecological cancer to be 20.3 and 50.3 for gastrointestinal cancers [38].

C. Autosomal Recessive Hereditary Colon Cancer

I. MYH Associated Polyposis (MAP)
The clinical symptoms of MYH associated polyposis (MAP) are similar to FAP and it is estimated that mutations in the MYH gene account for approximately 10% of classical FAP and 20 to 25% of attenuated FAP in subjects who do not carry mutations in the APC gene. This is an autosomal recessive diseases and affected individuals are either homozygous are compound heterozygous for mutations in the MYH gene. The MYH protein is a base excision repair glycolase involved in the repair of DNA damage caused by the oxidation of guanine leading to 8-oxo-guanine. During replication, MYH excises adenine mispaired to 8-oxo-guanine; when this protein is absent or dysfunctional, G:C to T:A mutations commonly occur in genes such as APC and KRAS [39, 40]. Symptoms included multiple adenomatous polyps and colorectal cancer. Approximately half of MAP patients get colorectal cancer or occasionally extracolonic manifestations, such as duodenal, adenomas, osteomas, congenital hypertrophy of the retinal pigment epithelium, and dental cysts. A study screening 170 patients with polyps but lacking APC or mismatch repair gene mutations found 23% (40) had MYH germline mutations; 22 of these were female and 4 (18%) of these were diagnosed with breast cancer between the ages of 49 and 76 [41]. This suggests that breast cancer is a risk factor in MAP. The management of both colorectal and breast cancer risk is still evolving for this syndrome.

D. Familial Pancreatic Cancer
Hereditary pancreatitis is an autosomal dominant syndrome with a penetrance of approximately 80%. Defects in the PRSS1 (cationic trypsinogen) gene increase the risk of pancreatic cancer up to 20 times. In addition, mutations in the p16 tumour suppressor gene (familial atypical multiple mole melanoma syndrome), STK11 (Peutz-Jegher syndrome), BRCA2 (hereditary breast cancer), and mismatch repair genes (HNPCC) are all associated with an increased risk for pancreatic cancer [42]. A study evaluating 41 pancreatic adenocarcinomas showed that 15 demonstrated loss of heterozygosity at BRCA2 and 4 had BRCA2 mutations [43].

E. Familial Breast Cancer Susceptibility Genes

I. BRCA1
In addition to the well documented increased risk for breast and ovarian cancers, BRCA1 mutation carriers may also be at greater risk for developing cancers of the pancreas and colon. The BRCA1 gene is located on chromosome 17 (17q21). BRCA1 is a tumour suppressor gene and its protein product interacts with numerous molecules including tumour suppressors, oncogenes, DNA damage repair proteins, cell cycle regulators, and transcriptional regulators. Loss of BRCA1 function leads to growth retardation, increased apoptosis, defective DNA damage repair, abnormal centrosome duplication, defective G2/M cell cycle checkpoint, impaired spindle checkpoint, and chromosome damage and aneuploidy. It is thought that BRCA1 mutations do not lead directly to tumour formation but instead cause genetic instability, subjecting cells to a high risk of malignant transformation [44].

The estimated cumulative risk for developing breast or ovarian cancers before the age of 70 for BRCA1 mutation carriers is 73%-87% and 41%-44% respectively [45, 46]. For male carriers of this mutation, prostate cancer is the most consistently reported site of cancer susceptibility [47]. In addition, it has been reported that BRCA1 mutation carriers are at increased risk for colon and pancreatic cancer, though this is not consistently observed. The relative risks for pancreatic cancer has been found to be between 2.3 and 3 [45, 48] and for colon cancer to be between 2 and 4.1 [45, 46]. A 4 times increased risk for stomach cancer has also been observed in a single study [45].

II. BRCA2
The BRCA2 familial breast cancer susceptibility gene is located on chromosome 13 (13q12-q13). The BRCA2 tumour suppressor plays an important role in the repair of DNA damage by homologous recombination and a major cellular function of BRCA2 is to regulate the Rad51 recombinase which catalyzes the initial strand invasion reaction in homologous recombination.

The cumulative risk associated with mutations in this gene for breast cancer in female carriers is approximately 60% by the age of 50 and 80% by the age of 70. Male carriers also have a 6% risk of developing breast cancer by the age of 70. Mutations in this gene also confer an increased risk for ovarian cancer (relative risk 17.7) and there is also a significant increase of laryngeal cancer (relative risk 7.7), and prostate cancer (relative risk 2.9).

There have been several reports that have reported an increased risk for stomach cancer for BRCA2 families. A study of 173 BRCA2 families found that the relative risk for stomach cancer was 2.6 and BRCA2 mutations were found to be associated with family aggregations of both breast and stomach cancers [49, 50]. The BRCA2 mutations 617delT frequency among an Ashkenazi Jewish population of stomach cancer patients was found to be five times higher than what is observed in the general population [51]. In addition, a study of relatives of BRCA2 mutation carriers demonstrated that the risk of colorectal cancer was increased 3-fold and found that ovarian, colorectal, stomach, pancreatic, and prostate cancers occurred among first degree relatives of BRCA2 mutations carriers only when the mutations were in the ovarian cancer cluster region of exon 11 [52]. There have also been reports of associations between BRCA2 and pancreatic cancers (see Familial Pancreatic Cancer).

III. CHK2 and p53
The p53 gene is found on chromosome 17 and the CHK2 gene in chromosome 22. CHK2 is a protein kinase involved in cell-cycle checkpoint. Its substrates include p53 and BRCA1. Serine 20 on p53 is phosphorylated by CHK2 which prevents p53 binding to Mdm2 and ubiquitination. Germline mutations in the p53 and CHK2 genes have been found in individuals with Li-Fraumeni syndrome and breast carcinomas are frequently found in families with this cancer susceptibility syndrome. Of the GI cancers, gastric carcinoma is often reported and germline p53 mutations have been found in gastric cancer families without CDH1 mutations [53-55]. However, a study of familial gastric cancer cases was unable to detect any CHK2 mutations [56].



Figure 1: Pedigree of family studied by Paul Broca [5] showing breast cancers and GI cancers through four generations.



Figure 2: Circle diagram/pie chart demonstrating relative incidence of sporadic breast cancer and breast cancer in various hereditary syndromes.

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