Teresa is a 45-year-old female recently diagnosed with lobular breast cancer. She has 1 brother, aged 42 years, and 3 children, a 14-yearold son, a 12-year-old daughter, and a 10-year-old daughter. Her father is 65 years of age and has 2 sisters, aged 55 and 62, both of whom have children, and none are reported to have cancer. Her paternal grandparents died in their 80s, and the stated cause was “old age.” Teresa’s mother was reported to have had breast cancer in her late 40s and died from an “abdominal cancer” in her 50s. She had zero siblings. Teresa’s maternal grandmother died in her 60s, cause unknown, and her maternal grandfather died at age 79 in a car accident. He had a sister who died from “abdominal cancer” in her 60s. Ethnic background is reported to be a mix of Irish and English and consanguinity is denied. To Teresa’s knowledge, nobody has undergone risk-reducing procedures or had colonic polyps. Should genetic consultation be considered? What else would you want to know?
The majority of breast cancers are sporadic and not inherited. However, up to 10% of breast cancer cases are associated with germline mutations in highly penetrant genes, including BRCA1, BRCA2, PTEN, TP53, CDH1, and STK11. Distinguishing among the different inherited breast cancer syndromes is important because each has its own cancer risks. Thus, medical management for the patient and his or her at-risk family members varies significantly based on the syndrome. According to NCCN Guidelines, referral to a cancer genetics professional is recommended for breast cancer survivors if any of the following criteria are met1:
- Early-age–onset breast cancer
- Triple-negative breast cancer
- Two breast cancer primaries in a single individual
Breast cancer at any age, and
- At least 1 close blood relative with breast cancer at age 50 or younger, or
- At least 1 close blood relative with epithelial ovarian cancer at any age, or
- At least 2 close blood relatives with breast cancer and/or pancreatic cancer at any age
- From a population at increased risk
- A combination of breast cancer with 1 or more of the following: thyroid cancer, sarcoma, adrenocortical carcinoma, endometrial cancer, pancreatic cancer, brain tumors, diffuse gastric cancer, dermatologic manifestations and/or macrocephaly, or leukemia/lymphoma on the same side of family (especially if early onset)
- Ovarian cancer
- Male breast cancer
Knowledge Applied to Teresa
Teresa’s personal and family history warrants further evaluation for a genetic syndrome. She was diagnosed with breast cancer at a young age. Additionally, she has multiple family members diagnosed with cancer, including her mother who was reported to have had both breast cancer and an “abdominal or stomach cancer.” Earlyonset cancer, multiple primary cancers, and multiple generations affected with cancer are features of hereditary cancer syndromes. You inquire if Teresa has seen a genetics professional. She states she cancelled a scheduled appointment because she had a negative result on a “BRACA test” performed by her primary care physician. You encourage Teresa to meet with a genetics professional, explaining that there are other cancer syndromes associated with breast cancer. You also encourage her to bring in a copy of her test results and to contact family members to obtain additional family history information.
Based on Teresa’s reported personal and family history, the most likely syndromes would be hereditary breast and ovarian cancer (HBOC) or hereditary diffuse gastric cancer (HDGC). HBOC is associated with mutations in the BRCA1/2 genes, while HDGC is associated with alterations in the CDH1 gene. Medical management differs significantly, as mutations in BRCA1/2 place a woman at high risk for breast and ovarian cancer as well as several other cancers. Mutations in the CDH1 gene place an individual at increased risk primarily for breast and gastric cancer.
Accurate family history information is essential in cancer risk assessment. When a cancer is reported using a generic term, such as abdominal, it is important to encourage the patient to obtain more information. Teresa contacted family members prior to her appointment but stated she was unable to learn additional information. If family members are unsure of the type of cancer deceased individuals experienced, sometimes the death certificate will have additional information. Medical records may be available if appropriate releases and documents are presented (state laws vary on who has the right to access or authorize release of records after death). Additional information was not available for Teresa’s maternal great-aunt. However, with the assistance of her father and a genetics professional, some medical records were obtained for her mother. Per these records, her mother was diagnosed with diffuse gastric cancer at age 54, but pathology reports were not available for her mother’s breast cancer.
Additionally, a copy of her previous genetic testing was obtained, and she underwent sequencing of BRCA1 and BRCA2 with a 5-site rearrangement panel for BRCA1. All was negative. Given Teresa’s diagnosis of lobular breast cancer, her mother’s diagnosis of breast cancer and diffuse gastric cancer, and her maternal great-aunt’s diagnosis of “abdominal cancer,” an alteration in CDH1 is more likely than an alteration in BRCA1/2 detected by BART (BRACAnalysis Rearrangement Test). Ultimately, Teresa undergoes analysis of the CDH1 gene and is found to have a mutation.
Hereditary Diffuse Gastric Cancer
There are 2 main categories of gastric cancer: intestinal and diffuse. The intestinal type is more common in the general population and more likely to be sporadic, while the diffuse type is less common and more likely to have inherited factors.2 It is estimated that 2% to 8% of gastric cancer is due to an inherited cancer syndrome, such as HDGC. CDH1 is the only gene known to be associated with HDGC. The typical pathology of HDGC is a poorly differentiated adenocarcinoma that infiltrates into the stomach wall causing thickening of the wall (linitis plastica) without forming a distinct mass. It is also called signet ring carcinoma due to the signet ring appearance of malignant cells.
In 1999, HDGC was defined as occurring in a family with either (1) two or more documented cases of diffuse gastric cancer in first- or second-degree relatives, with at least one diagnosed before the age of 50 years, or (2) three or more cases of documented diffuse gastric cancer in first- or second-degree relatives, independent of age of onset. Only about one-fourth of families meeting these criteria have a CDH1 mutation.3 The International Gastric Cancer Linkage Consortium broadened the above-stated clinical criteria as indications for genetic testing if any of the following were met4: (1) two gastric cancer cases in a family, one confirmed DGC before age 50 years; (2) three confirmed DGC cases in first or second-degree relatives independent of age; (3) simplex case (ie, a single occurrence in a family) of DGC occurring before age 40 years; and (4) personal or family history of DGC and lobular breast cancer, one diagnosed before age 50 years. Of importance, most criteria are tailored to individuals of low geographic risk for gastric cancer and may be too broad for individuals in high-risk areas, such as East Asia, Eastern Europe, and parts of Central and South America.5 It is likely criteria will continue to evolve as more individuals are found to have CDH1 mutations.
The estimated lifetime risk for gastric cancer by age 80 years is 67% for men and 83% for women.6 The average age of onset of hereditary diffuse gastric cancer is 38 years, with a range of 14 to 69 years. More recent data suggest at least an 80% risk for both men and women. Women also have up to a 39% risk for developing breast cancer, primarily of the lobular type.6 Colorectal cancer may also be associated. As at least half of the individuals with a clinical diagnosis of HDGC do not have a CDH1 mutation, it is likely other genes play a role in HDGC or there are unidentified mutations present in CDH1.7 HDGC is inherited in an autosomal dominant fashion. Thus, offspring of carriers have a 50% chance of also carrying the mutation. Typically, testing does not begin until at least age 18 years unless the family history has early-onset cancers suggesting medical management is needed prior to age 18.
Clinical diagnosis of gastric cancer is difficult in the early stages of the disease because the symptoms are nonspecific. Symptoms do not manifest until the disease is either locally advanced or metastatic. To date, there is no good screening for diffuse gastric cancer and prophylactic total gastrectomy is indicated for mutation carriers. For individuals not electing prophylactic gastrectomy, annual endoscopy with multiple biopsies is a surveillance option. However, as the malignant cells infiltrate and spread under normal-looking mucosa, they are virtually invisible and multiple biopsies must be performed. Furthermore, analysis of gastrectomy specimens suggests that the majority of mutation carriers have microscopic foci of signet ring cells, and approximately 30% of CDH1 carriers do not develop metastases.2 At this time, the natural history of DGC is not well understood, making it extremely difficult to determine at what point an individual on a surveillance program should proceed with prophylactic gastrectomy.
Management is more challenging in families meeting clinical criteria but not having an identifiable CDH1 mutation or in families with a CDH1 variant of uncertain significance. For these individuals, annual endoscopy with multiple biopsies is a screening option. All at-risk individuals electing endoscopy should be aware that multiple random biopsies may not detect cancer early. Additionally, management of HDGC should include input from a multidisciplinary team consisting of individuals with expertise in gastric surgery, gastroenterology, pathology, and nutrition.4 Surveillance and screening for lobular breast cancer should include annual mammogram and breast MRI beginning at age 35 unless suggested earlier by family history. Risk-reducing bilateral mastectomy is also an option.
- Pathology of cancer—including breast cancer—can be important when determining a genetic testing strategy
- Cancer reported as “abdominal” by patients and family members could be one of a variety of primary cancers (including ovarian, stomach, and colon) and should be factored into risk assessment
- If a patient reports a negative BRCA test result but extensive personal and family history is present, consider referral to an expert in cancer genetics
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2012. http://www.nccn.org/professionals/physician_ gls/pdf/genetics_screening.pdf. Accessed May 22, 2012.
- Lynch H, Lynch J, Shaw T. Hereditary gastrointestinal cancer syndromes. Gastrointest Cancer Res. 2011;4(supp 1):S9-S17.
- Caldas C, Carneiro F, Lynch HT, et al. Familial gastric cancer: overview and guidelines for management. J Med Genet. 1999;36:873-880.
- Fitzgerald RC, Hardwick R, Huntsman D, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010;47:436-444.
- Corso G, Marrelli D, Pascale V, et al. Frequency of CDH1 germline mutations in gastric carcinoma coming from high- and low-risk areas: metanalysis and systematic review of the literature. BMC Cancer. 2012;12:8.
- Pharoah PD, Guilford P, Caldas C. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology. 2001;121:1348-1353.
- Kaurah P, MacMillan A, Boyd N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007;297:2360-2372.