Genetic Testing in Gastrointestinal Tumors

Kristen M. Shannon¹ and Daniel C. Chung^1,2

¹Massachusetts General Hospital Cancer Center, Boston, MA, USA

²Harvard Medical School, Boston, MA, USA

Case study 125.1

A 76-year-old man undergoes hemicolectomy for colorectal adenocarcinoma. Immunohistochemistry (IHC) performed on his tumor demonstrates loss of MLH1 and PMS2 protein in the tumor sample. Genetic counseling reveals that he has no prior personal history of cancer and no family history of cancer.

1. What is the most likely reason for the absence of protein in the tumor?

MLH1 germline mutation
PMS2 germline mutation
Hypermethylation of the MLH1 gene promoter
BRAF mutation

IHC to detect loss of DNA mismatch repair (MMR) protein expression is used to screen for Lynch syndrome. Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited cancer syndrome characterized by early-onset colorectal cancer as well as endometrial, urinary tract, small bowel, ovarian, gastric, pancreatic, hepatobiliary, brain, and skin tumors. Individuals with germline mutations in one of the MMR genes (MLH1, MSH2, MSH6, PMS2, or EpCAM) are defined as having Lynch syndrome. Nearly all colon tumors in individuals with Lynch syndrome will exhibit loss of expression of one or more of these DNA MMR genes as well as DNA microsatellite instability (MSI). The correlation between abnormal MSI and IHC results is generally good. Loss of expression of MLH1 is almost always accompanied by loss of PMS2 expression. This specific pattern can indicate the presence of a germline mutation in the MLH1 gene but is also observed in approximately 15% of sporadic colorectal cancers due to nonheritable MLH1 promoter hypermethylation. Thus, when MLH1 and PMS2 are absent on IHC, MLH1 promoter methylation testing of the tumor sample helps to distinguish sporadic from hereditary tumors. In this case, the clinical phenotype of the patient is not suggestive of a diagnosis of Lynch syndrome (due to lack of family history of Lynch syndrome cancers and late age at diagnosis of cancer). Thus, it is more likely that his tumor is a sporadic tumor and that the loss of MLH1 protein is due to somatic MLH1 hypermethylation.

Case study 125.2

A 45-year-old man presents with five tubular adenomas on colonoscopy. His next colonoscopy 1 year later reveals an additional five tubular adenomas. He has no family history of cancer or polyps.

1. What genetic tests should be considered?

APC
MYH
MSH2, MLH1, MSH6, and PMS2
A + B
B + C
A + B + C

When a patient presents with multiple adenomas at a young age, one must consider the spectrum of inherited polyposis syndromes. The primary adenomatous polyposis syndromes are familial adenomatous polyposis (FAP), attenuated FAP (AFAP), or MYH-associated polyposis (MAP). FAP and AFAP are caused by mutations in the APC gene, and they are inherited in an autosomal dominant fashion. MYH-associated polyposis results from bi-allelic mutations in the MYH gene, and the syndrome is inherited in an autosomal recessive manner. If a patient with a suspected polyposis syndrome undergoes genetic testing and is not found to have an APC gene mutation, MYH gene testing should be performed to assess for MAP, as 10–20% of polyposis patients who do not have an APC gene mutation have bi-allelic MYH gene mutations. The clinical phenotype of MAP is often indistinguishable from FAP or AFAP. The typical polyp burden is usually 10–100 polyps, but sometimes more than 100 polyps can be seen. Family history often does not help to distinguish MAP from FAP. Consistent with the autosomal recessive inheritance pattern, there is often no family history of cancer in individuals with MAP. Of note, approximately 20–25% of individuals with FAP–AFAP have the disease as the result of a de novo (new) APC gene mutation and therefore do not have a family history of the disease. Because of the inability to rely on family history for cases such as these, genetic testing for APC and MYH is often performed concurrently.

Case study 125.3

A 35-year-old, nulliparous woman is diagnosed with a germline mutation in the MSH6 gene (Lynch syndrome).

1. What tumor is she most likely to develop in her lifetime?

Colon cancer
Endometrial cancer
Stomach cancer
Ovarian cancer

A germline mutation in any of the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, or EpCAM) establishes a diagnosis of Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC). Individuals with Lynch syndrome are typically counseled that they have a 50–80% lifetime risk of developing colon cancer. However, colon cancer risk estimates are gene dependent and are notably lower for MSH6 mutation carriers; the lifetime risk is estimated at 44% for males and 20% for females. Although MSH6 mutations are associated with a lower risk for colon cancer when compared to MLH1 or MSH2, female MSH6 carriers have a significantly increased (44%) risk for endometrial cancer. Thus, women with an MSH6 mutation are more likely to develop endometrial cancer than colon cancer. It is essential to recognize the spectrum of extracolonic tumors that are associated with Lynch syndrome.

Case study 125.4

A 40-year-old female is diagnosed with gastric cancer. Pathologic exam reveals signet ring cells (diffuse gastric cancer). Her family history is significant for a mother with breast cancer (lobular type) diagnosed at age 45 and a father with colon cancer at age 70.

1. What genetic test should be considered?

BRCA1/2
Lynch
CDH1
APC

Diffuse gastric cancers can occur in the setting of the hereditary diffuse gastric cancer (HDGC) syndrome, an autosomal dominant condition caused by an underlying germline mutation in the CDH1 (E-cadherin) gene. The lifetime risk of diffuse gastric cancer is estimated to be as high as 70%, and women have up to a 40% lifetime risk of lobular breast cancer. Prophylactic total gastrectomy is considered the standard of care, as microscopic foci of signet ring cancer cells are identified in over 90% of gene carriers. The age at which to perform gastrectomy is not standardized, but consideration should start in the early 20s. The median age of clinically detectable gastric cancer is 38 years. CDH1 testing identifies fewer than half of gene carriers who fulfill the following International Gastric Cancer Linkage Consortium (IGCLC) criteria: any family with two or more documented cases of diffuse gastric cancer in first- or second-degree relatives with one case under the age of 50, or three documented diffuse gastric cancers in first- or second-degree relatives at any age. In the absence of a positive CDH1 gene test, prophylactic gastrectomy is generally not recommended. Because conventional mammography may not be sensitive for lobular breast cancers, MRI or prophylactic mastectomy should be offered. Several other hereditary syndromes are associated with an increased risk for gastric cancer (Lynch, Li–Fraumeni, and Peutz–Jeghers), but the gastric cancers seen are typically intestinal-type cancers and not diffuse gastric cancers.

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125: Genetic Testing in Gastrointestinal Tumors

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