Genetic Counseling for Hereditary Cancer

Introduction

Genetic counseling should be an integral component of the management of hereditary cancer. This paper will provide an overview of genetic counseling in cancer using hereditary nonpolyposis colorectal cancer (HNPCC) as a prototype. Our purpose will be to describe an approach to genetic counseling that is in concert with the genetics, natural history, surveillance, and management of HNPCC.

Hereditary Nonpolyposis Colorectal Cancer

Hereditary colorectal cancers are exceedingly heterogeneous (Figure 1). Hereditary nonpolyposis colorectcal cancer, one subset of these disorders, is subdivided into Lynch syndromes I and II. Lynch syndrome I is characterized by early-onset (age, 40 years) colorectal cancer that shows a predilection (70%) for the proximal colon (ie, to the right of the splenic flexure) and has a high rate of metachronous colorectal carcinoma. (In patients who undergo less than a subtotal colectomy for the initial cancer, the rate of metachronous cancer is approximately 45% by age 40.) The Lynch syndrome II variant has all of the features of Lynch syndrome I, but in addition, includes a litany of extracolonic cancers. Foremost among these is endometrial carcinoma, followed by carcinoma of the ovary, small bowel, stomach, and pancreas, and transitional-cell carcinoma of the ureter and renal pelvis. The penetrance of the HNPCC genes is about 90% [1,2].

Although HNPCC is not a polyposis disorder, affected individuals do form colonic adenomas, and there is strong circumstantial evidence that these adenomas are precursor lesions to malignancy.

Histologic Features

The colorectal malignancies in HNPCC do not have unique histologic features, but some differences have been observed when large series of HNPCC and sporadic colon cancer cases have been compared. Most comparison studies indicate that HNPCC is more likely to produce poorly differentiated carcinoma, coupled with an excess of mucinous and signet-cell histologies. A small, but significant percentage (9%) [3] of colorec tal cancers in HNPCC form solid sheets of cells with an expanding growth pattern and a marked host lymphocytic response-a pattern that has been referred to as "medullary carcinoma" by Jessurun and Manivel [4]. This pattern is interesting because it is the usual histology of sporadic colon cancers with defective mismatch repair [5]. In turn, this immunologic response may be responsible for the improved prognosis noted in some HNPCC patients [6].

Molecular Genetics

Molecular genetic studies have identified germ-line mutations in an increasingly large number of hereditary cancer syndromes (Table 1). The genetic basis for HNPCC has been proved by genetic linkage between cancer occurrences and chromosome 2p in some families and chromosome 3p in other families [7,8].

Localization of a DNA mismatch repair gene in the critical region of chromosome 2p was documented by Leach et al [9] and Fishel et al [10] with the discovery of hMSH2 mutations in this gene in several HNPCC families. Subsequently, a second mismatch repair gene (hMLH1) was identified in the critical region of chromosome 3p, and mutations of that gene were found in the HNPCC families previously linked to chromosome 3p [11,12]. Mutations in these genes appear to account for 90% of all known HNPCC families [13]. Also, hPMS1 and hPMS2 have been demonstrated to be mismatch repair genes in HNPCC [14].

Defective DNA mismatch repair results in a steady accumulation of mutations. The mutation load can be detected as errors in long tandem repeat sequences, which produce microsatellite instability. A tumor with microsatellite instability is said to show replication error phenotype (RER+).

Interval Cancers

Vasen et al [15] followed a cohort of 51 HNPCC families that included 394 first-degree relatives who participated in a nationwide colonoscopy surveillance program. During mean follow-up of 5 years, these researchers observed an unexpectedly high rate of advanced colorectal cancers, which were diagnosed within 2 to 5 years after a negative colon screening examination. The shortest interval between a negative screening examination and the diagnosis of colorectal carcinoma was 2 to 3 years (six patients).

Our experience with interval cancers has been comparable. For example, a woman with Lynch syndrome II who had manifested endometrial carcinoma at age 36 years underwent colonoscopies every 2 years. Eighteen months after a normal colonoscopic evaluation, she was diagnosed with a Duke's B1 cancer of the transverse colon and underwent a segmental colonic resection. At that point, she insisted on having colonoscopies every 6 months. Five months after her most recent colonoscopy, she was found to have two primary colon cancers-a Duke's B1 tumor in the cecum and a Duke's A lesion in the lower rectum.

There are several possible explanations for these interval cancers: First, lesions may have been missed at the time of colonoscopy. Also, it is possible that the gene accelerates the progression of adenomas, even those that are very small, to cancer. The latter explanation is consonant with postulates of Jass et al [16] who suggested that adenomas in HNPCC are more likely to show a villous growth pattern with a high degree of dysplasia than are adenomas in a necropsy series, and that these features cause the HNPCC adenomas to undergo more rapid malignant transformation. The hypothesized rapid progression of the adenoma-carcinoma sequence in HNPCC, which may be as short as 2 to 3 years, is in striking contrast to findings from the National Polyp Study, which found that the adenoma-carcinoma sequence in the general population is about 8 to 10 years.

Another potential explanation for interval cancers in HNPCC is that gene carriers develop "de novo" cancers [17,18].

Adenomas and Accelerated Carcinogenesis

As mentioned above, strong circumstantial evidence suggests that adenomas are precursor lesions to malignancy in patients with HNPCC [19-21]. Leach et al [9], however, found that the HNPCC genes do not initiate adenoma development, but rather accelerate adenoma evolution. In turn, Cannon-Albright et al [22] have shown that genetic factors are responsible for proneness to develop adenomas.

It is hypothesized that when adenomas do occur in patients with HNPCC, they are more likely to progress to carcinoma than are adenomas in the general population. In theory, the "mutator phenotype" of HNPCC could drive the promotion of adenoma to carcinoma, once the neoplastic process has been initiated. The existence of "aggressive adenomas" in HNPCC is supported by prospective surveillance studies showing a much lower adenoma-to-carcinoma ratio than in the general population. Jarvinen et al [23], for example, found 22 adenomas and 5 cancers in HNPCC families over a 3-year period. In the Netherlands, 14 adenomas and 6 cancers were discovered in a screening program of HNPCC kindreds [24], and Jass et al [25] in New Zealand found 25 adenomas and 2 cancers. In contrast, data from the National Polyp Study suggest that 41 to 119 polypectomies are required to prevent 1 colorectal cancer in the general population [17,18].

Surveillance and Management Guidelines

Knowledge of the natural history and molecular genetics of HNPCC has been useful in developing the following guidelines for surveillance (Table 2) and management of high-risk patients:

Genetic Counseling is initiated at age 20 years.

Full Colonoscopy--We recommend that these patients undergo full colonoscopy beginning sometime between age 20 and 25 (flexible sigmoidoscopy is not adequate). Colonoscopy is repeated every 2 years to age 35 and annually thereafter. If colonoscopy expertise is unavailable, double air-contrast barium enema can be used instead.

Endometrial Curettage should be done yearly, beginning at age 30 years.

Ovarian Screening--Transvaginal ultrasound, Doppler color blood flow imaging, and CA 125 determinations are all initiated at age 30 years and are repeated annually thereafter.

Patients Who Develop Colorectal Cancer--If colorectal cancer occurs, surgical resection must be no less than a subtotal colectomy because the entire colonic mucosa is at risk for malignant transformation. Women who have completed their families at the time they manifest colorectal cancer are given the option of undergoing a prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy at the time of their subtotal colectomy.

Prophylactic Surgery--Individuals who have germ-line mutations (hMSH2, hMLH1, hPMS1, hPMS2) are given the option of prophylactic subtotal colectomy or lifetime colonoscopy screening.