extracolonic cancer in hereditary nonpolyposis colorectal cancer

9
677 Extracolonic Cancer in Hereditary Nonpolyposis Colorectal Cancer Patrice Watson, Ph.D., and Henry T. Lynch, M.D. Background. It has been hypothesized that in some but not all families with hereditary nonpolyposis colorec- tal cancer (HNPCC) there is a high risk of certain cancers other than colon cancer. The authors compared the observed fre- quency of cancer at specific sites in more than 1300 high- risk members of 23 kindreds with HNPCC with expecta- tions based on general population incidence and evalu- ated the hypothesis that there was heterogeneity in cancer frequency among families. Results. The authors observed significantly in- creased numbers of cancers of the stomach, small intes- tine, upper urologic tract (renal pelvis and ureter), and ovary. No excess was seen in other cancer types that have been associated previously with HNPCC, including cancer of the breast, pancreas, and urinary bladder. Sig- nificant heterogeneity among families was observed in the frequencies of endometrial, ovarian, and upper uro- logic system cancer. Conclusion. In addition to early onset cancers of the colorectum, HNPCC family members are at increased risk for cancers of other gastrointestinal tract organs, and, especially in some families, cancers of the upper uro- logic and female genital tract. Cancer 1993;71:677-85. Key words: hereditary nonpolyposis colorectal cancer, Lynch syndrome, cancer genetics, tumor spectrum. Many researchers and physicians studying families with hereditary nonpolyposis colorectal cancer (HNPCC) have observed high frequencies of certain extracolonic malignant neoplasms. Endometrial cancer is reported to occur most frequently, and to cosegregate with colon cancer in families,'P2 but a wide variety of other cancers, mostly adenocarcinomas, have been re- Methods. From the Department of Preventive Medicine/Public Health, Creighton University School of Medicine, Omaha, Nebraska. Supported by the National Cancer Institute, grant #5 R01 CA41371. Diane Stanley, Thomas Egelston, and Rodney Hoden provided technical assistance; this research would not have been possible with- out the cooperation of family members of patients and their physi- cians and the efforts of the numerous colleagues who have studied them during the last 25 years. Address for reprints: Patrice Watson, Ph.D., Department of Pre- ventive Medicine, Creighton University School of Medicine, Califor- nia at 24th Street, Omaha, NE 67178. Accepted for publication July 20, 1992. ported to occur at high frequencies in specific families. Families also have been reported who are affected al- most exclusively by colon ~ a n c e r . ~ Two hypotheses have been put forward: that HNPCC is a disorder in- volving an increased risk for development of extraco- lonic cancers in addition to an increased risk for colorec- tal cancer; and that there is heterogeneity among fami- lies with HNPCC in the risk for development of cancer at specific extracolonic sites. We now report the find- ings of the first study, to our knowledge, to systemati- cally evaluate these hypotheses. Methods We studied the frequency of specific types of cancer in members of families with HNPCC from the Creighton University/Hereditary Cancer Institute colon cancer family resource. All families in the resource had been found because of excess cases of colon cancer among family members. They had been studied by our stan- dard methods, which have been described previously4 and which include contacts with many family members and a vigorous effort to verify reported cancer diag- noses through retrieval of primary medical and pathol- ogy documents. This study was approved by the Insti- tutional Review Board at Creighton University. All families included at least one cluster of first-de- gree relatives of which three were affected by colon or endometrial cancer, at least two with colon cancer at 50 years of age or younger. Familial adenomatous polypo- sis was ruled out with traditional criteria. All families with HNPCC in the resource were included as long as the process of cancer verification and data computeri- zation was completed at the time of the study. Twenty- three unrelated families met these criteria. The members of these families were classified as follows into high-risk and low-risk categories: (1) the pedigrees were reviewed, and the common ancestors of the family members affected with early-onset and/or multiple primary colon cancers were identified; (2) all people not descendant from these ancestors were clas- sified as low risk; (3) of those remaining, all reported to have colorectal cancer or endometrial cancer, or with progeny with these cancers, and all first-degree rela-

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677

Extracolonic Cancer in Hereditary Nonpolyposis Colorectal Cancer Patrice Watson, Ph.D., and Henry T. Lynch, M.D.

Background. It has been hypothesized that in some but not all families with hereditary nonpolyposis colorec- tal cancer (HNPCC) there is a high risk of certain cancers other than colon cancer.

The authors compared the observed fre- quency of cancer at specific sites in more than 1300 high- risk members of 23 kindreds with HNPCC with expecta- tions based on general population incidence and evalu- ated the hypothesis that there was heterogeneity in cancer frequency among families.

Results. The authors observed significantly in- creased numbers of cancers of the stomach, small intes- tine, upper urologic tract (renal pelvis and ureter), and ovary. No excess was seen in other cancer types that have been associated previously with HNPCC, including cancer of the breast, pancreas, and urinary bladder. Sig- nificant heterogeneity among families was observed in the frequencies of endometrial, ovarian, and upper uro- logic system cancer.

Conclusion. In addition to early onset cancers of the colorectum, HNPCC family members are at increased risk for cancers of other gastrointestinal tract organs, and, especially in some families, cancers of the upper uro- logic and female genital tract. Cancer 1993; 71:677-85.

Key words: hereditary nonpolyposis colorectal cancer, Lynch syndrome, cancer genetics, tumor spectrum.

Many researchers and physicians studying families with hereditary nonpolyposis colorectal cancer (HNPCC) have observed high frequencies of certain extracolonic malignant neoplasms. Endometrial cancer is reported to occur most frequently, and to cosegregate with colon cancer in families,'P2 but a wide variety of other cancers, mostly adenocarcinomas, have been re-

Methods.

From the Department of Preventive Medicine/Public Health, Creighton University School of Medicine, Omaha, Nebraska.

Supported by the National Cancer Institute, grant #5 R 0 1 CA41371.

Diane Stanley, Thomas Egelston, and Rodney Hoden provided technical assistance; this research would not have been possible with- out the cooperation of family members of patients and their physi- cians and the efforts of the numerous colleagues who have studied them during the last 25 years.

Address for reprints: Patrice Watson, Ph.D., Department of Pre- ventive Medicine, Creighton University School of Medicine, Califor- nia at 24th Street, Omaha, NE 67178.

Accepted for publication July 20, 1992.

ported to occur at high frequencies in specific families. Families also have been reported who are affected al- most exclusively by colon ~ a n c e r . ~ Two hypotheses have been put forward: that HNPCC is a disorder in- volving an increased risk for development of extraco- lonic cancers in addition to an increased risk for colorec- tal cancer; and that there is heterogeneity among fami- lies with HNPCC in the risk for development of cancer at specific extracolonic sites. We now report the find- ings of the first study, to our knowledge, to systemati- cally evaluate these hypotheses.

Methods

We studied the frequency of specific types of cancer in members of families with HNPCC from the Creighton University/Hereditary Cancer Institute colon cancer family resource. All families in the resource had been found because of excess cases of colon cancer among family members. They had been studied by our stan- dard methods, which have been described previously4 and which include contacts with many family members and a vigorous effort to verify reported cancer diag- noses through retrieval of primary medical and pathol- ogy documents. This study was approved by the Insti- tutional Review Board at Creighton University.

All families included at least one cluster of first-de- gree relatives of which three were affected by colon or endometrial cancer, at least two with colon cancer at 50 years of age or younger. Familial adenomatous polypo- sis was ruled out with traditional criteria. All families with HNPCC in the resource were included as long as the process of cancer verification and data computeri- zation was completed at the time of the study. Twenty- three unrelated families met these criteria.

The members of these families were classified as follows into high-risk and low-risk categories: (1) the pedigrees were reviewed, and the common ancestors of the family members affected with early-onset and/or multiple primary colon cancers were identified; (2) all people not descendant from these ancestors were clas- sified as low risk; (3) of those remaining, all reported to have colorectal cancer or endometrial cancer, or with progeny with these cancers, and all first-degree rela-

678 CANCER February 1, 1993, Volume 71, No. 3

tives of these patients were classified as high risk; and (4) all remaining family members were classified as low risk. Family members were excluded from study only if critical data (sex, year of birth, and year of death if dead) were missing or if they were born before 1880.

Our first aim was to compare the observed num- bers of cancer diagnoses in each risk group with the expected numbers, based on general population inci- dence data and the person-years at risk. Two methods were used to calculate the expected numbers of cancer cases among family members, and the result closest to the observed number was used in statistical testing to provide the most conservative test. In the first method, computation of expected numbers of cancer cases was done with the USDR program, version 58a,5 with age- specific, sex-specific, and year-specific incidence rates from the Connecticut Cancer Registry, which allowed adjustment of expected numbers for the secular trends in cancer rates. In the second method, age-specific and sex-specific average annual incidence rates for malig- nant neoplasms for specific primary sites were obtained from Surveillance, Epidemiology, and End Results pro- gram tables‘ and used to calculate cancer risk up to the end of each 5-year age interval, with the use of the density method for calculating risk.’ These risks were multiplied by the number of people in each age and sex category and summed across categories to compute the expected number of cases of cancer. This method al- lowed calculation of expected numbers of specific types of cancer not tabulated separately in the Connecticut Cancer Registry tables.

When the observed numbers of cancer cases were counted, only diagnoses documented specifically in a pathology report, medical record, or death certificate were included. We excluded all cancers of the types used in the risk coding (colorectal and endometrial cancers), cancers with an unknown primary site, skin cancers other than melanoma, and benign or in situ lesions.

Statistical tests of the hypothesis that the observed number of cancers differed from the expected number were performed with an accurate approximation of an exact Poisson test, attributed to Byar and described by Breslow and Day.8 Ratios of actual to expected numbers of cancer cases also were calculated as an approxima- tion of the relative risk.

Use of the Poisson test requires the assumption of homogeneous risk among members of the studied group. Heterogeneity of risk for extracolonic cancer has been hypothesized (see beginning of this article). There- fore, each excess of a specific type of cancer observed in the Poisson test was reevaluated with a second analytic method that did not rest on an assumption of homoge- neity of risk. This method, developed by Chakraborty

et al.,9 assesses evidence of excess risk in each family, comparing the cancer affection status of each member with that expected in a randomly selected person. We based the risk for each person on the Surveillance, Epi- demiology, and End Results incidence data (as de- scribed above). A test statistic was computed for each family, as was the empiric distribution of the test statis- tic for that family. Whenever the percentile rank of the test statistic in the empiric distribution was greater than 95%, the family was judged to have a significant excess of cancer of that type. Then, the significance of the ex- cess for the collection of 23 families was evaluated with the binomial distribution. For example, because the probability was 0.05 that a family would have a signifi- cant excess under the null hypothesis, the probability was 0.025 that 4 or more families of 23 would be found to have a significant excess.

Our second aim was to evaluate whether the distri- bution of extracolonic cancer among families was con- sistent with the null hypothesis that risk for these cancers was homogeneous among families. We used an approach similar to that used in previous studies of cancer aggregations in families.”-’* The statistical evalu- ation involved the calculation of an index of cancer fre- quency (relative to the pooled collection of families) for each family, which was adjusted for the age, sex, and year of birth of family members; calculation of an index of the variability of these indices across families; and evaluation of whether the variability was larger than expected, given equal risk across families, with a per- mutation test.13 The statistical methods are described more fully below. The null hypothesis of homogeneity was evaluated for the general category of any extraco- Ionic cancer and for specific cancer types or sites found to be increased significantly in comparison with general population rates (Aim 1 mentioned above). The test was performed twice-once with documented cancers only and once with all reported cancers (to allow evaluation of the possibility that variation among families might result from documentation differences). Unless other- wise stated, only the results obtained with documented cancer cases are reported here, and a consistent result was observed in the analyses that included both docu- mented and undocumented cancer cases.

All eligible high-risk members of the families were pooled and divided into 16 strata, based on year of birth (before versus after 1930), sex, and age at death/pres- ent age (younger than 45,45-54,55-64, and older than 64 years of age). For each high-risk member in each family, we calculated the cancer probability (p, the ratio of number of cancer cases to number of members in his or her stratum) and the variance (p[l-p]). These vari- ables were summed for each family to arrive at the ex- pected number of cancer cases in the family and the

Extracolonic Cancer in HNPCC/ Watson and Lynch 679

variance. Then, a z-score was calculated for each family by taking the ratio of the difference between the ob- served and expected numbers to the square root of the within-family variance. This z-score was an index of the frequency of cancer in the family relative to the pooled high-risk group, adjusted for the age, sex, and year of birth of the family members. Next, the between- family variance of the z-scores of the 23 families was calculated, and the probability of finding a variance of that size (or larger) was determined under the null hy- pothesis of homogeneity.

Because the sampling distributions of z-scores and their variance under these conditions are unknown, random permutations of the data were used to deter- mine the distribution of z-score variances empirically under the null hypothesis of homogeneity. Each per- mutation involved reconstructing each of the families at random from the pooled set of relatives (within restric- tions for sex, age, and year of birth), recalculating z- scores, and calculating the variance of z-scores among families. At least 99 permutations were used for each statistical test. Whenever the variance of the actual z- scores was larger than 95% of the variances found in the permutations, the hypothesis of homogeneity was rejected in favor of the alternative hypothesis that sig- nificant heterogeneity existed among families in the prevalence of extracolonic cancer.

Relationships among z-scores for the various cancer types were explored with correlation coefficients and graphic methods.

Results

The 23 families included 1424 persons who were classi- fied as high risk. Of these, 59 were dropped from all analyses because their sex, date of birth, and/or date of death was unknown, and 48 were dropped from all analyses because they were born before 1880. Thus, 131 7 high-risk family members were retained for analy- sis. Of these, 301 members were affected by colorectal or endometrial cancer. Among the 301 affected per- sons, 75% had at least one diagnosis of these carci- nomas verified by pathology or autopsy report, and an- other 16% had at least one such diagnosis documented by medical records or a death certificate.

Comparison W i t h the General Population

Members of the high-risk group had significantly more cancer diagnoses than expected at specific sites, includ- ing the stomach, small bowel, hepatobiliary system, kidney/ureter, and ovary. This result from the Poisson test was reevaluated with the method of Chakraborty et al.,9 and a significant excess of each cancer type was

confirmed ( P < 0.01 in all cases). No excess of cancer of the pancreas, lymphatic/hematopoietic system, larynx, breast, brain, or lung/bronchus was detected. In fact, significantly fewer lung/bronchus cancer cases oc- curred than were expected, even when unverified cases were included. Details, including the results of the Poisson test, are provided in Table 1.

Medical record review showed no evidence of screening examinations for cancer other than colon and endometrial cancer among family members that might have been prompted by family history. Review of the cases of cancer of the stomach, small bowel, hepatobili- ary system, kidney, ureter, and ovary showed no cases that were discovered through screening examinations.

All family members who were not the designated common ancestors or in the high-risk group were clas- sified as low risk, and this included 6089 eligible per- sons. No significantly excessive numbers of cancer diagnoses were observed in this group for any general organ system or any specific site.

Interfamily Heterogeneity in Cancer Prevalence

Significant heterogeneity was observed ( P < 0.01) in the frequencies of endometrial and upper urologic tract cancers. Significant but less noticeable heterogeneity also was observed ( P < 0.04) in verified ovarian cancer. Cancers of the stomach, hepatobiliary system, and small bowel were distributed homogeneously among families. In the categories that combine organs by sys- tems, significant heterogeneity ( P < 0.01) was observed in all cancers, all urologic cancers, and all female genital cancers. The category of all gastrointestinal system cancers (except colorectal) differed significantly from homogeneous ( P < 0.05) when only verified cancers were included but not when unverified gastrointestinal cancers were included ( P < 0.08).

Figure 1 shows the distribution of z-scores among the 23 families for two selected cancer types that are similar in overall frequency and dissimilar in extent of heterogeneity. The distribution of variances of z-scores among the simulated families created in the permuta- tion process also is shown. Z-scores of each family for selected cancer types are presented in Figure 2 (also see Table 2).

Because two of the families (Families 6 and 2764) have been identified as having a distinct colonic pheno- type,I4 analyses were rerun without these families. No substantial changes in results were observed. Analyses also were rerun with only the 12 families in whom there were at least 50 high-risk members. No substantial changes in results were observed except that the distri- bution of ovarian cancer did not differ significantly from homogeneity (P < 0.14).

680 CANCER February 1, 1993, Volume 71, No. 3

Table 1. Gastric, Small Intestine, Biliary System, Urologic System, and Ovarian Cancer in High-Risk Members of Families With Hereditary Nonpolyposis Colorectal Cancer

O/E ratio (Poisson test Median

Cancer site Observed Expected result) age (yr) Comments

Colorectum 287 46 Not analyzed Endometrium 53 46 Not analyzed Stomach 17 4.1 4.1 ( P < 0.001) 54 All adenocarcinoma Small intestine 10 0.4 25.0 ( P < 0.001) 53 9 adenocarcinomas, 1

Hepatobiliary system 7 1.4 4.9 ( P < 0.05) 66 4 adenocarcinomas, 3

Urinary bladder 5 4.6 1.1 (NS) 65 All transitional cell carcinoma Kidney 10 3.1 3.2 ( P < 0.01) 66 3 renal cell, 7 transitional cell

Ureter 5 0.2 22.0 (P < 0.001) 56 All transitional cell carcinoma Ovary 13 3.6 3.5 (P < 0.001) 40 All adenocarcinoma Lung/bronchus 5* 12.0 0.4 ( P < 0.05) 62 Pancreas 6 4.1 1.4 (NS) 52 All adenocarcinoma/

Breast 19 22.0 0.9 (NS) 51 All adenocarcinoma Hematogenous system 5 7.9 0.6 (NS) Various types Skin 2 2.0 1.0 (NS) Malignant melanoma Larynx 1 2.2 0.4 (NS) Squamous cell carcinoma Brain tumors 3 1.9 1.6 (NS) Malignant astrocytoma or

O/E: observed/expected; NS: not significant. * Includes unverified cases.

carcinoid

unspecified

carcinomas

carcinoma

unspecified

Significant but modest correlations were observed between the z-scores for small bowel and pancreatic cancer (r = 0.52, P < 0.05) and ovarian and upper uro- logic system cancer (r = 0.49, P < 0.05). Many other correlation coefficients between pairs of z-scores were positive and nearly significant ( P < 0.10). Because of the peculiar distributions of some of the z-scores, corre- lation coefficients computed from ranks were evaluated as well. This produced a slightly different set of signifi- cantly and nearly significantly positive correlations. Re- gardless of the correlational method, there were no strong positive correlations between pairs of z-scores and no negative correlations. Figure 2 (also see Table 2) shows the z-scores of each of the 23 families for five selected cancer types to enable the viewer to judge the extent of association between the indices of endome- trial and other cancer types.

Discussion

A wide variety of cancers were reported in the original family study of the “Cancer Family Syndrome,” now known as HNPCC.z4 There was a predominance of car- cinoma of the colon and endometrium, which appeared to segregate in an autosomal dominant mode of genetic transmission. It now is accepted widely that carcinomas

of the colon and endometrium are most characteristic of the disorder. Knowledge of the natural history of the colonic cancer has been refined, with evidence of proxi- mal colon predominance, early age of cancer diagnosis, and high frequency of multiple primary cancers.z5

Other tumors have been observed to occur at high frequencies in single or selected families with HNPCC, including cancers of the ovary, brain, bile duct, small bowel, urologic system, and breast^'^,^^,^^; larynxz3; stomach26; pancreas27; and lymphatic/hematopoietic s y ~ t e m . ~ ~ , ~ ~ Vasen et a1.’ reported on cancer occurrences in 24 kindreds with HNPCC and concluded that stom- ach, urinary tract, and endometrial cancers were part of the hereditary tumor spectrum. However, uncertainty remained about the extent to which the results could be explained by normal cancer incidence rates.

Our results provide good evidence that increased risks of carcinoma of the small bowel and stomach are associated with HNPCC. Family members at high risk for carrying the putative HNPCC gene had 25 times and 4 times the expected number of diagnoses of these tumors, respectively. These cancers occurred at early ages, relative to stomach and small bowel cancers in the general population, in whom the median age at diagno- sis is 65-70 years.6 The significance in this shift in age at diagnosis, which also was observed for cancer at other

Extracolonic Cancer in HNPCC/ Watson and Lynch

15

681

-

Frequency I

A

-1.5 -0.5 0.5 1.5 2.5 3.5 4.5

2-Score

Freauencv

-1.5 -0.5 0.5 1.6 2.5 3.5 4.5

2-Score

Percent

I Actual Variance B

10 -

5 -

n I " 0.1 0.6 1.1 1.6 2.1 2.6 3.1

Variance

Percent

D

Actual Variance

10 1 -

5 -

I 8 I I I " 3.1 0.6 1.1 1.6 2.1 2.6 3.1

Variance Figure 1. Results of heterogeneity test. (A) Distribution of actual z-scores for stomach cancer (variance = 0.89). (B) Distribution of z-score variances obtained in 1000 permutations of the stomach cancer data. The variance of the actual z-scores (0.89, indicated by arrow) occurs at the 51st percentile of this distribution. (C) Distribution of actual z-scores for kidney and ureteral cancer (variance = 2.30). (D) Distribution of z-score variances obtained in 1000 permutations of ureteral and kidney cancer data. The variance of the actual z-scores (2.30, indicated by arrow) occurs at the 99th percentile of this distribution

sites, is unclear because HNPCC gene carriers may have a shorter lifespan and, thus, fewer years at risk in the highest age brackets. With respect to hepatobiliary system cancer, we did observe a significant excess of cancer cases, but for several of the cases the exact site and histologic findings were unknown. Mecklin et aL3' studied clinical data and/or histologic materials from 18 family members with HNPCC with biliopancreatic carcinoma. They found that most were primary cancers of the biliary tract or ampulla of Vater, rather than the pancreas or gallbladder. Familial adenomatous polypo- sis, another hereditary colon cancer syndrome, also shows an excess risk of cancers in these organs, al- though periampullary/duodenal cancers appear to be far more common than cancers of the stomach and the remainder of the small bowel in familial adenomatous p o l y p ~ s i s . ~ ~ Among the nine small bowel adenocarci-

nomas observed in this study, only two were reported to be duodenal. Our heterogeneity analyses indicated that risk for both stomach and small bowel cancer was uniform across the families studied.

In the urologic system, we found that high-risk rela- tives had 3 times as many kidney cancers and 22 times as many ureteral cancers as expected, with no evidence for an elevated risk of urinary bladder cancer. There was no excess of renal cell cancer: because more than 90% of kidney cancers in the general population are renal cell cancer^,^' the expected number of renal cell cancers in the high-risk group is at least 2.8, and 3 were observed. By the same logic, the expected number of carcinomas of the renal pelvis is no more than 0.4, and 7 were observed, indicating that the high-risk group actu- ally had 17 times the expected number of cancers of this site. The median age at diagnosis of the renal pelvis and

682

F A M I L Y

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S C 0 R E S

CANCER F e b r u n q 2, 2993, Volume 71, No. 3

Figure 2 Family history z-scores for five cancer types in 23 families with HNPCC 2-scores are plotted on

with horizontal lines at -2, 0, and +2 Scores at approximately 0 indicate that the relative frequency

ENDOMETRIUM (variance=2.78,p~0.05) 1 identical scales for each cancer type,

I' ' ' * I 1 1

qVARY (karipnce=1.63,pc0.05) 1 of the specihc cancer type in the I

I family was approximately the same i--+ I L L -

as in the pooled high-risk group, whereas scores at approximately -2 indicate that signihcantly fewer cancers of the specihc type occurred in the family and scores at approxtmately + 2 indicated significantly more cancers of the specific type occurred in the family P values indicate the result of the heterogeneity test of the z-score distribution Families are ordered

- from lowest to highest endometrial cancer z-score to enable the reader to evaluate the relationship between the relative frequency of endornetrial

A B C D E F G H I J K L M N 0 P Q R S T U V W cancer(higheston theright)andthe

1

1

FAM I L I ES

ureteral cancers was 56, 10 years earlier than is typical in the general population.6 Heterogeneity analyses in- dicated that these cancers were aggregated in a subset of families, and, in fact, all 15 kidney and ureteral cancers occurred in eight families. Transitional cell carci- noma was the histologic type observed both in the renal pelvis and ureter. This tumor is a frequent component of the Muir-Torre syndrome,33 which has been asso- ciated with HNPCC. One of the families included in this study (Family 621) included members with the cuta- neous features of the Muir-Torre syndrome.34 Several cases of familial transitional cell carcinoma have been reported,35 and in at least some cases a high incidence of other tumors in family members is indicated.

As indicated in Table 1, endometrial cancer is much more common in these families than any other extraco- Ionic cancer. The median age at diagnosis was 46 years (versus nearly 60 years in the general population).6 Our use of endometrial cancer in identifying high-risk fam- ily members precludes our making an unbiased esti- mate of the relative risk of cancer at this site. Risk for another gynecologic cancer, ovarian cancer, was found to be increased in families with HNPCC; approximately four times the expected number of these diagnoses oc- curred in high-risk family members. The median age at diagnosis was 20 years earlier than the median age at diagnosis in the general population.6 We saw no evi- dence of an increase in rates of uterine cervical cancer. In the heterogeneity analysis, both ovarian and endo-

relative frequency of other cancer types.

metrial cancers were shown to be aggregated in certain families. However, endometrial cancer was probably the most important of the extracolonic cancers in in- fluencing family ascertainment. This, in addition to its use in identifying high-risk family members, means that extra caution must be used in interpreting the het- erogeneity test results for this cancer.

Bronchogenic carcinoma, common in the general population, occurred very rarely among the high-risk family members. In the high-risk group, none of the five persons reported to have lung cancer were putative gene carriers (i.e., affected with colon or endometrial cancer or having offspring with these cancers). A recent report of cancer in relatives of patients with colon cancer36 showed that lung cancer occurred only 60% as often in relatives of patients compared with control subjects. Mecklin et al.' reported lung cancer in only 4 of 196 cancer-affected family members of 40 families with HNPCC. We have no evidence that members of the families we studied avoid exposure to carcinogens. In a recent survey of five families with HNPCC in this study, 58% of 497 family members older than 19 years of age who responded indicated that they were current or former cigarette smokers.

Cancers of the breast, brain, larynx, pancreas, and lymphatic/hematopoietic system were observed to oc- cur approximately as frequently as expected in these families. It is possible that specific families would have an excess of cancer at one of these sites, which would be

Extracolonic Cancer in HNPCC/Watson and Lynch

Table 2. Families Included in Analysis.

ID Kindred no. No. of males No. of females Reference

A 4 59 54 15 B 2516 107 89 4 C 6 29 23 16 D 1712 24 25 17 E 28 31 25 F 7 42 47 18 G 2764 12 18 14 H 2822 8 7 I 1797 13 11 1 1933 24 28 K 9 26 28 19 L 2059 13 11 M 62 1 35 42 20 N 12 15 20 17 0 2786 38 20 17 P 2068 4 9 20 Q 2049 39 37 21 R 3 10 14 15 S 2107 17 20 22 T 8 48 35 23 U 10 48 58 20 V 2070 22 20 20 w 1 4 8 N o f c Families are listed in order from lowest to highest endometrial cancer family history Z-score, as in Figure 2 Numbers of high-risk male and female memher5 in each family are listed, as well as the references to published reports from Lynch et al that have included a pedigree of the family

-

- -

-

-

-

undetectable in the pooled analysis. However, no be- tween-family variation was detected for these cancers in the heterogeneity tests.

To our knowledge, only one other study has been reported in which rates of cancer in high-risk members of families with HNPCC have been compared with the rates in the general population. Itoh et al.37 evaluated the relative risk of death of several types of cancer in female members of 130 pedigrees classified as having HNPCC-Lynch syndrome I1 and identified through a clinic serving patients concerned about their family his- tory of cancer. They found a significant increase in mel- anoma and ovarian, breast, stomach, pancreatic, uter- ine, and colorectal cancer risk in female relatives and colon and stomach cancer risk in male relatives. We also observed a slight (nonsignificant) increase in pancreatic cancer frequency in our analysis; we did not observe any increase in the frequency of breast cancer or mela- noma (Table 1). However, their definition of HNPCC- Lynch syndrome I1 differed from ours, involving a vari- ety of cancer types and not requiring a predominance, or even a single case, of colorectal cancer. Thus, their study appears to have included pedigrees that we would have classified as belonging to some other syn- drome, such as the hereditary breast and ovarian cancer

syndrome, and this discrepancy in methods makes our results incomparable.

Lynch Syndromes I and II

In the literature on HNPCC, a distinction has been made between two variants, Lynch syndrome I and 11, based on the presence or absence of extracolonic cancers, especially endometrial cancer^.^ If the hypoth- esis is correct that there are two variants of HNPCC, one colon specific and one involving cancer at various organs, we should expect to find significant heterogene- ity among families in the tendency for cancer to develop at specific extracolonic sites and some association be- tween the tendency for endometrial cancer to develop and the tendency for cancer to develop at other specific sites where heterogeneity was observed.

The results of the heterogeneity tests indicated that risk for specific extracolonic cancers does vary across families with HNPCC, and the generally positive corre- lations among z-scores are consistent with the view that there is heterogeneity among families in some sort of general tendency for cancer to develop at extracolonic sites. However, the weakness of the correlations among z-scores and the actual distribution of z-scores as seen in Figure 2 argue against the view that there are two variants, in which, in one, only colorectal cancer risk is affected, and, in the other, risk for colorectal cancer, endometrial cancer, and cancer at several other sites is increased. Stomach and small bowel cancer appeared to be distributed homogeneously among these 23 families (8 of which had no endometrial cancer). Urologic and ovarian cancers were found to be aggregated in certain families, but not necessarily those with endometrial cancers; there was no evidence for a strong association between the prevalence of endometrial cancer in the family history and the prevalence of ovarian or urologic cancers. The distribution shown in Figure 2 may indi- cate that this collection of 23 families includes several variants, all of which affect the risk for colorectal, stom- ach, and small bowel cancer, but with heterogeneity of effect on other organs.

Our data on relationships among z-scores must be interpreted with caution because ovarian and urologic cancers are rare events, even in these families, and so a single diagnosis produces a large difference in the z- score. This is particularly so in small families. Further- more, we must acknowledge the uncertainty involved in discerning relationships between variables when only 23 cases (families) are included in the sample. Nev- ertheless, we believe that the collection of families stud- ied is the largest available in terms of number of high- risk members, number of families, and extent of docu- mentation of cancer diagnoses. We believe that it

684 CANCER February 1, 1993, Volume 71, No. 3

provides the best current evidence on the distribution of extracolonic cancer in families with HNPCC.

Variations in cancer prevalence among families with HNPCC do not necessarily result from genetic het- erogeneity. Familial patterns of environmental expo- sures (e.g., dietary and reproductive practices) may con- tribute to differences in the expression of the HNPCC gene among families. It is also possible that referral pat- terns and ascertainment bias could produce a collection of families with significant heterogeneity even if the true HNPCC population was homogeneous with re- spect to risk for extracolonic cancer. Additional study will be necessary to determine the cause of the heteroge- neity we have observed, especially studies of collections ascertained in different ways and studies of the under- lying genetic mechanism of the cancer susceptibility.

Our failure to support the Lynch I/Lynch I1 hy- pothesis (at least in its simplest form) has unfortunate clinical implications in that it appears unlikely that sim- ple rules can be applied in judging the risk for extraco- Ionic cancers in specific families. The existence of het- erogeneity among families implies that family members with HNPCC with a positive family history of a particu- lar extracolonic cancer (such as endometrial, ovarian, or upper urologic system cancers) may be regarded as be- ing at higher risk for a cancer of that type than family members with HNPCC lacking such a family history. However, the low correlations among family history z-scores implies that a family history of one type of cancer should have little impact on our assessment of the risk for cancer of another type.

Flat Adenoma Syndrome

Two families who were classified as having HNPCC at the beginning of this study since have been found to have a peculiar colonic phenotype and now are classi- fied as having hereditary flat adenoma syndrome. These two families (Families 6 and 2764) were similar in having generally negative z-scores for all cancer types. Genetic linkage to markers on chromosome 5q in fami- lies with hereditary flat adenoma syndrome, not seen in families with ordinary HNPCC, supports the view that these are distinct disorder^.'^ When we omitted these two families, significant heterogeneity still remained for all cancer types previously found to be heterogeneous. However, we cannot rule out the possibility that the features of hereditary flat adenoma syndrome would be discovered in other families if results of colonoscopic examinations or more detailed pathology reports of co- lonic surgery were available. If more detailed descrip- tions of the colonic phenotype in the various families were available, and if, on this basis, additional families with hereditary flat adenoma syndrome were identified and found to resemble the previously identified two, a

substantial proportion of the heterogeneity in the col- lection of families might be attributable to this phenom- enon.

The limitations of this study should be mentioned. The method we used depends on the assumption that the included families are classified correctly as having HNPCC, that as a set they are representative of HNPCC and that the model of HNPCC as an autoso- ma1 dominant trait is correct. We believe that these as- sumptions are justified (however, see Discussion above). Similar studies of other collections of families with HNPCC, including collections ascertained through different procedures, will be required before the generality of our findings can be evaluated and ex- tended. The specific results we have obtained also de- pend on the correct classification of family members into risk groups. There is no currently available fail-safe rule for doing so, and any errors would result in dilution of genetic effects on risks for extracolonic cancer.

Expected numbers of cancers were calculated from incidence rates based on one national (Surveillance, Epi- demiology, and End Results) and one state (Connecti- cut) tumor registry. Members of the 23 families are dis- persed widely throughout the United States, which provides a rationale for using the Surveillance, Epidemi- ology, and End Results data; however, national inci- dence statistics are unavailable for the early part of the century, during which many of these family members lived and died. For cancers that have changed dramati- cally in incidence over this century, such as stomach and lung cancer, expected numbers based on the two different registries varied substantially. However, in no case did the two expected numbers point to a different conclusion: whenever an expected number of a specific type of cancer was calculable from both registries, ei- ther the observed number differed significantly from both or from neither. Because we relied on the expected number that was closest to the observed number, the P values may be overestimated and the observed/ex- pected ratios may be underestimated.

In summary, we have found that putative HNPCC gene carriers and their high-risk relatives have had cancers other than endometrial and colorectal cancer diagnosed more frequently than expected based on gen- eral population incidence figures. Specific sites where elevations were seen included the stomach, small intes- tine, renal pelvis and ureter, and ovary. Study of the distribution of cancers at these sites among the families indicated that there was significant variation in the fre- quency of endometrial, ovarian, and urologic system cancer among families; that stomach and small bowel cancer were distributed homogeneously among fami- lies; and that there was only a weak association be- tween the frequency of cancer at the various sites.

Extracolonic Cancer in HNPCC/ Watson and Lynch 685

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